Search

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. This study aimed to investigate the therapeutic effects and mechanism of Jujuboside A on PCOS using a dehydroepiandrosterone (DHEA)-induced PCOS mouse model. Estrogen and androgen homeostasis was evaluated in serum from both clinical samples and PCOS mice. The stages of the estrous cycle were determined based on vaginal cytology. The ovarian morphology was observed by stained with hematoxylin and eosin. Moreover, we analyzed protein expression of cytochrome P450 1A1 (CYP1A1), cytochrome P450 1A2 (CYP1A2) and aryl hydrocarbon receptor (AhR) in ovary and KGN cells. Molecular docking, immunofluorescence, and luciferase assay were performed to confirm the activation of AhR by Jujuboside A. Jujuboside A effectively alleviated the disturbance of estrogen homeostasis and restored ovarian function, leading to an improvement in the occurrence and progression of PCOS. Furthermore, the protective effect of JuA against PCOS was dependent on increased CYP1A2 levels regulated by AhR. Our findings suggest that Jujuboside A improves estrogen disorders and may be a potential therapeutic agent for the treatment of PCOS. [ABSTRACT FROM AUTHOR]

The incidence of breast cancer is increasing year by year, and its pathogenesis is highly complex. The dysregulation of gut microbiota function is closely related to the occurrence and development of breast cancer. The estrogen levels through enterohepatic circulation is regulated by β -glucuronidase produced by the gut microbiota, thereby influencing the occurrence and development of hormone receptor-positive breast cancer and leading to tamoxifen resistance. The metabolites from the gut microbiota, such as short-chain fatty acids (SCFAs) and lithocholic acid (LCA), can participate in regulating the tumor cell cycles and cell proliferation. The colonization of gut microbiota maintains the integrity of the intestinal barrier and regulates the anti-tumor immunity mediated by T lymphocytes. Maintaining gut microbiota homeostasis can enhance the efficacy of tumor chemotherapy and immunotherapy and reduce the adverse reactions in anti-tumor treatments. The targeted action of engineered probiotics in immunotherapy can improve the precision of drug treatment. The effect of gut microbiota on radiotherapy is not yet clear, but regulating gut microbiota can aid in the treatment of radiation enteritis. This review discusses the correlation and effect of gut microbiota on breast cancer and analyzes its role in the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

There is evidence suggesting that endocrine interventions such as hormone replacement therapy and hormonal contraception can increase breast cancer (BC) risk. Sexual steroid hormones like estrogens have long been known for their adverse effects on BC development and progression via binding to estrogen receptor (ER) α. Thus, in recent years, endocrine interventions that include estrogens have been discussed more and more critically, and their impact on different BC subgroups has increasingly gained interest. Carriers of pathogenic variants in BRCA1/2 genes are known to have a high risk of developing BC and ovarian cancer. However, there remain open questions to what extent endocrine interventions targeting ERα or the progesterone receptor further increase cancer risk in this subgroup. This review article aims to provide an overview and update on the effects of endocrine interventions on breast cancer risk in the general population in comparison to BRCA1/2 mutation carriers. Finally, future directions of research are addressed, to further improve the understanding of the effects of endocrine interventions on high-risk pathogenic variant carriers. [ABSTRACT FROM AUTHOR]

The high mortality rate due to chemoresistance in patients with high-grade ovarian cancer (HGSOC) emphasizes the urgent need to determine optimal treatment strategies for advanced and recurrent cases. Our study investigates the interplay between estrogens and chemoresistance in HGSOC and shows clear differences between platinum-sensitive and -resistant tumors. Through comprehensive transcriptome analyzes, we uncover differences in the expression of genes of estrogen biosynthesis, metabolism, transport and action underlying platinum resistance in different tissues of HGSOC subtypes and in six HGSOC cell lines. Furthermore, we identify genes involved in estrogen biosynthesis and metabolism as prognostic biomarkers for HGSOC. Additionally, our study elucidates different patterns of estrogen formation/metabolism and their effects on cell proliferation between six HGSOC cell lines with different platinum sensitivity. These results emphasize the dynamic interplay between estrogens and HGSOC chemoresistance. In particular, targeting the activity of steroid sulfatase (STS) proves to be a promising therapeutic approach with potential efficacy in limiting estrogen-driven cell proliferation. Our study reveals potential prognostic markers as well as identifies novel therapeutic targets that show promise for overcoming resistance and improving treatment outcomes in HGSOC.

Objective: Explore whether racial differences in prevalence of CYP1A2∗1F polymorphism underlies estrogen metabolism differences among Asians and Caucasians. Design: Prospective cohort study. Setting: University-based fertility practice. Patient(s): Asian or Caucasian patients who underwent ovarian stimulation (OS) or programmed cycle frozen embryo transfer (FET) between October 2019 and April 2021. Intervention(s): None. Main Outcome Measure(s): Trigger-day serum E2 per oocyte retrieved in OS cycles, and E2 on day of lining check in FET cycles. Result(s): Seventy-one participants were enrolled, 55 in OS group (29 Caucasian and 26 Asian) and 16 in FET group (10 Caucasian and 6 Asian). Peak E2 per oocyte retrieved in the OS group (n = 48) differed by race, with significantly lower levels in Caucasians compared with Asians (177.5 ± 64.2 vs. 261.1 ± 139.5 pg/mL). Prevalence of CYP1A2∗1F polymorphism did not significantly differ by race. Compared using Kruskal–Wallis test, peak E2 per oocyte retrieved did not differ by CYP1A2∗1F genotype. In multivariate linear regression model, adjusting for body mass index, caffeine intake, and self-reported race, there remained no significant correlation. In FET group, serum E2 on day of lining check was also not significantly different by CYP1A2∗1F genotype. Conclusion(s): Although a consistent difference in serum E2 between Asians and Caucasians undergoing OS was noted, the CYP1A2∗1F polymorphism is unlikely the primary driver of this difference.

There is evidence suggesting that endocrine interventions such as hormone replacement therapy and hormonal contraception can increase breast cancer (BC) risk. Sexual steroid hormones like estrogens have long been known for their adverse effects on BC development and progression via binding to estrogen receptor (ER) α. Thus, in recent years, endocrine interventions that include estrogens have been discussed more and more critically, and their impact on different BC subgroups has increasingly gained interest. Carriers of pathogenic variants in BRCA1/2 genes are known to have a high risk of developing BC and ovarian cancer. However, there remain open questions to what extent endocrine interventions targeting ERα or the progesterone receptor further increase cancer risk in this subgroup. This review article aims to provide an overview and update on the effects of endocrine interventions on breast cancer risk in the general population in comparison to BRCA1/2 mutation carriers. Finally, future directions of research are addressed, to further improve the understanding of the effects of endocrine interventions on high-risk pathogenic variant carriers.

