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The problem of resistance of non atypical endometrial hyperplasia (NEH) to traditionally accepted, pathogenetically sound therapy with different types of progestins is currently an unsolved problem. In about 17-20% of cases there is a recurrence or even progression of atypical forms of endometrial hyperplasia (AEH), which required the use of surgical treatments. The aim of the study was to investigate the results of hormone therapy with different types of progestins for the treatment of endometrial hyperplasia in women with different types of expression of estrogen and progesterone receptors in combination with the expression of intercellular adhesion molecules E-cadherin and β-catenin to determine the cause of hormonal resistance, formation of groups of women with progestogen-sensitive endometrial hyperplasia (EH) non atypical type NEH (+), which can use progestogens for treatment, and progestogen-resistant forms of endometrial hyperplasia with non atypical NEH (-), which should be offered alternative therapy. The study was performed on the morphological material of the endometrium obtained by diagnostic biopsy in women with abnormal uterine bleeding who were diagnosed with NEH by histological examination. For immunohistochemical study, 80endometrial samples were taken from women with abnormal uterine bleeding (AUВ) and in the same women after treatment of endometrial hyperplasia without atypia in 3 and 6 months of therapy. The control group (CG) consisted of a group of 20women who were followed-up without treatment tactics. All women were divided into 3 groups in which different types of progestins were used for treatment: groupI – continuous intake of 100mg of micronized progesterone per os twice a day for 6 months, groupII – 20mg of dihydrogesterone per os twice a day for 6 months, group III – in which LNG-IUD was used. The state of proliferation and differentiation in the studied tissues was assessed by the expression of their key molecular participants – estrogen receptors (ERα) and progesterone (PGR), transmembrane glycoproteins of E-cadherin and β-catenin. ERα and PGR expression were determined by immu­nohistochemistry and calculated by the semi-quantitative H-index method. Evaluation of the expression of E-cadherin and β-catenin was performed by determining the percentage of IHH-positive cells to these antigens depending on the degree of their color. The criterion for the effectiveness of NEH treatment was considered to be a biopsy in 3 and 6months of treatment in the absence of pathological changes in the endometrium. The results showed that after the use of progestogens in group I there was a change in the endometrium to the secretory type in 45% of cases, in group II with dydrogesterone therapy – in 55% there was a reduction of EH to normal histological picture. The intrauterine system with levonorgestrel (LNG-IUD) showed the greatest efficiency, with the use of which in 75% of cases normalization of the endometrial structure was observed. In the control group in 32% of cases the structure of the endometrium normalized. After 6 months of treatment with gestagens, both oral forms (micronized progesterone, dydrogesterone) and the use of LNG-IUDs showed a positive effect from their use; the therapeutic form of gestagens for therapy is not significant in reducing excessive endometrial proliferation. In the control group of patients who did not receive therapy or discontinued therapy for various reasons, it was shown that 47% of patients had spontaneous regression of EH. The overall percentage of no effect from treatment was 20% in groups I, II and III. Determination of ERα expression in all groups showed a pronounced expression in glands and stroma, which did not differ significantly in the group with NEH (+) and in NEH (-). Analysis of PGR expression of NEH in endometrium (-) showed that in glandular cells (50.82±0.73) and in the stroma (47.34±0.82) it was lower than in the endometrium of women with NEH (+) (gland 187±3.1; stroma 166.4±2.3; p

Our previous study on the idiopathic progressive subglottic stenosis (IPSS) highlighted a possible hormonal mechanism, with over-expression of estrogen receptors alpha (ER-α) and progesterone receptors (PR). We tested whether such over-expression take place in non-idiopathic subglottic stenosis (NISS) as well.37 specimens of iatrogenic NISS were analyzed (20 females; mean age, 59 ± 12 years; range 41-85). Immunoreactivity of ER-α and PR was calculated as the product of intensity (1 = weak, 2 = moderate, 3 = strong) and positive cells percentage (1 to 4, for 10%, 10-50%, 50-80%, and 80%). This score was calculated on the stenotic tissue (ST), and stenosis margins (SM).The expression of PR was significantly higher in ST of IPSS compared with female and male NISS patients (8.7 ± 3.1 vs. 4.9 ± 3.2, p 0.001 for IPSS vs. female and 8.7 ± 3.1 vs. 2.1 ± 2.7, p 0.01 for IPSS vs. male NISS patients). Contrarily, ER-α showed gender differences, as both IPSS and female NISS patients had similar, yet higher ER-α expression compared with male NISS patients (7.0 ± 4.2 vs. 6.5 ± 2.5, p = NS for IPSS vs. female and 7.0 ± 4.2 vs. 3.4 ± 2.0, p 0.02 for IPSS vs. male NISS patients). There was no difference in fibroblast receptor expression between ST and SM. However, ER-α and PR expression was significantly lower in marginal mucous glands when compared with ST.The IPSS pathogenesis appears to be driven by hormonal mechanisms, in particular, by over-expression of PR. Marginal cells display a reduced hormone receptor density. This finding could be interpreted as a compensatory mechanism. These findings could open up for targeted IPSS treatment.

Menopause is a physiological process that occurs in a woman's life, the result of irreversible changes in the hormonal functions of the ovaries. During the reproductive period of a woman's life, estrogens have a controlling effect on various organs and tissues through interaction with their binding sites - estrogen receptors [Suri V., Suri V., 2014]. In addition to the uterus and mammary glands, these receptors are located in the urethra, vagina, brain, heart cells, mucous membrane of the oral cavity, larynx, periodontal tissues and other places [Leimola-Virtanen R, 2000; Lopez V.S. et al., 2011]. Pathological changes can occur in any of the listed organs, including the periodontium, against the background of estrogen deficiency during menopause.