This article is intended to deepen our knowledge to date regarding the functions of the resident microbiota/microbiome in the urinary system for human health and disease. First, we sought to report the general characteristics (composition and stability) of the normal urinary system microbiota in the different anatomical sites in relation to some factors such as the effect of age, gender and diet, analyzing in detail the functions and the composition of the microbiota in the light of current knowledge. Several pieces of evidence suggest the importance of preserving the micro-ecosystem of the urinary system, and in some cases their relationship with diseases is important for maintaining human health is well understood. The female and male reproductive microbiota have mainly been studied over the past decade. In the past, the arrest was thought to have taken place in a sterile environment. Microorganisms of the microbiota form biofilms, three-dimensional structures, that differ in the reproductive organs and interact with both gametes and the embryo as well as with maternal tissues. These biofilms from the reproductive system also interact with others, such as that of the gastrointestinal tract. Reduction in its diversity intestinal microbiota can disrupt estrogen metabolism and affect the reproductive microbiota. It is therefore understood that its quantitative and qualitative identification is important for microbiota, but also the study of the structures formed by the microorganisms. A dysbiosis with local or systemic causes can lead to serious diseases. The role of probiotics in maintaining microbial population harmony (eubiosis) and preventing certain pathologies of the urinary and reproductive system was also investigated. A negative variation in the qualitative and quantitative composition of certain strains of microorganisms (dysbiosis) due to local or systemic causes can even lead to serious diseases. The role of probiotics in maintaining the healthy balance of microorganism populations (eubiosis), and thus in the prevention of certain pathologies of the urinary and reproductive system, has also been studied. [ABSTRACT FROM AUTHOR]

Estrogens are in the list of carcinogenic chemicals from the World Health Organization (WHO). However, estrogens require additional factors such as stromal factors or progestogens to increase the ratio of proliferation/apoptosis for initiation of replication errors and consequent mutations to occur. These mutations require at least 5–10 years to develop into clinically detectable cancer, whereby this review is focused on breast cancer. The US National Cancer Institute highlighted a second mechanism of carcinogenicity: certain estrogen metabolites are capable of inducing DNA damage, even in low concentration. They can be assessed in the tissue and circulation. However, those deleterious reactions require excessive unrestricted oxidative cell stress, for example in industrial areas with heavy pollution. We have shown that this can be avoided using transdermal instead of oral estradiol treatment, especially important in smokers. The spectrum of metabolites is also influenced by other exogenous factors such as nutrition, physical activity and certain diseases. Reduction of breast cancer risk as demonstrated in the Women's Health Initiative (WHI) was explained by pro-apoptotic estrogen effects working after a certain 'time gap'. In addition, certain estrogen metabolites are carcinoprotective, if no genetic polymorphisms would impair their beneficial activities. Thus, since additional factors are required for both main pathways of carcinogenicity and because estrogens can even have carcinoprotective effects, we cannot agree with the statement from the WHO. [ABSTRACT FROM AUTHOR]

Abstract Background Several anthropometric measures have been associated with hormone-related cancers, and it has been shown that estrogen metabolism in postmenopausal women plays an important role in these relationships. However, little is known about circulating estrogen levels in African women, and the relevance to breast cancer or breast cancer risk factors. To shed further light on the relationship of anthropometric factors and estrogen levels in African women, we examined whether measured body mass index (BMI), waist-to-hip ratio (WHR), height, and self-reported body size were associated with serum estrogens/estrogen metabolites in a cross-sectional analysis among postmenopausal population-based controls of the Ghana Breast Health Study. Methods Fifteen estrogens/estrogen metabolites were quantified using liquid chromatography-tandem mass spectrometry in serum samples collected from postmenopausal female controls enrolled in the Ghana Breast Health Study, a population-based case–control study conducted in Accra and Kumasi. Geometric means (GMs) of estrogens/estrogen metabolites were estimated using linear regression, adjusting for potential confounders. Results Measured BMI (≥ 30 vs. 18.5–24.9 kg/m2) was positively associated with parent estrogens (multivariable adjusted GM for unconjugated estrone: 78.90 (66.57–93.53) vs. 50.89 (43.47–59.59), p-value

Background: In China, the association between estrogen metabolism and breast cancer risk and the differences in metabolic pattern between breast can cer patients and controls are poorly understood. Methods: A total of 84 patients with invasive breast cancer and 47 controls with benign breast diseases were included in this study. Estrogen metabolites from their morning urine were determined by HPLC-MS/MS and evaluated in both groups, and the predictive value of each estrogen metabolite in the malignant group according to their menstrual status was analyzed. Results: Urinary concentration of estrogen metabolites 2-hydroxyestrone (2-OHE1), 2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2), 4-methoxyestrone (4-MeOE1), and 16α-hydroxyestrone were lower in postmenopausal patients with breast cancer, compared with benign controls. In logistic regression model, breast cancer risk increased with the decline in the levels of 4-OHE2 and 4-MeOE1. In premenopausal patients, a difference in the level of 2-OHE2 was observed between both grou ps, and 2-OHE2 was found to have predictive value for breast cancer. Additionally, urinary 2-OHE2 level in premenopausal hormone receptor positive (HR+) patients was considerably higher compared with hormone receptor negative patients. Conclusions: We found that lower urinary levels of 4-OHE2 and 4-MeOE1 had predictive value for breast cancer, and higher 2-OHE1 were associated with HR+ breast cancer in premenopausal women.

In recent years, many studies have shown that the gut microbiota can affect the occurrence and development of a variety of human diseases. A variety of skin diseases are related to the regulation of the gut-skin axis, such as psoriasis, atopic dermatitis, and acne. Gut microbial dysbiosis can promote the development of these diseases. The gut microbiota can affect estrogen metabolism, ß-glucuronidase secreted by the gut microbiota can promote the reabsorption of estrogen by the gut, and estrogen is transported to other parts of the body through the circulatory system. The occurrence and development of melasma are closely related to abnormal metabolism of estrogen. The relationship between the structure of the gut microbiota and melasma remains unclear. Epidemiological surveys were conducted in patients with melasma and healthy subjects (control group) in this study. The feces were collected for 16S rRNA sequencing analysis of the gut microbiota. To compare the similarities and differences in species diversity of the gut microbiota between these two groups, we calculated the a-diversity and ß-diversity indices and analyzed the differences between them. We found that the abundance of Collinsella spp., Actinomyces spp. (belonging to Actinobacteria), Parabacteroides spp., Bacteroides spp., Paraprevotella spp. (belonging to Bacteroidetes), Blautia spp., and Roseburia spp. (belonging to Firmicutes) in the melasma group were significantly different compared with that in the healthy group. The largest difference was found in Actinobacteria (p < 0.05), and there were also significant differences in the abundance of Coriobacteriia, Actinobacteria, Coriobacteriales, Coriobacteriaceae, and Collinsella spp. between the two groups (all p < 0.05). Many of these differences in the microbiota were closely related to the production of ß-glucuronidase and the regulation of estrogen synthesis or metabolism. Changes in the gut microbiota structure and the biological effects of Collinsella spp. in the microbiota in patients with melasma can play an important role in the occurrence and development of melasma by affecting the body's estrogen metabolism. This study provides a theoretical basis and experimental data reference for future studies on the relationship between the gut microbiota and melasma, and may be helpful for the prevention and treatment of melasma. [ABSTRACT FROM AUTHOR]

Current heightened recognition of the importance of sulfated steroids led to the examination of conjugates in media from incubations of estrogens in tissues from the reproductive tract of stallions. Previously, we had reported a 'new' unidentified metabolite of estrone (E1) and [³H]-E1, located between 17β-estradiol (E2) and E1 reference standards on chromatography (HPLC) and identified tentatively as a stable 5α,6α-estrone epoxide. Stallion tissues were minced and incubated for 2 h with [³H]-E1 (1 × 106 cpm). Solid-phase extraction of unconjugated and conjugated steroids from media was followed by liquid scintillation counting (LSC), where radioactivity was mostly in the conjugate fractions (>80%). HPLC of conjugated steroids used an isocratic solvent system of acetonitrile/water (8:92) at 700 µL/min with detection by LSC. A radioactive peak between reference standards of E1 and E2 sulfates was examined, after solvolysis, in a second solvent system. Sulfated steroids yielded largely E1, whereas acid treatment of the unconjugated E1 epoxide had earlier formed 6α-OH-E1 almost exclusively. With sulfatase enzyme, at neutral pH, radioactivity was also seen mostly as E1 with trace amounts of polar material. Reduction with KBH4, however, led also to desulfation; radioactivity had alignment with E2 but even more had low retention times as for 6α/6β-OH-E2. These findings point to a different hydrolysis for desulfation; even more, they reveal an additional oxygen atom at C6 and are supportive of biological formation of 5α,6α-epoxides of E1 and E2. As possible alternatives to catechol estrogens, implicated in cancer, the 'new' estrogen metabolites and their sulfated forms may have special interest. [ABSTRACT FROM AUTHOR]

Osteoporosis is a significant concern in bone health, and understanding its pathomechanism is crucial for developing effective prevention and treatment strategies. This article delves into the relationship between estrogen metabolism and bone mineralization, shedding light on how phytoestrogens can influence this intricate process. Estrogen, a hormone primarily associated with reproductive health, plays a pivotal role in maintaining bone density and structure. The article explores the positive effects of estrogen on bone mineralization, highlighting its importance in preventing conditions like osteoporosis. Phytoestrogens, naturally occurring compounds found in certain plant-based foods, are the focal point of the discussion. These compounds have the remarkable ability to mimic estrogen's actions in the body. The article investigates how phytoestrogens can modulate the activity of estrogen, thereby impacting bone health. Furthermore, the article explores the direct effects of phytoestrogens on bone mineralization and structure. By regulating estrogen metabolism, phytoestrogens can contribute to enhanced bone density and reduced risk of osteoporosis. Finally, the article emphasizes the role of plant-based diets as a source of phytoestrogens. By incorporating foods rich in phytoestrogens into one's diet, individuals may potentially bolster their bone health, adding a valuable dimension to the ongoing discourse on osteoporosis prevention. In conclusion, this article offers a comprehensive overview of 137 positions of literature on the intricate interplay between phytoestrogens, estrogen metabolism, and bone health, shedding light on their potential significance in preventing osteoporosis and promoting overall well-being., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Estrogen hormone is one of the steroid hormones has a critical role in breast cancer etiology. It has been implicated in proliferation and differentiation of cells through its action promoting binding of its receptor to DNA, changing transcriptional expression of target genes. In addition to the classical DNA binding mechanism, estrogen can also regulate gene expression through a no genomic mechanism associated with activation a variety of signal transduction pathways (e.g. PI3`K/AKT, ERK/MAPK, PLC/PKCs, p38/MAPK). Dysregulation of the balance between pro-apoptotic and anti-apoptotic members of the Bcl-2 family, would result in apoptosis inhibition and tumor genesis (Chimento et al., 2022). Also, poor responses towards hormonal therapy, radiotherapy, and chemotherapy and treatment resistance are likely caused by dysregulation of apoptosis. Importantly, E2 has been shown to prevent apoptosis, first through its action in activation of anti-apoptotic proteins like Bcl-xl and Bcl-2 in breast cells like MCF-7, T47D and ZR-75-1 or due to its metabolites independently of ER. Estrogen metabolism includes several very important pathways that can possibly induce de novo DNA mutation. These pathways include:2, &4-hydroxylation, 16 α hydroxylation and 4 hydroxyestradiol-quinone-adenine/guanine adduct depurination, which subsequently participate in DNA damage that can lead to breast cancer. Endocrine resistance is considered one of the most permanent problems that can reduce the benefits of breast cancer treatment. Alteration of microRNAs expression, polymorphisms occurring in tamoxifen metabolism, and using redundant alternative signaling pathways, resulting in poor treatment responses of breast cancer patients and induction of endocrine resistance. Thus, most proposed therapeutic strategies will be based on a combination of drugs targeting various pathways alongside endocrine therapy that may improve the outcomes of endocrine responses in resistant breast cancer cells. [ABSTRACT FROM AUTHOR]

BackgroundGenistein is a dietary supplement with phyto-estrogenic properties. Therefore, high intake of genistein during pregnancy may have adverse effects on the genetic integrity of testes and germ cells of male offspring. In this study, we examined whether maternal exposure to genistein during pregnancy induced oxidative DNA damage in the male germline at adolescence.MethodsAtm-ΔSRI mice have lower glucose-6-phosphate dehydrogenase (G6PDH) activity, which is important for maintaining levels of reduced glutathione and therefore these mice have an increased susceptibility to oxidative stress. Parental heterozygous Atm-ΔSRI mice received a genistein-rich or control diet, after which they were mated to obtain offspring. During pregnancy, mothers remained on the respective diets and after delivery all animals received control diets. Redox status and oxidative DNA damage were assessed in testes and sperm of 12 weeks old male offspring. Gene expression of Cyp1b1, Comt, and Nqo1 was assessed in testes, and DNA methylation as possible mechanism for transmission of effects to later life.ResultsIntake of genistein during pregnancy increased oxidative DNA damage in testes of offspring, especially in heterozygous Atm-ΔSRI mice. These increased DNA damage levels coincided with decreased expression of Comt and Nqo1. Heterozygous Atm-ΔSRI mice had higher levels of DNA strand breaks in sperm compared to wild type littermates, and DNA damage was further enhanced by a genistein-rich maternal diet. G6PDH activity was higher in mice with high maternal intake of genistein compared to control diets, suggesting compensation against oxidative stress. A positive correlation was observed between the levels of DNA methylation and oxidative DNA damage in testes.ConclusionThese data indicate that prenatal exposure to genistein altered gene expression and increased DNA damage in testes and sperm of adolescent male offspring. These effects of genistein on DNA damage in later life coincided with alterations in DNA methylation.