Aim. To assess the expression of estrogen (ER) and progesterone receptors (PR) in the endometrium during the implantation "window" in women with impaired reproductive function with low (16.1P30 nmol/l) and high (P30 nmol/l)) functional activity of the corpus luteum of the ovary. Materials and methods. A prospective single-center cohort comparative study. The main group included patients with infertility (n=93) and miscarriage (n=47) of unclear reason in the anamnesis, the control group 16 healthy fertile women. In all cases, vacuum-aspiration endometrial biopsy was performed on the 68 days after ovulation with simultaneous collection of a peripheral blood sample to determine the levels of estradiol and progesterone. Endometrial samples were studied by histological and immunohistochemical (ER, PR expression) methods. Results. Women of the main (1) and control (2) groups had an ovulatory menstrual cycle. The serum estradiol (E2) level was 691.326.5 pmol/l (1) and 707.466.1 pmol/l (2); progesterone (P) 46.11.8 nmol/l (2) and 39.14.9 nmol/l (2). Mid-secretory endometrium (results of histological examination) was determined in all healthy women (n=16) and in 46% (n=64) of the patients of the main group. All women in the control group had adequate hormone-receptor characteristics of the endometrium, in women in the main group in 45% (n=63). Comparative analysis of the expression of ER, PR in the endometrium in patients with different functional activity of the corpus luteum of the ovary was carried out in the groups 1 and 2, in women with different reproductive dysfunctions in the anamnesis (without significant differences; p0.05); subgroup analysis was performed in cohorts of women with normal (63 women in group 1 and 16 in group 2) and inadequate (77 patients in group 1) hormone-receptor status of the endometrium. There were no significant differences in the expression of ER, PR in the endometrium with low/high functional activity of the corpus luteum of the ovary with similar morphological characteristics of the endometrium (p0.05). Correlation analysis did not reveal significant relationships between the level of P in the blood and indicators of endometrial expression ER, PR (p0.05). Conclusion. In the studied cohorts, the prognostic significance of the functional activity of the corpus luteum of the ovary for the adequate expression of estrogen and progesterone receptors has not been established. To clarify the presence/absence of endometrial dysfunction in women with a history of reproductive failures, a morphological examination of the endometrium of the middle secretion phase should be carried out.

Introduction Urinary bladder cancer is worldwide one of the most diagnosed and costly types of cancer. One puzzle in the bladder cancer diagnosis is the disproportional relationship between genders. Males are more likely to be diagnosed with bladder cancer whereas females typically are diagnosed with more adverse disease and worse prognosis, which has led to speculation of the potential role of sex hormones and their receptors in this disease. Estrogen receptors are present in the human bladder and their role in bladder cancer oncogenesis is increasingly becoming a focus for researchers around the world. This mini-review aims to give a brief overview of the status of female bladder cancer, and to which extend the sex hormones receptors play a role in this. Methods A literature search was performed and included all female original studies on bladder cancer and hormone receptors. Results Estrogen-receptor alpha seems to be anti-oncogenic whereas Estrogen-receptor beta is exhibiting its function pro-oncogenic. The receptor functions may be exercised through mRNA transcriptions and enzymes. Epidemiological studies indicate a potential increase in incidence of bladder cancer for females with earlier age at menopause and clinical trials are investigating Tamoxifen as a potential treatment in bladder cancer. Conclusion Increasing evidence supports the theory of bladder cancer development and progression as being partly hormone-dependent. This can lead to a change in conceptual background of bladder cancer etiology and development in the future. Further studies are required to more precise map the use of anti-hormonal drugs in the treatment of this cancer.

Aim — to investigate receptivity of the vaginal epithelium in women with the female sexual dysfunction and hypoandrogenism.Materials and methods. The immunohistochemical investigation has been performed to define the density of androgen receptors (AR) and estrogen receptors (ER) in the distal part of the vaginal tract of women of reproductive age with hypoandrogenic provision of their hormonal background. For immunohistological examination, a biopsy of the lower third of the vaginal mucosa was taken using a dermopunch with a diameter of 3 mm in 20 women with female sexual dysfunction (FSD) and hypo­andro­genism. The control group consisted of 20 women of reproductive age without FSDmanifestations and disturbances in their hormonal levels. The survey was carried out at the stage of pre-conceptional preparation. Location: Ukrainian Scientific and Prac­tical Center for Endocrine Surgery, Transplantation of Endocrine Organs and Tissues of the Ministry of Health of Ukraine.Results. Immunoreactivity of ERα in the epithelium in the main and control groupswas 47.2 ± 22.2 and 86.1 ± 8.0 (p < 0.001), in the stroma — respectively 13.9 ± 16.8 and 86.1 ± 8.3 (p < 0.001), that is, immunoreactivity in the epithelium was significantly higher thanin the stroma (p < 0,01). The ERα locationin the vaginal epithelium was the samein both groups: cellsof the basal-intermediate layer along the basement membrane and the intermediate layer. No cells, expressing ERα, were detected in the surface layer. In stromal cells, ERαcontained in fibroblasts and smooth muscle cells. ERβ was found in cellsof thebasal — parabasal layer, the intermediate layer, occasionally —on the surface layerof vaginal epithelium, as well as in fibroblasts, vascular endothelium, where both nuclear andcytoplasmic staining was revealed. According to the results of immunohistochemical study of AR invagina, the proportion of AR-positive cells in healthy women was negligible (3.8 ± 2.2), that is considerably less than in patients with androgen deficiency (18.8 ± 8.3) and compared withother receptors. AR were localized mainly in the basal layer alongbasement membrane. Single AR-positive fibroblasts occurred in the stroma.Conclusions. Estrogen receptors α (ERα) are involved in the regulation of the processes of proliferation and differentiation of the vaginal epithelium under the influence of estrogen, as evidenced by a 1.8-fold increase in the density of stained ERα in women of the control group. The absence of correlations between ЕRα and ЕRβ receptors (r = 0.24; p < 0.05) may indicate the ability to change in the same tissue depending on the strength of estrogen effects on the body of a woman. Topical localization of androgen receptors in the basal layer testifies in favour of the safe use of local formsof androgensto overcome the reduced lubrication., Мета роботи — дослідити рецептивність вагінального епітелію у жінок із жіночою сексуальною дисфункцією (ЖСД) та гіпоандрогенізмом.Матеріали та методи. Проведено імуногістохімічне дослідження щільності андрогенних (АР) та естрогенових рецепторів (ЕР) у дистальному відділі вагінального тракту жінок репродуктивного віку із гіпоандрогенним забезпеченням їхнього гормонального тла. Для імуногістологічного дослід­ження використовували біоптат нижньої третини слизової вагіни, взятий за допомогою дермопанча діаметром 3 мм у 20 жінок із ЖСД та гіпоандрогенізмом. Контрольну групу утворено із 20 жінок репродуктивного віку без виявів ЖСД та порушень гормонального тла. Обстеження виконане на етапі прегравідарної підготовки. Місце проведення: Український науково-практичний центр ендокринної хірургії, трансплантації ендокринних органів і тканин МОЗ України.Результати. Імунореактивність ЕРα в епітелії в основній та контрольній групі становила 47,2 ± 22,2 і 86,1 ± 8,0 (p < 0,001), у стромі — відповідно 13,9 ± 16,8 та 86,1 ± 8,3 (p < 0,001), тобто імунореактивність в епітелії була статистично значущо вище, ніж у стромі (р < 0,01). Розташування ЕРα у вагінальному епітелії обох груп: клітини базально-проміжного шару вздовж базальної мембрани та проміжний шар. Клітин, які експресують ЕРα, в поверхневому шарі не виявлено. У стромальних клітинах ЕРα містилися у фібробластах та гладеньком’язових клітинах. ЕРβ виявлено у клітинах базально-парабазального шару, проміжного шару, зрідка — поверхневого шару епітелію вагіни, а також у фібробластах, ендотелії судин, де відзначено як ядерне, так і цитоплазматичне забарвлення. За результатами імуногістохімічного дослідження АР у вагіні частка АР-позитивних клітин у здорових жінок була мізерною (3,8 ± 2,2), що суттєво менше, ніж у пацієнток з андрогенним дефіцитом (18,8 ± 8,3), та порівняно з іншими рецепторами. Локалізувалися АР переважно в базальному шарі вздовж базальної мембрани. У стромі траплялися поодинокі АР-позитивні фібробласти. Висновки. Рецептори естрогену α беруть участь у регуляції процесів проліферації та диференціювання вагінального епітелію під впливом естрогенів, про що свідчить збільшена у 1,8 разу щільність забарвлених рецепторів естрогену α у здорових жінок. Відсутність кореляційних зв’язків між рецепторами естрогену α та β (r = 0,24; р < 0,05) може свідчити про здатність змінюватися в одній і тій самій тканині залежно від сили впливу естрогенів на організм жінки. Топічна локалізація андрогенних рецепторів у базальному шарі свідчить на користь безпечності застосування місцевих форм андрогенів для подолання зниження лубрикації.