The high mortality rate due to chemoresistance in patients with high-grade ovarian cancer (HGSOC) emphasizes the urgent need to determine optimal treatment strategies for advanced and recurrent cases. Our study investigates the interplay between estrogens and chemoresistance in HGSOC and shows clear differences between platinum-sensitive and -resistant tumors. Through comprehensive transcriptome analyzes, we uncover differences in the expression of genes of estrogen biosynthesis, metabolism, transport and action underlying platinum resistance in different tissues of HGSOC subtypes and in six HGSOC cell lines. Furthermore, we identify genes involved in estrogen biosynthesis and metabolism as prognostic biomarkers for HGSOC. Additionally, our study elucidates different patterns of estrogen formation/metabolism and their effects on cell proliferation between six HGSOC cell lines with different platinum sensitivity. These results emphasize the dynamic interplay between estrogens and HGSOC chemoresistance. In particular, targeting the activity of steroid sulfatase (STS) proves to be a promising therapeutic approach with potential efficacy in limiting estrogen-driven cell proliferation. Our study reveals potential prognostic markers as well as identifies novel therapeutic targets that show promise for overcoming resistance and improving treatment outcomes in HGSOC. [Display omitted] • Estrogen-related gene expression differs in HGSOC with platinum sensitivity. • HSD17B14 , SULT1A1 , CYP19A1 and NQO2 affect survival of HGSOC patients. • Estrogen metabolism varies in HGSOC cell lines with platinum sensitivity. • STX64 emerges as a targeted therapy for estrogen-associated HGSOC. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is an aggressive malignancy originating from the epithelium of the bile duct. The prognosis of patients is poor regardless of radical resection and chemoradiotherapy. The current classification and prognostic model of CCA are unable to satisfy the requirements for predicting the clinical outcome and exploring therapeutic targets. Estrogen signaling is involved in diverse cancer types, and it has long been established that CCA could be regulated by estrogen. In our study, estrogen response was identified to be significantly and stably correlated with poor prognosis in CCA. Employing several algorithms, CCA was classified into ES cluster A and B. ES cluster B was mainly composed of patients with fluke infection and overlapped with CCA cluster 1/2, and ES cluster A was mainly composed of patients without fluke infection and overlapped with CCA cluster 3/4. COMT and HSD17B1 were identified to be responsible for the differential estrogen response between ES clusters A and B, and the estrogen response may be correlated with the differentiation and cancer stemness of CCA at the single-cell level. Complement activation and the expression of C3 and C5, which are mainly expressed by CCA cells, were significantly downregulated in ES cluster B. An estrogen response risk score (ESRS) model was constructed to predict the prognosis of CCA, followed by a nomogram integrating ESRS and clinical features. Finally, altered pathways, applicable drugs and sensitivity to chemical drugs were analyzed specific to the estrogen response. In summary, our results provide insights into the role of the estrogen response in CCA progression as well as applicable drugs and potential therapeutic targets in estrogen metabolism, the complement system and ESRS-related pathways. [ABSTRACT FROM AUTHOR]

The female reproductive tract hosts a specific microbiome, which plays a crucial role in sustaining equilibrium and good health. In the majority of reproductive women, the microbiota (all bacteria, viruses, fungi, and other single-celled organisms within the human body) of the vaginal and cervical microenvironment are dominated by Lactobacillus species, which benefit the host through symbiotic relationships, in comparison to the uterus, fallopian tubes, and ovaries, which may contain a low-biomass microbiome with a diverse mixture of microorganisms. Although disruption to the balance of the microbiota develops, the altered immune and metabolic signaling may cause an impact on diseases such as cancer. These pathophysiological modifications in the gut–uterus axis may spark gynecological cancers. New information displays that gynecological and gastrointestinal tract dysbiosis (disruption of the microbiota homeostasis) can play an active role in the advancement and metastasis of gynecological neoplasms, such as cervical, endometrial, and ovarian cancers. Understanding the relationship between microbiota and endometrial cancer is critical for prognosis, diagnosis, prevention, and the development of innovative treatments. Identifying a specific microbiome may become an effective method for characterization of the specific microbiota involved in endometrial carcinogenesis. The aim of this study was to summarize the current state of knowledge that describes the correlation of microbiota with endometrial cancer with regard to the formation of immunological pathologies. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is an aggressive malignancy originating from the epithelium of the bile duct. The prognosis of patients is poor regardless of radical resection and chemoradiotherapy. The current classification and prognostic model of CCA are unable to satisfy the requirements for predicting the clinical outcome and exploring therapeutic targets. Estrogen signaling is involved in diverse cancer types, and it has long been established that CCA could be regulated by estrogen. In our study, estrogen response was identified to be significantly and stably correlated with poor prognosis in CCA. Employing several algorithms, CCA was classified into ES cluster A and B. ES cluster B was mainly composed of patients with fluke infection and overlapped with CCA cluster 1/2, and ES cluster A was mainly composed of patients without fluke infection and overlapped with CCA cluster 3/4. COMT and HSD17B1 were identified to be responsible for the differential estrogen response between ES clusters A and B, and the estrogen response may be correlated with the differentiation and cancer stemness of CCA at the single-cell level. Complement activation and the expression of C3 and C5, which are mainly expressed by CCA cells, were significantly downregulated in ES cluster B. An estrogen response risk score (ESRS) model was constructed to predict the prognosis of CCA, followed by a nomogram integrating ESRS and clinical features. Finally, altered pathways, applicable drugs and sensitivity to chemical drugs were analyzed specific to the estrogen response. In summary, our results provide insights into the role of the estrogen response in CCA progression as well as applicable drugs and potential therapeutic targets in estrogen metabolism, the complement system and ESRS-related pathways.

Background: Several anthropometric measures have been associated with hormone-related cancers, and it has been shown that estrogen metabolism in postmenopausal women plays an important role in these relationships. However, little is known about circulating estrogen levels in African women, and the relevance to breast cancer or breast cancer risk factors. To shed further light on the relationship of anthropometric factors and estrogen levels in African women, we examined whether measured body mass index (BMI), waist-to-hip ratio (WHR), height, and self-reported body size were associated with serum estrogens/estrogen metabolites in a cross-sectional analysis among postmenopausal population-based controls of the Ghana Breast Health Study.Methods: Fifteen estrogens/estrogen metabolites were quantified using liquid chromatography-tandem mass spectrometry in serum samples collected from postmenopausal female controls enrolled in the Ghana Breast Health Study, a population-based case-control study conducted in Accra and Kumasi. Geometric means (GMs) of estrogens/estrogen metabolites were estimated using linear regression, adjusting for potential confounders.Results: Measured BMI (≥ 30 vs. 18.5-24.9 kg/m2) was positively associated with parent estrogens (multivariable adjusted GM for unconjugated estrone: 78.90 (66.57-93.53) vs. 50.89 (43.47-59.59), p-value < 0.0001; and unconjugated estradiol: 27.83 (21.47-36.07) vs. 13.26 (10.37-16.95), p-value < 0.0001). Independent of unconjugated estradiol, measured BMI was associated with lower levels of 2-pathway metabolites and higher levels of 16-ketoestradriol. Similar patterns of association were found with WHR; however, the associations were not entirely independent of BMI. Height was not associated with postmenopausal estrogens/estrogen metabolite levels in African women.Conclusions: We observed strong associations between measured BMI and parent estrogens and estrogen metabolite patterns that largely mirrored relations that have previously been associated with higher breast cancer risk in postmenopausal White women. The consistency of the BMI-estrogen metabolism associations in our study with those previously noted among White women suggests that estrogens likely explain part of the BMI-postmenopausal breast cancer risk in both groups. These findings merit evaluation in Black women, including prospective studies. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a complex and devastating disease with a poor long-term prognosis. While women are at increased risk for developing PAH, they exhibit superior right heart function and higher survival rates than men. Susceptibility to disease risk in PAH has been attributed, in part, to estrogen signaling. In contrast to potential pathological influences of estrogen in patients, studies of animal models reveal estrogen demonstrates protective effects in PAH. Consistent with this latter observation, an ovariectomy in female rats appears to aggravate the condition. This discrepancy between observations from patients and animal models is often called the “estrogen paradox.” Further, the tissue-specific interactions between estrogen, its metabolites and receptors in PAH and right heart function remain complex; nonetheless, these relationships are essential to characterize to better understand PAH pathophysiology and to potentially develop novel therapeutic and curative targets. In this review, we explore estrogen-mediated mechanisms that may further explain this paradox by summarizing published literature related to: (1) the synthesis and catabolism of estrogen; (2) activity and functions of the various estrogen receptors; (3) the multiple modalities of estrogen signaling in cells; and (4) the role of estrogen and its diverse metabolites on the susceptibility to, and progression of, PAH as well as their impact on right heart function.

The female reproductive tract hosts a specific microbiome, which plays a crucial role in sustaining equilibrium and good health. In the majority of reproductive women, the microbiota (all bacteria, viruses, fungi, and other single-celled organisms within the human body) of the vaginal and cervical microenvironment are dominated by Lactobacillus species, which benefit the host through symbiotic relationships, in comparison to the uterus, fallopian tubes, and ovaries, which may contain a low-biomass microbiome with a diverse mixture of microorganisms. Although disruption to the balance of the microbiota develops, the altered immune and metabolic signaling may cause an impact on diseases such as cancer. These pathophysiological modifications in the gut–uterus axis may spark gynecological cancers. New information displays that gynecological and gastrointestinal tract dysbiosis (disruption of the microbiota homeostasis) can play an active role in the advancement and metastasis of gynecological neoplasms, such as cervical, endometrial, and ovarian cancers. Understanding the relationship between microbiota and endometrial cancer is critical for prognosis, diagnosis, prevention, and the development of innovative treatments. Identifying a specific microbiome may become an effective method for characterization of the specific microbiota involved in endometrial carcinogenesis. The aim of this study was to summarize the current state of knowledge that describes the correlation of microbiota with endometrial cancer with regard to the formation of immunological pathologies.

There are many risk factors associated with breast cancer (BC) such as the familial history of BC, using hormone replacement therapy, obesity, personal habits, and other clinical factors; however, not all BC cases are attributed to these risk factors. Recent researches show a correlation between patient microbiome and BC suggested as a new risk factor. The present review article aimed at evaluating the role of the microbiome as a risk factor in the occurrence of BC, investigating the proposed mechanisms of interaction between the microbiome and human genes involved in BC, and assessing the impact of the altered composition of breast, gut, and milk microbiome in the physiological status of normal breast as well as cancerous or non-cancerous breast lesions. The study also evaluated the growing evidence that these altered populations may hinder chemotherapeutic treatment. The role of microbiome in the development and maintenance of inflammation, estrogen metabolism, and epigenetic alterations was properly investigated. Finally, clinical and therapeutic applications of the microbiome- e.g., probiotics, microbiome genome modulation, and engineered microbiome enzymes in the management of BC were reviewed.

trans-Resveratrol, a polyphenolic stilbene of plant origin is structurally similar to natural and synthetic estrogens and has been classified a phytoestrogen. Direct binding of resveratrol to the nuclear estrogen receptor (ER) and modulation of its genomic activity was among the first of its reported pharmacological actions. Additionally, resveratrol in some investigations interacted with membrane bound ER and modulated non-genomic estrogenic activities. The compound was also reported to interfere in steroidogenesis and estrogen biosynthesis at multiple steps along the pathway. Resveratrol also inhibited hepatic and intestinal metabolism of estrogens and increased circulating levels of sex hormone binding globulin (SHBG). Recent investigations report estrogenic activities for resveratrol metabolites, especially for the predominant sulfate conjugate. The majority of these estrogenic effects have been observed in vitro using micro-molar concentrations. However, the daily consumption of 0.5–1 g of resveratrol supplements is sufficient to furnish plasma levels sufficient to initiate most of these actions. The diverse modes of estrogenic and hormonal activities of resveratrol can produce a progressive shift in the homeostatic balance of estrogens and other steroidal hormones to a new operational set point. While this could represent an opportunity for therapeutic benefit in a variety of endocrine related diseases, it may also pose risk of endocrine disruption following chronic exposure that warrants caution. Herein, a review of the current knowledge of resveratrol's estrogenic activity at the molecular, cellular and whole organism since it was reported two decades ago is provided followed by an assessment of endocrine disruption via an estrogenic mode of action. Resveratrol interacts with ER and modulates its genomic and non-genomic activities. It also inhibits several enzymes in steroidogenesis and competes in estrogen metabolism. Commercial supplements reach dosages of 1000 mg per serving and the consumption of 0.5–1 g per day furnishes low micro-molar plasma levels sufficient to start these activities. The pleiotropic hormonal actions of resveratrol open an opportunity for clinical benefit, but also risk endocrine disruption if exposure is chronic or during critical windows of development. [ABSTRACT FROM AUTHOR]

There are many risk factors associated with breast cancer (BC) such as the familial history of BC, using hormone replacement therapy, obesity, personal habits, and other clinical factors; however, not all BC cases are attributed to these risk factors. Recent researches show a correlation between patient microbiome and BC suggested as a new risk factor. The present review article aimed at evaluating the role of the microbiome as a risk factor in the occurrence of BC, investigating the proposed mechanisms of interaction between the microbiome and human genes involved in BC, and assessing the impact of the altered composition of breast, gut, and milk microbiome in the physiological status of normal breast as well as cancerous or non-cancerous breast lesions. The study also evaluated the growing evidence that these altered populations may hinder chemotherapeutic treatment. The role of microbiome in the development and maintenance of inflammation, estrogen metabolism, and epigenetic alterations was properly investigated. Finally, clinical and therapeutic applications of the microbiome- e.g., probiotics, microbiome genome modulation, and engineered microbiome enzymes in the management of BC were reviewed. [ABSTRACT FROM AUTHOR]

Fuchs endothelial corneal dystrophy (FECD) is a leading cause of corneal endothelial (CE) degeneration resulting in impaired visual acuity. It is a genetically complex and age-related disorder, with higher incidence in females. In this study, we established a nongenetic FECD animal model based on the physiologic outcome of CE susceptibility to oxidative stress by demonstrating that corneal exposure to ultraviolet A (UVA) recapitulates the morphological and molecular changes of FECD. Targeted irradiation of mouse corneas with UVA induced reactive oxygen species (ROS) production in the aqueous humor, and caused greater CE cell loss, including loss of ZO-1 junctional contacts and corneal edema, in female than male mice, characteristic of late-onset FECD. UVA irradiation caused greater mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) damage in female mice, indicative of the sex-driven differential response of the CE to UVA, thus accounting for more severe phenotype in females. The sex-dependent effect of UVA was driven by the activation of estrogen-metabolizing enzyme CYP1B1 and formation of reactive estrogen metabolites and estrogen-DNA adducts in female but not male mice. Supplementation of N-acetylcysteine (NAC), a scavenger of reactive oxygen species (ROS), diminished the morphological and molecular changes induced by UVA in vivo. This study investigates the molecular mechanisms of environmental factors in FECD pathogenesis and demonstrates a strong link between UVA-induced estrogen metabolism and increased susceptibility of females for FECD development. [ABSTRACT FROM AUTHOR]