SUMMARY: Estrogen receptors (ER) have been identified in human nasal mucosa, but its physiologic and pathologic impacts are not totally established. ER have been demonstrated in nasal mucosa by several authors, mainly by immunohistochemical method in nasal mucosa samples surgically removed. The present study aimed to quantify ERα and ERβ mRNA concentration by using an absolute quantitative real-time PCR in cells from nasal mucosa smear of women under oral contraceptive therapy. Nasal epithelium smear samples were collected from 110 patients divided in two groups: 55 women who present regular menstrual cycle without using contraceptives and 55 women who present regular menstrual cycle and have been using oral contraceptives for more than 3 months. All the patients answered a rhinitis symptoms questionnaire. The current study showed the potential usefulness of nasal turbinate mucosa cell sourcing, collected through swab, for extracting useful RNA for gene expression. We have identified the predominant expression of ERα isoform in a ratio 10-15 times higher compared to ERβ isoform. There is a tendency for positive correlation between the ERb isoform and the rhinitis severity score.

In the presence of established atherosclerosis, estrogens are potentially harmful. MMP-2 and MMP-9, their inhibitors (TIMP-2 and TIMP-1), RANK, RANKL, OPG, MCP-1, lysyl oxidase (LOX), PDGF-β, and ADAMTS-4 play critical roles in plaque instability/rupture. We aimed to investigate (i) the effect of estradiol on the expression of the abovementioned molecules in endothelial cells, (ii) which type(s) of estrogen receptors mediate these effects, and (iii) the role of p21 in the estrogen-mediated regulation of the aforementioned factors. Human aortic endothelial cells (HAECs) were cultured with estradiol in the presence or absence of TNF-α. The expression of the aforementioned molecules was assessed by qRT-PCR and ELISA. Zymography was also performed. The experiments were repeated in either ERα- or ERβ-transfected HAECs and after silencing p21. HAECs expressed only the GPR-30 estrogen receptor. Estradiol, at low concentrations, decreased MMP-2 activity by 15-fold, increased LOX expression by 2-fold via GPR-30, and reduced MCP-1 expression by 3.5-fold via ERβ. The overexpression of ERα increased MCP-1 mRNA expression by 2.5-fold. In a low-grade inflammation state, lower concentrations of estradiol induced the mRNA expression of MCP-1 (3.4-fold) and MMP-9 (7.5-fold) and increased the activity of MMP-2 (1.7-fold) via GPR-30. Moreover, p21 silencing resulted in equivocal effects on the expression of the abovementioned molecules. Estradiol induced different effects regarding atherogenic plaque instability through different ERs. The balance of the expression of the various ER subtypes may play an important role in the paradoxical characterization of estrogens as both beneficial and harmful.

Objective: The molecular classification for endometrial cancer (EC) introduced by The Cancer Genome Atlas Research Network (TCGA) and the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) proved the existence of four molecular prognostic subtypes; however, both classifications require costly technology. We suggest a prognostic model for EC based on immunohistochemistry (IHC) and tumor-infiltrating lymphocytes (TILs). Study design: One hundred patients were included. We retrospectively investigated IHC prognostic parameters: mismatch repair (MMR)-deficient tumors, p53 mutation status, progesterone receptors (PgRs), and estrogen receptors (ERs). We further evaluated TILs. These parameters were related to the clinical and morphological features and to the outcome. Results: We classified tumors into three groups (IHC analysis): MMR-deficient, p53-mutated, p53 wild-type. MMR-deficient tumors had a good prognosis, p53 wild-type tumors an intermediate one, and p53-mutated tumors had the poorest outcomes. Disease-free (DFS) and overall survival (OS) were significantly better among PgR+ tumors (respectively p = 0.011 and p = 0.001) and PgR expression is an independent prognostic factor for a better DFS frommultivariate analysis (OR = 0.3; CI: 0.1–0.9; p = 0.03).No significant correlation was observed between DFS and TILs. However, among MMR-deficient tumors, the mean value of TILs was higher than among the other tumors(111 versus 71, p = 0.01) Conclusions: The prognostic model based on IHC markers could potentially be a valid and applicable alternative to the TCGA one. The PgR determination could represent an additional prognostic factor for EC.

Ovarian and endometrial cancers are affected by estrogens and their receptors. It has been long known that in different types of cancers, estrogens activate tumor cell proliferation via estrogen receptor α (ERα). In contrast, the role of ERs discovered later, including ERβ and G-protein-coupled ER (GPER1), in cancer is less well understood, but the current state of knowledge indicates them to have a considerable impact on both cancer development and progression. Moreover, estrogen related receptors (ERRs) have been reported to affect pathobiology of many tumor types. This article provides a summary and update of the current findings on the role of ERβ, GPER1, and ERRs in ovarian and endometrial cancer. For this purpose, original research articles on the role of ERβ, GPER1, and ERRs in ovarian and endometrial cancers listed in the PubMed database have been reviewed.

Objectives This study aims to investigate the relationship between estrogen receptors (ERs) and progesterone receptors (PRs) and histopathological findings in synovial tissue in rheumatoid arthritis (RA) and osteoarthritis (OA) patients. Patients and methods Synovial tissue samples obtained from synovial surgery from 30 RA (10 males, 20 females) and 92 OA (27 males, 65 females) patients with median age of 59 (range, 50 to 67) years were analyzed retrospectively between January 2010 and January 2019. The relationship between histopathological features and hormone receptor presence was analyzed. Results There was a meaningful relationship between histopathological parameters and RA and OA (p=0.01). The sex hormone receptor's presence was significantly higher in females with RA (p=0.01). Additionally, in the RA group, there was a remarkable relationship between ER and focal aggregates of lymphocytes (p=0.01), perivascular infiltrates of lymphocytes (p=0.03), and diffuse infiltrates of lymphocytes (p=0.01). In the OA group, a significant relationship was observed between PR and subchondral inflammation (p=0.01). In multivariate analysis, it was observed that ER was an independent risk factor for focal aggregates of lymphocytes in RA group (odds ratio [OR]=1.51 [1.02-2.25], p=0.04). Besides, PR was found to be an independent risk factor for subchondral inflammation in OA group (OR=3.90 [1.28-11.80], p=0.02). Conclusion The presence of the sex hormone receptor in the synovium may change histopathological features and affect the clinical course.

This study aimed to investigate the function of estrogen receptors (ERs) in myoregeneration and intermuscular adipogenesis. Ovariectomized (OVX) ERα knockout (KO) mice and ERβ KO mice were used to assess the effect of estrogen on the myoregenerative process. Tibialis anterior muscle was collected on days 7, 10, and 14 after cardiotoxin injection to assess myotube morphology and adipogenesis area. Regenerated myotubes from OVX-ERβ KO mice were consistently smaller in diameter than those from OVX-ERα KO and OVX-wild-type mice, whereas the adipogenesis area of OVX-ERβ KO mice was consistently greater than that of the other types. Therefore, ERβ may be an influential factor in promoting myoregeneration and adipogenesis inhibition compared to ERα.

Background Esophageal cancers, both squamous cell and adenocarcinoma, have poor outcomes with high morbidity and mortality. Our hospital-based registry for the year 2017 to 2018 showed that esophageal cancer constituted 22.7% of annual caseload. Most of our patients present in advanced stages. The aim of this article was to study the role of hormonal receptors in patients with esophageal cancer. Methods This is a single-institution, prospective, observational study in patients with esophageal carcinoma. Hormonal receptors (estrogen receptor [ER]-α and progesterone receptors) were studied in tumor tissue. Of 160 patients, receptor status was analyzed in 133 patients. Chi-square test was used for the correlation of categorical variables. The value of p < 0.05 was considered as statistically significant. Results A total of 133 patients was taken into the study of which 96 were males and 37 were females. The mean age of patients was 52 years. Carcinoma esophagus was predominantly seen in males. Estrogen and progesterone receptors were positive in 9.02 and 4.51% of the study population, respectively. Patients with hormonal receptor positivity presented with poor functional status, higher grades of dysphagia, higher stage, and most of the tumors were poorly differentiated with statistically significant p-values. Conclusion Despite recent advances in various fields of oncology, outcomes of esophageal carcinoma have not improved significantly. Hence, a study of new pathways of pathogenesis in carcinogenesis of esophageal carcinoma is essential. Few recent evidences including our study shows that the hormonal milieu is responsible in the pathogenesis of carcinoma esophagus. The utilization of this data and future study of the role of hormonal therapy might lead to improved outcomes in patients with carcinoma esophagus.

Background and Objective: Palladacycles have been reported to exert significant anticancer activities against different cancer cells. The current study conducted to evaluate the anti-tumor activity of a new palladacycle complex (ASH10) in estrogen receptor-positive (MCF7) and triple-negative (HCC1937) breast cancer cells. Materials and Methods: The effect of ASH10 on cell proliferation was tested by MTT assay. Scratch assay was used to test the anti-migration ability of ASH10. Apoptosis induced by ASH10 was measured by different methods including nuclear staining and detection of apoptosis markers by western blotting. Autophagy induced by ASH10 also measured by LC3II puncta staining and western blotting using the LC3II antibody. Results: The MTT results showed that the ASH10 compound has a strong anti-growth effect. Data showed that ASH10 induces its cytotoxic effect by inducing DNA damage followed by cell cycle arrest, intrinsic apoptosis and autophagy. Compared to untreated cells, ASH10 treated cells showed high levels of DNA damage markers p-H2AX, p-ATM and p53. Importantly, the cell cycle arrest marker p21 was similarly induced by ASH10 treatment. Furthermore, ASH10 induced significant levels of apoptosis as evidenced by nuclear fragmentation and an increase in the levels of PARP cleavage. Interestingly, ASH10 also activated the formation of autophagosomes and increased the autophagy marker LC3II. Inhibition of autophagy led to a decrease in ASH10 cytotoxicity suggesting that ASH10 induced autophagy was a cytotoxic mechanism. Conclusion: These results demonstrated that ASH10 is a potential effective compound in the treatment of both ER-negative and ER-positive breast cancer cells. Background and Objective: Palladacycles have been reported to exert significant anticancer activities against different cancer cells. The current study conducted to evaluate the anti-tumor activity of a new palladacycle complex (ASH10) in estrogen receptor-positive (MCF7) and triple-negative (HCC1937) breast cancer cells. Materials and Methods: The effect of ASH10 on cell proliferation was tested by MTT assay. Scratch assay was used to test the anti-migration ability of ASH10. Apoptosis induced by ASH10 was measured by different methods including nuclear staining and detection of apoptosis markers by western blotting. Autophagy induced by ASH10 also measured by LC3II puncta staining and western blotting using the LC3II antibody. Results: The MTT results showed that the ASH10 compound has a strong anti-growth effect. Data showed that ASH10 induces its cytotoxic effect by inducing DNA damage followed by cell cycle arrest, intrinsic apoptosis and autophagy. Compared to untreated cells, ASH10 treated cells showed high levels of DNA damage markers p-H2AX, p-ATM and p53. Importantly, the cell cycle arrest marker p21 was similarly induced by ASH10 treatment. Furthermore, ASH10 induced significant levels of apoptosis as evidenced by nuclear fragmentation and an increase in the levels of PARP cleavage. Interestingly, ASH10 also activated the formation of autophagosomes and increased the autophagy marker LC3II. Inhibition of autophagy led to a decrease in ASH10 cytotoxicity suggesting that ASH10 induced autophagy was a cytotoxic mechanism. Conclusion: These results demonstrated that ASH10 is a potential effective compound in the treatment of both ER-negative and ER-positive breast cancer cells.