Objective: The elevated incidence of obesity has been paralleled with higher risks of breast cancer. High adiposity increases leptin secretion from adipose tissue, which in turn increases cancer cell proliferation. The interplay between leptin and estrogen is one of the mechanisms through which leptin influences breast carcinogenesis. An unbalanced estrogen metabolism increases the formations of catechol estrogen quinones, DNA adducts, and cancer mutations. This study aims to investigate the effect of leptin on some estrogen metabolic enzymes and DNA adduction in breast cancer cells. Methods: High performance liquid chromatography (HPLC) was performed to analyze the DNA adducts 4-OHE1[E2]-1-N3 adenine and 4-OHE1[E2]-1-N7 guanine. Reporter gene assay, real time reverse transcription polymerase chain reaction (real time RT-PCR), and Western blot were used to assess the expression of estrogen metabolizing genes and enzymes: Cytochrome P-450 1B1 (CYP1B1), Nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase1 (NQO1), and Catechol-O-methyl transferase (COMT).Results: Leptin significantly increased the DNA adducts 4-OHE1[E2]-1-N3 adenine and 4-OHE1[E2]-1-N7 guanine. Furthermore, leptin significantly upregulated CYP1B1 promoter activity and protein expression. The luciferase promoter activities of NQO1 and mRNA levels were significantly reduced. Moreover, leptin greatly reduced the reporter activities of the COMT-P1 and COMT-P2 promoters and diminished the protein expression of COMT.Conclusions: Leptin increases DNA adduct levels in breast cancer cells partly by affecting key genes and enzymes involved in estrogen metabolism. Thus, increased focus should be directed toward leptin and its effects on the estrogen metabolic pathway as an effective approach against breast cancer.

Fuchs endothelial corneal dystrophy (FECD) is a genetically complex, age-related, female-predominant disorder characterized by loss of post-mitotic corneal endothelial cells (CEnCs). Ultraviolet-A (UVA) light has been shown to recapitulate the morphological and molecular changes seen in FECD to a greater extent in females than males, by triggering CYP1B1 upregulation in females. Herein, we investigated the mechanism of greater CEnC susceptibility to UVA in females by studying estrogen metabolism in response to UVA in the cornea. Loss of NAD(P)H quinone oxidoreductase 1 (NQO1) resulted in increased production of estrogen metabolites and mitochondrial-DNA adducts, with a higher CEnC loss in Nqo1 -/- female compared to wild-type male and female mice. The CYP1B1 inhibitors, trans-2,3',4,5'-tetramethoxystilbene (TMS) and berberine, rescued CEnC loss. Injection of wild-type male mice with estrogen (E2; 17β-estradiol) increased CEnC loss, followed by increased production of estrogen metabolites and mitochondrial DNA (mtDNA) damage, not seen in E2-treated Cyp1b1 -/- male mice. This study demonstrates that the endo-degenerative phenotype is driven by estrogen metabolite-dependent CEnC loss that is exacerbated in the absence of NQO1; thus, explaining the mechanism accounting for the higher incidence of FECD in females. The mitigation of estrogen-adduct production by CYP1B1 inhibitors could serve as a novel therapeutic strategy for FECD., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Nonylphenol (NP) is one widely distributed representative of environmental estrogens that disturb reproductive activities, bone metabolism and brain function through interfering diverse signal pathways leading to hormone metabolic dysfunctions, immunologic derangement, and tumorigenesis. Few of previous studies have observed the subacute toxicity on rodents, and little has been focused on the mechanism underneath the toxicities observed. The 32 male Sprague-Dawley (SD) rats were randomly divided into four groups, the negative control group (corn oil) NP low, medium and high dose groups [30, 90, 270 mg/(kg·d)]. SD rats administrated with different dosage of NP every other day for 28d. Elisa and RT-PCR was employed to observe estrogen metabolism markers or mRNA expressions. In serum, NP exposure caused testosterone (T) (p < 0.001), progesterone (PROG) (p < 0.05) and estrone (E1) (p < 0.05) increased. In testicle, NP exposure caused T (p < 0.001), PROG (p < 0.05), E1 (p < 0.05), 17β-estradiol (E2) (p < 0.05) and ERα mRNA (p < 0.01) increased, while P450 aromatizing enzyme (p < 0.001) decreased in NPL and ERβ mRNA (p < 0.001) decreased in NPM and NPH. In liver, NP exposure caused 17β-HSD2 mRNA (p < 0.01) increased, while P450 aromatizing enzyme decreased (p < 0.05). NP exposure exhibited general and estrogenic toxicity in rats through disturbing estrogen secretion network and estrogen receptor expression network, inducing abnormal metabolism of estrogen, whether in serum, liver and testicle. • NP exposure exhibited general toxicity in rats. High-dose exposure induced the weigh, weigh gain, food unity and organ coefficient decreasing. • On the way of estrogen resynthesis and decomposition, NP changes leads to the changes of hormones and enzymes both in the liver,serum and testis in rat • In receptor binding pathway, NP can affect the transcription level of AR, ERα, ERβ genes in testis, then finally changing the free E2 and T levels. [ABSTRACT FROM AUTHOR]

Copyright of Hungarian Medical Journal / Orvosi Hetilap is the property of Akademiai Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The WHI found an unexpected reduced breast cancer risk in women using CEE alone. We hypothesized CEE alone induces estrogen hydroxylation along the 2‐pathway rather than the competing 16‐pathway, a pattern linked to reduced postmenopausal breast cancer risk. One thousand eight hundred and sixty‐four women in a WHIOS case–control study of estrogen metabolism and ovarian and endometrial cancer were studied of whom 609 were current E + P users (351 used CEE + MPA), while 272 used E alone (162 used CEE). Fifteen EM were measured, and analyses were conducted for each metabolite, hydroxylation pathway (2‐, 4‐, or 16‐pathway) and ratios of pathway concentrations using inverse probability weighted linear regression. Compared to E + P users, all EM were higher in E alone users (significant for unconjugated estrone, total/conjugated estradiol, total/unconjugated 2‐methoxyestrone, 4‐methoxyestrone and unconjugated estriol). The relative concentrations of 2‐ and 4‐pathway EM did not differ between the MHT users (2‐pathway EM comprised 15% and 4‐pathway EM <2% of the total), but 16‐pathway EM were lower in E alone users (p = 0.036). Ratios of 2‐ and 4‐pathway EM compared to 16‐pathway EM were significantly higher in E alone compared to E + P users. Similar but not significant patterns were observed in CEE‐alone and CEE + MPA users. Our data suggest that compared to E + P users, women using E alone have more extensive metabolism via the 2‐ vs. the competing 16‐pathway. This is consistent with epidemiologic evidence of reduced postmenopausal breast cancer risk associated with this metabolic profile and may provide a clue to the breast cancer risk reduction in CEE alone users during the WHI. What's new? The Women's Health Initiative discovered that women taking conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) together increased their risk of breast cancer, but surprisingly, taking CEE alone reduced the risk of cancer. Here, the authors investigate the mechanism involved. To trace the pathway of CEE metabolism, they measured 15 different estrogen metabolites, using serum from women in the WHI Observational Study. In women taking estrogen alone, they found more activity in the "2‐pathway" over the "16‐pathway" of estrogen metabolism, which leads to reduced cancer risk. Those taking estrogen and progestin together showed more activity in the "16‐pathway," associated with higher cancer risk. [ABSTRACT FROM AUTHOR]