Aim. To analyze and systematize the available information on pathogenetic mechanisms of hormonal carcinogenesis. Materials and methods. The review includes data from foreign articles published in PubMed and Medline and national works posted on elibrary.ru over the past 20 years. Results. Currently, the term estrogen is often used in the context of hormonal carcinogenesis. According to most researchers, it should not fit into the narrow framework of receptor-mediated proliferation induced by estrogens in target tissues. The concept of estrobiome as a combination of all mechanisms providing the realization of estrogen effects should include not only hormones and native receptors themselves, but also the enzymes involved in their synthesis, estrogen metabolites, intestinal microbiota, as well as genetic and epigenetic factors. Conclusions. When analyzing cancer risk, it is necessary to comprehensively assess contributing factors and hormonal-metabolic preconditions for neoplastic process.

17β-estradiol protects pancreatic β-cells from apoptosis via the estrogen receptors ERα, ERβ and GPER. Conversely, the endocrine disruptor bisphenol-A (BPA), which exerts multiple effects in this cell type via the same estrogen receptors, increased basal apoptosis. The molecular-initiated events that trigger these opposite actions have yet to be identified. We demonstrated that combined genetic downregulation and pharmacological blockade of each estrogen receptor increased apoptosis to a different extent. The increase in apoptosis induced by BPA was diminished by the pharmacological blockade or the genetic silencing of GPER, and it was partially reproduced by the GPER agonist G1. BPA and G1-induced apoptosis were abolished upon pharmacological inhibition, silencing of ERα and ERβ, or in dispersed islet cells from ERβ knockout (BERKO) mice. However, the ERα and ERβ agonists PPT and DPN, respectively, had no effect on beta cell viability. To exert their biological actions, ERα and ERβ form homodimers and heterodimers. Molecular dynamics simulations together with proximity ligand assays and coimmunoprecipitation experiments indicated that the interaction of BPA with ERα and ERβ as well as GPER activation by G1 decreased ERαβ heterodimers. We propose that ERαβ heterodimers play an antiapoptotic role in beta cells and that BPA- and G1-induced decreases in ERαβ heterodimers lead to beta cell apoptosis. Unveiling how different estrogenic chemicals affect the crosstalk among estrogen receptors should help to identify diabetogenic endocrine disruptors. This work was supported by Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) grants BPU2017-86579-R (AN), PID2020-117294RB-I00 (AN, JM-P), Generalitat Valenciana PROMETEO II/2020/006 (AN) and European Union’s Horizon 2020 research and innovation programme under grant agreement GOLIATH No. 825489 (AN). Author laboratories hold grants from Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación y Fondo Europeo de Desarrollo Regional (FEDER) RTI2018-096724-B-C21 (J-AE) and PID2020-117569RA-I00 (LM). PROMETEO/2016/006 (J-AE) and SEJI/2018/023 (LM) supported by Generalitat Valenciana, Spain. Robert A. Welch Foundation (grant E-0004) (J-AG). CIBERDEM is an initiative of the Instituto de Salud Carlos III.

Flow-mediated dilation (FMD) of resistance arteries is essential for tissue perfusion but it decreases with ageing. As estrogen receptor alpha (Erα encoded by Esr1), and more precisely membrane ERα, plays an important role in FMD in young mice in a ligand-independent fashion, we evaluated its influence on this arteriolar function in ageing. We first confirmed that in young (6-month-old) mice, FMD of mesenteric resistance arteries was reduced in Esr1−/− (lacking ERα) and C451A-ERα (lacking membrane ERα). In old (24-month-old) mice, FMD was reduced in WT mice compared to young mice, whereas it was not further decreased in Esr1−/− and C451A-ERα mice. Markers of oxidative stress were similarly increased in old WT and C451A-ERα mice. Reduction in oxidative stress with superoxide dismutase plus catalase or Mito-tempo, which reduces mitochondrial superoxide restored FMD to a normal control level in young C451A-ERα mice as well as in old WT mice and old C451A-ERα mice. Estradiol-mediated dilation was absent in old WT mice. We conclude that oxidative stress is a key event in the decline of FMD, and that an early defect in membrane ERα recapitulates phenotypically and functionally ageing of these resistance arteries. The loss of this function could take part in vascular ageing.

Estrogen receptors were initially identified in the uterus, and later throughout the brain and body as intracellular, ligand-regulated transcription factors that affect genomic change upon ligand binding. However, rapid estrogen receptor signaling initiated outside of the nucleus was also known to occur via mechanisms that were less clear. Recent studies indicate that these traditional receptors, estrogen receptor-α and estrogen receptor-β, can also be trafficked to act at the surface membrane. Signaling cascades from these membrane-bound estrogen receptors (mERs) not only rapidly effect cellular excitability, but can and do ultimately affect gene expression, as seen through the phosphorylation of CREB. A principal mechanism of neuronal mER action is through glutamate-independent transactivation of metabotropic glutamate receptors (mGluRs), which elicits multiple signaling outcomes. The interaction of mERs with mGluRs has been shown to be important in many diverse functions in females, including, but not limited to, reproduction and motivation. Here we review membrane-initiated estrogen receptor signaling in females, with a focus on the interactions between these mERs and mGluRs.

17 beta-estradiol protects pancreatic beta-cells from apoptosis via the estrogen receptors ER alpha, ER beta and GPER. Conversely, the endocrine disruptor bisphenol-A (BPA), which exerts multiple effects in this cell type via the same estrogen receptors, increased basal apoptosis. The molecular-initiated events that trigger these opposite actions have yet to be identified. We demonstrated that combined genetic downregulation and pharmacological blockade of each estrogen receptor increased apoptosis to a different extent. The increase in apoptosis induced by BPA was diminished by the pharmacological blockade or the genetic silencing of GPER, and it was partially reproduced by the GPER agonist G1. BPA and G1-induced apoptosis were abolished upon pharmacological inhibition, silencing of ER alpha and ER beta, or in dispersed islet cells from ER beta knockout (BERKO) mice. However, the ER alpha and ER beta agonists PPT and DPN, respectively, had no effect on beta cell viability. To exert their biological actions, ER alpha and ER beta form homodimers and heterodimers. Molecular dynamics simulations together with proximity ligand assays and coimmunoprecipitation experiments indicated that the interaction of BPA with ER alpha and ER beta as well as GPER activation by G1 decreased ER alpha beta heterodimers. We propose that ER alpha beta heterodimers play an antiapoptotic role in beta cells and that BPA- and G1-induced decreases in ER alpha beta heterodimers lead to beta cell apoptosis. Unveiling how different estrogenic chemicals affect the crosstalk among estrogen receptors should help to identify diabetogenic endocrine disruptors.

Sophora japonica is a source of several flavonol, flavone and isoflavone glycosides that are reported to positively affect menopausal symptoms including osteoporotic complications. In the present study fructus Sophorae extract (FSE) was administered orally for three months at a dose of 200 mg kg–1 in ovariectomized (OVX) New Zealand rabbits. 3D computed tomography scans and histopathological images revealed microstructural disturbances in the bones of the castrated animals. FSE recovered most of the affected parameters in bones in a manner similar to zoledronic acid (ZA) used as a positive control. The aglycones of the main active compounds of FSE, daidzin, and genistin, were docked into the alpha and beta estrogen receptors and stable complexes were found. The findings of this study provide an insight into the effects of FSE on bone tissue loss and suggest that it could be further developed as a potential candidate for the prevention of postmenopausal osteoporotic complications.

Lacrimal gland dysfunction causes dry eye disease (DED) due to decreased tear production. Aqueous-deficient DED is more prevalent in women, suggesting that sexual dimorphism of the human lacrimal gland could be a potential cause. Sex steroid hormones are a key factor in the development of sexual dimorphism. This study aimed to quantify estrogen receptor (ER) and androgen receptor (AR) expression in the human lacrimal gland and compare it between sexes. RNA was isolated from 35 human lacrimal gland tissue samples collected from 19 cornea donors. AR, ERα, and ERβ mRNA was identified in all samples, and their expression was quantified using qPCR. Immunohistochemical staining was performed on selected samples to evaluate protein expression of the receptors. ERα mRNA expression was significantly higher than the expression of AR and ERβ. No difference in sex steroid hormone (SSH) receptor mRNA expression was observed between sexes, and no correlation was observed with age. If ERα protein expression is found to be concordant with mRNA expression, it should be investigated further as a potential target for hormone therapy of DED. Further research is needed to elucidate the role of sex steroid hormone receptors in sex-related differences of lacrimal gland structure and disease.

Neuroinflammation is a hallmark of traumatic brain injury (TBI)’s acute and chronic phases. Despite the medical and scientific advances in recent years, there is still no effective treatment that mitigates the oxidative and inflammatory damage that affects neurons and glial cells. Therefore, searching for compounds with a broader spectrum of action that can regulate various inflammatory signaling pathways is of clinical interest. In this study, we determined not only the in vitro antioxidant capacity of apple pomace phenolics, namely, phlorizin and its metabolite, phloretin, but we also hypothesize that the use of these bioactive molecules may have potential use in TBI. We explored the antioxidant effects of both compounds in vitro (DPPH, iron-reducing capacity (IRC), and Folin–Ciocalteu reducing capacity (FCRC)), and using network pharmacology, we investigated the proteins involved in their protective effects in TBI. Our results showed that the antioxidant properties of phloretin were superior to those of phlorizin in the DPPH (12.95 vs. 3.52 mg ascorbic acid equivalent (AAE)/L), FCRC (86.73 vs. 73.69 mg gallic acid equivalent (GAE)/L), and iron-reducing capacity (1.15 vs. 0.88 mg GAE/L) assays. Next, we examined the molecular signature of both compounds and found 11 proteins in common to be regulated by them and involved in TBI. Meta-analysis and GO functional enrichment demonstrated their implication in matrix metalloproteinases, p53 signaling, and cell secretion/transport. Using MCODE and Pearson’s correlation analysis, a subcluster was generated. We identified ESR1 (estrogen receptor alpha) as a critical cellular hub being regulated by both compounds and with potential therapeutic use in TBI. In conclusion, our study suggests that because of their vast antioxidant effects, probably acting on estrogen receptors, phloretin and phlorizin may be repurposed for TBI treatment due to their ease of obtaining and low cost.

It is known that estrogen stimulates growth and inhibits apoptosis through estrogen receptor(ER)-mediated mechanisms in many cancer cell types. Interestingly, there is strong evidence that estrogens can also induce apoptosis, activating different ER isoforms in cancer cells. It has been observed that E2/ERα complex activates multiple pathways involved in both cell cycle progression and apoptotic cascade prevention, while E2/ERβ complex in many cases directs the cells to apoptosis. However, the exact mechanism of estrogen-induced tumor regression is not completely known. Nevertheless, ERs expression levels of specific splice variants and their cellular localization differentially affect outcome of estrogen-dependent tumors. The goal of this review is to provide a general overview of current knowledge on ERs-mediated apoptosis that occurs in main hormone dependent-cancers. Understanding the molecular mechanisms underlying the induction of ER-mediated cell death will be useful for the development of specific ligands capable of triggering apoptosis to counteract estrogen-dependent tumor growth.