• Genetic variation in estrogen metabolism may affect menopause symptoms. • Lower CYP3A4 and higher COMT activity were associated with less severe menopause symptoms in the present study. • No association was found between other genetic variants and menopause symptom severity. • The complex impact of genetic variability in estrogen metabolism on the menopause experience requires further study. The severity of menopause-related symptoms varies considerably among women. The determinants of this variation are incompletely understood. The aim of this study was to assess the association between genetic variation in estrogen metabolism and transport pathways and the severity of menopause symptoms. This was a cross-sectional study of 60 peri- and postmenopausal women in the Mayo Clinic RIGHT study (which involved sequencing of genes involved in drug metabolism and transport), who had also been evaluated in the Women's Health Clinic at Mayo Clinic in Rochester, MN. All participants completed the Menopause Rating Scale (MRS) for assessment of menopause symptoms, including hot flashes. The association between severity of menopause symptoms and the variation in genes encoding 8 enzymes and transporters involved in estrogen metabolism was evaluated. Lower CYP3A4 activity and higher COMT activity were associated with lower severity of somatic menopause symptoms (p = 0.04 and 0.06, respectively). These associations did not persist after adjustment for hormone therapy use. No differences in MRS scores or hot flash severity were noted among other genetic variant groups. Age at natural menopause was not affected by variations in the genes studied. The current study did not show an association between genetic variation in estrogen metabolism and transport pathways and the severity of menopause symptoms. Further studies with larger sample sizes may be required to understand this potentially complex association. [ABSTRACT FROM AUTHOR]

We investigated the relative expression of genes responsible for the estrogen reception and metabolism - CYP1A 1, CYP1A 2, CYP1B 1, CYP19A, ESR1, ESR2, GPER, STS, SULT1A and SULT1E1 - by real-time PCR in tumor and conditionally healthy uterine tissues of 27 female patients in Southern Russia aged 38-72 years with histologically confirmed diagnosis of uterine cancer. It is found that transcription activity of these genes during malignancy of uterine tissues depends of female patients age and the stage of tumor cells differentiation. It is potentially allow to use investigated genes as biomarkers of uterine tissues malignancy with considering age features of female patients and stages of cancer process development.

Objective: Explore whether racial differences in prevalence of CYP1A2∗1F polymorphism underlies estrogen metabolism differences among Asians and Caucasians., Design: Prospective cohort study., Setting: University-based fertility practice., Patients: Asian or Caucasian patients who underwent ovarian stimulation (OS) or programmed cycle frozen embryo transfer (FET) between October 2019 and April 2021., Interventions: None., Main Outcome Measures: Trigger-day serum E2 per oocyte retrieved in OS cycles, and E2 on day of lining check in FET cycles., Results: Seventy-one participants were enrolled, 55 in OS group (29 Caucasian and 26 Asian) and 16 in FET group (10 Caucasian and 6 Asian). Peak E2 per oocyte retrieved in the OS group (n = 48) differed by race, with significantly lower levels in Caucasians compared with Asians (177.5 ± 64.2 vs. 261.1 ± 139.5 pg/mL). Prevalence of CYP1A2∗1F polymorphism did not significantly differ by race. Compared using Kruskal-Wallis test, peak E2 per oocyte retrieved did not differ by CYP1A2∗1F genotype. In multivariate linear regression model, adjusting for body mass index, caffeine intake, and self-reported race, there remained no significant correlation. In FET group, serum E2 on day of lining check was also not significantly different by CYP1A2∗1F genotype., Conclusions: Although a consistent difference in serum E2 between Asians and Caucasians undergoing OS was noted, the CYP1A2∗1F polymorphism is unlikely the primary driver of this difference., Competing Interests: A.K. has nothing to disclose. A.A. reports consulting fees from Flo Health; shareholder in Carrot. B.T. has nothing to disclose. V.Y.F. has nothing to disclose., (© 2023 The Authors.)

Highlights • A novel method for a highly sensitive and accurate measurement of SULT1E1 activity is presented. • The sulfatase pathway is actively present in the endometrium and in EC. • STS seems the major route of intracellular estrogen supply in endometrial cells. Abstract Objective Contradictory results are reported about the level of steroid sulfatase (STS), estrogen sulfotransferase (SULT1E1; together, the sulfatase pathway) and aromatase (CYP19A1) in endometrial cancer (EC). The aim of this study was to explore the levels of these enzymes in a well-characterized cohort of EC patients and postmenopausal controls. Materials and Methods Endometrial tissues from 31 EC patients (21 grade 1 and 10 grade 2–3) and 19 postmenopausal controls were collected. Levels of mRNA (RT-qPCR) and protein (immunohistochemistry) were determined. STS enzyme activity was measured by HPLC, whereas SULT1E1 enzyme activity was determined using a novel method based on liquid chromatography-mass spectrometry (LC-MS/MS). Results No significant differences in STS, SULT1E1 mRNA or protein levels and STS:SULT1E1 ratio were found. STS enzyme activity and STS:SULT1E1 activity ratio were significantly decreased in ECs compared with controls. CYP19A1 mRNA levels were lower in ECs than in controls. Conclusion A novel highly sensitive and accurate protocol to assess SULT1E1 activity is presented. STS enzyme activity and the STS:SULT1E1 activity ratio seem to be lower in ECs than in controls. STS is an important route for estrogen supply in endometrial cells. [ABSTRACT FROM AUTHOR]

Increased exposure to estrogen is a risk factor for postmenopausal breast cancer, and dietary factors can influence estrogen metabolism. However, studies of diet and breast cancer have been inconclusive. We developed a dietary pattern associated with levels of unconjugated estradiol and the ratio of 2‐ and 16‐hydroxylated estrogen metabolites in a subsample of Prostate, Lung, Colorectal and Ovarian Screening Trial (PLCO) participants (n = 653) using reduced rank regression, and examined its association with postmenopausal breast cancer prospectively in the larger PLCO cohort (n = 27,488). The estrogen‐related dietary pattern (ERDP) was comprised of foods with positively‐weighted intakes (non‐whole/refined grains, tomatoes, cruciferous vegetables, cheese, fish/shellfish high in ω‐3 fatty acids, franks/luncheon meats) and negatively‐weighted intakes (nuts/seeds, other vegetables, fish/shellfish low in ω‐3 fatty acids, yogurt, coffee). A 1‐unit increase in the ERDP score was associated with an increase in total (HR: 1.09, 95% CI: 1.01–1.18), invasive (HR: 1.13; 95% CI: 1.04–1.24) and estrogen receptor (ER)‐positive (HR: 1.13, 95% CI: 1.02–1.24) breast cancer risk after adjustment for confounders. Associations were observed for the fourth quartile of ERDP compared with the first quartile for overall breast cancer (HR: 1.14; 95% CI: 0.98–1.32), invasive cases (HR: 1.20, 95% CI: 1.02–1.42) and ER‐positive cases (HR: 1.19; 95% CI: 0.99–1.41). The increased risk associated with increasing ERDP score was more apparent in strata of some effect modifiers (postmenopausal hormone therapy non‐users and non‐obese participants) where the relative estrogen exposure due to that factor was lowest, although the p values for interaction were not statistically significant. Results suggest a dietary pattern based on estrogen metabolism is positively associated with postmenopausal breast cancer risk, possibly through an estrogenic influence. [ABSTRACT FROM AUTHOR]