Triclocarban is a highly effective and broadly used antimicrobial agent. Humans are continually exposed to triclocarban, but the safety of prenatal exposure to triclocarban in the context of neurodevelopment remains unknown. In this study, we demonstrated for the first time that mice that had been prenatally exposed to environmentally relevant doses of triclocarban had impaired estrogen receptor 1 (ESR1) signaling in the brain. These mice displayed decreased mRNA and protein expression levels of ESR1 as well as hypermethylation of the Esr1 gene in the cerebral cortex. Prenatal exposure to triclocarban also diminished the mRNA expression of Esr2, Gper1, Ahr, Arnt, Cyp19a1, Cyp1a1, and Atg7, and the protein levels of CAR, ARNT, and MAP1LC3AB in female brains and decreased the protein levels of BCL2, ARNT, and MAP1LC3AB in male brains. In addition, exposure to triclocarban caused sex-specific alterations in the methylation levels of global DNA and estrogen receptor genes. Microarray and enrichment analyses showed that, in males, triclocarban dysregulated mainly neurogenesis-related genes, whereas, in females, the compound dysregulated mainly neurotransmitter-related genes. In conclusion, our data identified triclocarban as a neurodevelopmental risk factor that particularly targets ESR1, affects apoptosis and autophagy, and in sex-specific ways disrupts the epigenetic status of brain tissue and dysregulates the postnatal expression of neurogenesis- and neurotransmitter-related genes.

In this study, we aimed to assess the effect of diet ZEA on serum hormones, the location and expression of estrogen receptor ERα/β and progesterone receptor (PR) of the uterus in weaned piglets and to reveal the mechanism underneath. A total of 40 healthy weaned gilts were randomly allocated to basal diet supplemented with 0 (Control), 0.5 (ZEA0.5), 1.0 (ZEA1.0) and 1.5 (ZEA1.5) mg ZEA/kg and fed individually for 35 days. Meanwhile, the porcine endometrial epithelial cells (PECs) were incubated for 24 h with ZEA at 0 (Control), 5 (ZEA5), 20 (ZEA20) and 80 (ZEA80) μmol/L, respectively. The results showed that nutrient apparent digestibility (CP and GE), nutrient apparent availability (ME/GE, BV and NPU), the uterine immunoreactive integrated optic density (IOD), relative mRNA and protein expression of ER-α, ER-β and PR and the relative mRNA and protein expression of ER-α and ER-β in PECs all increased linearly (p < 0.05) with ZEA. Collectively, ZEA can interfere with the secretion of some reproductive hormones in the serum and promote the expression of estrogen/progesterone receptors in the uterus and PECs. All these indicate that ZEA may promote the development of the uterus in weaned gilts through estrogen receptor pathway.

Background Chemotherapy is still the main first-line treatment for advanced metastatic gastric cancer, but it has the limitations of serious side effects and drug resistance. Conventional liposome has been substantially used as drug carriers, but they lack targeting character with lower drug bioavailability in tumor tissues. Based on the above problems, a novel estrogen-targeted PEGylated liposome loaded with oxaliplatin (ES-SSL-OXA) was prepared to further improve the metabolic behavior, the safety profile, and the anti-tumor efficacy of oxaliplatin. Methods Four kinds of oxaliplatin (OXA) liposomes were prepared by film hydration method. The obtained formulations were characterized in terms of entrapment efficiency (EE), particle size, and so on by HPLC and DLS (dynamic light scanning). The morphology of ES-SSL-OXA was detected by transmission electron microscope (TEM). The in vitro and in vivo targeting effect of ES-SSL-OXA was verified by fluorescence microscopy and in vivo imaging system in gastric cancer cells (SGC-7901) and tumor-bearing athymic mice. The in vitro and in vivo antitumor efficacies of ES-SSL-OXA were investigated on SGC-7901 cells and athymic tumor-bearing mice. Pharmacokinetic, biodistribution, and acute toxicity tests of ES-SSL-OXA were performed on ICR mice. Results The ES-SSL-OXA exhibited an average particle size of about 153.37 nm with an encapsulation efficiency of 46.20% and low leakage rates at 4°C and 25°C. In vivo and in vitro targeting study confirmed that ES-SSL-OXA could effectively target the tumor site. The antitumor activity demonstrated the strongest inhibition in tumor growth of ES-SSL-OXA. Pharmacokinetics and acute toxicity study showed that ES-SSL-OXA could significantly improve the metabolic behavior and toxicity profile of oxaliplatin. Conclusion In this study, a novel estrogen-targeted long-acting liposomal formulation of OXA was successfully prepared. ES fragment effectively targeted the delivery system to tumor tissues which highly express estrogen receptor, providing a promising therapeutic method for gastric cancer in clinic., Graphical Abstract

Background Clinical options for lung squamous carcinoma (LUSC) are still quite limited. Carcinogenesis is an exceedingly complicated process involving multi-level dysregulations. Therefore, only looking into one layer of genomic dysregulation is far from sufficient. Methods We identified differentially expressed genes with consistent upstream genetic or epigenetic dysregulations in LUSC. Random walk was adopted to identify genes significantly affected by upstream abnormalities. Expression differentiation and survival analysis were conducted for these significant genes, respectively. Prognostic power of selected gene was also tested in 102 male LUSC samples through immunohistochemistry assay. Results Twelve genes were successfully retrieved from biological network, including ERα (ESRS1), EGFR, AR, ATXN1, MAPK3, PRKACA, PRKCA, SMAD4, TP53, TRAF2, UBQLN4 and YWHAG, which were closely related to sex hormone signaling pathway. Survival analysis in public datasets indicated ERα was significantly associated with a poor overall survival (OS) in male LUSC. The result of our immunohistochemistry assay also demonstrated this correlation using R0 resected tumors (n = 102, HR: 2.152, 95% CI: 1.089–4.255, p = 0.024). Although disease-free survival (DFS) difference was non-significant (n = 102, p = 0.12), the tendency of distinction was straight-forward. Cox analysis indicated ERα was the only independent prognostic factor for male patients’ OS after R0 resection (HR = 2.152, p = 0.037). Conclusion ERα was significantly related to a poor prognosis in LUSC, especially for male patients after radical surgery, confirmed by our immunohistochemistry data.