Purpose: Healthy or unhealthy lifestyle behaviors are often adopted together. We aimed to investigate the combined effect of estrogen-related lifestyle factors on postmenopausal breast cancer risk.Methods: Data from 27,153 women enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial were used. We created an estrogen-related lifestyle score (ERLS) by incorporating a previously developed measure of estrogenic diet, alcohol intake, body mass index (BMI), and physical activity. The scores ranged from 0 to 6 with alcohol and BMI accounting for higher weights than the other factors. To evaluate the preventive possibilities of a low estrogen-related lifestyle and to be consistent with other published lifestyle scores, higher scores were set to correspond with potentially lower estrogenic lifestyle. The association between the ERLS and incident breast cancer was examined using Cox proportional hazards models.Results: Participants with an ERLS of 4 or ≥ 5 had a 23% (HR 0.77; 95% CI 0.67-0.89) and 34% (HR 0.66; 95% CI 0.56-0.78) lower risk of breast cancer, respectively, compared to those with an ERLS ≤ 2 after multivariable adjustment. Estimates were similar when restricting to invasive cases or estrogen receptor-positive subtypes. No single lifestyle component appeared to drive the association.Conclusions: Our findings suggest that the combined effect of a lifestyle characterized by a low estrogenic diet, low alcohol consumption, low body weight, and high levels of physical activity are associated with a reduction in postmenopausal breast cancer risk, possibly through an influence on estrogen metabolism. [ABSTRACT FROM AUTHOR]

Sphingolipids are critical regulators of tumor microenvironments and play an important role in estrogen-dependent cancers. Estrogen and estrogen metabolites were found to be involved in prostate cancer. Fingolimod (FTY720) is a sphingokinase-1 (SphK1) inhibitor with anticancer properties against various tumor cell types. Herein, we investigated the interference of FTY720 with the cross talk between sphingolipid metabolism and estrogen metabolism within prostate cancer cells. FTY720 showed cytotoxic antiproliferative effects against androgen-dependent and -independent prostate cancer cells with IC 50 ranging from 3.0 ± 0.3 to 6.8 ± 1.7 μM. Exposure of prostate cancer cells to FTY720 resulted in a dramatic decrease in the concentration of estradiol, estrone, 4-hydroxyestradiol and 16α-hydroxyestrone compared to control cells. However, FTY720 significantly increased the concentration of 2-methoxyestrone and 2-methoxyestradiol within prostate cancer cells. This was mirrored by significant downregulating of the expression of estrogen and catechol estrogen-synthesizing enzymes (CYP19, CYP1A1 and CYP1B1) within prostate cancer cells. On the other hand, FTY720 significantly upregulated the expression of catechol estrogen-detoxifying enzyme (COMT). Additionally, FTY720 abolished estrogen-stimulated expression of ERα and basal expression of ERβ within prostate cancer cells. Furthermore, FTY720 suppressed the expression of the ER-downstream regulated genes, CXCR4 and cyclin D1. Reciprocally, it was found that estradiol and catechol estrogens significantly induced the expression of SphK1 while methoxylated catechol estrogen suppressed its expression within prostate cancer cells in a dose-dependent manner. Current research has highlighted the hazardous influence of the estrogenic component to prostate cancer. We found that fingolimod (FTY720) could modulate the estrogenic micromilieu and interrupt its cross talk with sphingolipid metabolism. [ABSTRACT FROM AUTHOR]

Abstract: The enzyme type 1 17β‐hydroxysteroid dehydrogenase (17β‐HSD‐1), responsible for generating active 17β‐estradiol (E2) from low‐active estrone (E1), is overexpressed in endometrial cancer (EC), thus implicating an increased intra‐tissue generation of E2 in this estrogen‐dependent condition. In this study, we explored the possibility of inhibiting 17β‐HSD‐1 and impairing the generation of E2 from E1 in EC using in vitro, in vivo, and ex vivo models. We generated EC cell lines derived from the well‐differentiated endometrial adenocarcinoma Ishikawa cell line and expressing levels of 17β‐HSD‐1 similar to human tissues. In these cells, HPLC analysis showed that 17β‐HSD‐1 activity could be blocked by a specific 17β‐HSD‐1 inhibitor. In vitro, E1 administration elicited colony formation similar to E2, and this was impaired by 17β‐HSD‐1 inhibition. In vivo, tumors grafted on the chicken chorioallantoic membrane (CAM) demonstrated that E1 upregulated the expression of the estrogen responsive cyclin A similar to E2, which was impaired by 17β‐HSD‐1 inhibition. Neither in vitro nor in vivo effects of E1 were observed using 17β‐HSD‐1‐negative cells (negative control). Using a patient cohort of 52 primary ECs, we demonstrated the presence of 17β‐HSD‐1 enzyme activity (ex vivo in tumor tissues, as measured by HPLC), which was inhibited by over 90% in more than 45% of ECs using the 17β‐HSD‐1 inhibitor. Since drug treatment is generally indicated for metastatic/recurrent and not primary tumor, we next demonstrated the mRNA expression of the potential drug target, 17β‐HSD‐1, in metastatic lesions using a second cohort of 37 EC patients. In conclusion, 17β‐HSD‐1 inhibition efficiently blocks the generation of E2 from E1 using various EC models. Further preclinical investigations and 17β‐HSD‐1 inhibitor development to make candidate compounds suitable for the first human studies are awaited. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Schistosoma haematobium is a human blood fluke causing a chronic infection called urogenital schistosomiasis. Squamous cell carcinoma of the urinary bladder (SCC) constitutes chronic sequelae of this infection, and S. haematobium infection is accounted as a risk factor for this type of cancer. This infection is considered a neglected tropical disease and is endemic in numerous countries in Africa and the Middle East. Schistosome eggs produce catechol-estrogens. These estrogenic molecules are metabolized to active quinones that induce modifications in DNA. The cytochrome P450 (CYP) enzymes are a superfamily of mono-oxygenases involved in estrogen biosynthesis and metabolism, the generation of DNA damaging procarcinogens, and the response to anti-estrogen therapies. IL6 Interleukin-6 (IL-6) is a pleiotropic cytokine expressed in various tissues. This cytokine is largely expressed in the female urogenital tract as well as reproductive organs. Very high or very low levels of IL-6 are associated with estrogen metabolism imbalance. In the present study, we investigated the polymorphic variants in the CYP2D6 gene and the C-174G promoter polymorphism of the IL-6 gene on S. haematobium-infected children patients from Guine Bissau. CYP2D6 inactivated alleles (28.5%) and IL6G-174C (13.3%) variants were frequent in S. haematobium-infected patients when compared to previously studied healthy populations (4.5% and 0.05%, respectively). Here we discuss our recent findings on these polymorphisms and whether they can be predictive markers of schistosome infection and/or represent potential biomarkers for urogenital schistosomiasis associated bladder cancer and infertility. [ABSTRACT FROM AUTHOR]