Author(s): Aoki, Rhonda-Lee F; Uong, Stephen P; Gomez, Scarlett Lin; Alexeeff, Stacey E; Caan, Bette J; Kushi, Lawrence H; Torres, Jacqueline M; Guan, Alice; Canchola, Alison J; Morey, Brittany N; Lin, Katherine; Kroenke, Candyce H | Abstract: BackgroundLow socioeconomic status (SES) has been associated with a higher risk of aggressive breast cancer (BC) subtypes, but few studies have examined the independent effects of both neighborhood-level socioeconomic status (nSES) and individual-level SES measures.MethodsThis study included 5547 women from the Pathways and Life After Cancer Epidemiology cohorts who were diagnosed with invasive BC. Generalized estimating equation models were used to examine associations of nSES (a composite score based on income, poverty, education, occupation, employment, rent, and house value) and individual-level SES (income and education) with BC subtypes: luminal B (LumB), Her2-enriched (Her2-e), and triple-negative breast cancer (TNBC) relative to luminal A (LumA). Models controlled for age, race, nativity, stage, days from diagnosis to survey, and study cohort and simultaneously for nSES and individual-level SES.ResultsIn fully adjusted models, low nSES was significantly associated with the LumB (odds ratio for quartile 1 vs quartile 4 [ORQ1vQ4 ], 1.31; 95% confidence interval [CI], 1.11-1.54; P for trendn=n.005) and TNBC subtypes (ORQ1vQ4 , 1.32; 95% CI, 1.02-1.71; P for trendn=n.037) relative to LumA. Conversely, individual education was significantly associated with only the Her2-e subtype (odds ratio for high school degree or less vs postgraduate, 1.68; 95% CI, 1.03-2.75; P for trendn=n.030) relative to LumA. Individual income was not significantly associated with any BC subtype.ConclusionsnSES and individual-level SES are independently associated with different BC subtypes; specifically, low nSES and individual-level education are independent predictors of more aggressive BC subtypes relative to LumA.

Estradiol exerts neuroprotective actions that are mediated by the regulation of a variety of signaling pathways and homeostatic molecules. Among these is neuroglobin, which is upregulated by estradiol and translocated to the mitochondria to sustain neuronal and glial cell adaptation to injury. In this paper, we will discuss the role of neuroglobin in the neuroprotective mechanisms elicited by estradiol acting on neurons, astrocytes and microglia. We will also consider the role of neuroglobin in the neuroprotective actions of clinically relevant synthetic steroids, such as tibolone. Finally, the possible contribution of the estrogenic regulation of neuroglobin to the generation of sex differences in brain pathology and the potential application of neuroglobin as therapy against neurological diseases will be examined., This research received no external funding.

G protein-coupled estrogen receptor 1 (GPER1) is a seven-transmembrane receptor that mediates rapid cell signaling events stimulated by estrogens. While the role that GPER1 has in the modulation of E2-responsive tissues and cancers is well documented, the molecular mechanisms that regulate GPER1 expression are currently not well defined. The recently identified GPER1-dependent mechanism of tamoxifen action in breast cancer cells underscores the importance of identifying mechanisms that regulate GPER1 expression in this cell type. We hypothesized that GPER1 expression in breast cancer cells is sensitive to [D-glucose] and provide data showing increased GPER1 expression when cells were cultured in low [D-glucose]. To determine if the observed accumulation of GPER1 was AMP-activated protein kinase (AMPK)-dependent, small molecule stimulation or inhibition of AMPK was performed. AMPK inhibition decreased GPER1 accumulation in cells grown in low [D-glucose] while the AMPK-activating compound AICAR increased GPER1 accumulation in cells grown in high [D-glucose] media. Additionally, transfection of cells with a plasmid expressing constitutively active AMPK resulted in increased GPER1 accumulation. To determine if [D-glucose]-dependent GPER1 accumulation altered breast cancer cell response to tamoxifen, cells grown in the presence of decreasing [D-glucose] were co-treated with tamoxifen and IGFBP-1 transcription was measured. The results from these experiments reveal that D-glucose deprivation increased GPER1-mediated and tamoxifen-induced IGFBP-1 transcription suggesting that [D-glucose] may increase breast cancer cell sensitivity to tamoxifen. Taken together, these results identify a previously unknown mechanism that regulates GPER1 expression that modifies one aspect tamoxifen action in breast cancer cells.

Estrogens receptors (ER) are involved in several sociosexual behaviors and fear responses. In particular, the ERα is important for sexual behaviors, whereas ERβ modulates anxiolytic responses. Using shRNA directed either against the ERα or the ERβ RNAs (or containing luciferase control) encoded within an adeno-associated viral vector, we silenced these receptors in the ventromedial nucleus of the hypothalamus (VMN) and the central amygdala (CeA). We exposed ovariectomized female rats, sequentially treated with estradiol benzoate and progesterone, to five stimuli, previously reported to elicit positive and negative affect. The subjects were housed in groups of 4 females and 3 males in a seminatural environment for several days before hormone treatment. We analyzed the frequency of a large number of behavior patterns. In addition, we performed analyses of co-occurrence in order to detect changes in the structure of behavior after infusion of the vectors. Silencing the ERα in the VMN disrupted lordosis and showed some anxiolytic properties in aversive situations, whereas silencing of the ERβ in this structure had no effect. This was also the case after silencing the ERα in the CeA. Silencing of the ERβ in this structure increased risk assessment, an expression of anxiety, and increased olfactory exploration of the environment. We hypothesize that the ERβ in the CeA has an important role in the well-established anxiolytic effects of estrogens, and that it may modulate arousal level. Furthermore, it seems that the ERα in the VMN is anxiogenic in aversive or threatening situations, in agreement with other studies.

Background. Assessment of hormone receptor status plays a crucial role in treatment of patients with breast cancer. currently, clinicians are limited to determining the expression status of estrogen receptor (ER), progesterone receptor (pR) and HER2 only in primary breast cancer tissues, even in the presence of regional metastases.The purpose of the study was to review available data on heterogeneity of ER, pR and HER2/neu expressions in primary breast cancer and regional metastases.Material and methods. We analyzed publications available from pubmed, medline etc. using the keywords «discordance», «breast cancer», «locally advanced», «regional lymph nodes», «ER», «pR», and «HER2».Results. The clinical and prognostic role in assessing the heterogeneity of the receptor status of primary tumors and synchronous regional metastases, as well as the effect of detected discordance on treatment tactics was assessed.Conclusion. Data on the frequency of discordance in hormone receptor status between primary and metastatic breast cancer tumors and its effect on the further prognosis in breast cancer are still contradictory. However, the fact of the presence of such heterogeneity suggests that some patients with affected lymph nodes will have significant benefits from determining the status of steroid hormones and HER2 not only in the primary tumor, but also in the lymph nodes, since it will open up new opportunities for subsequent targeted therapy.

The leading role of ovarian steroid hormones in the pathogenesis of uterine fibroids is confirmed by epidemiological, clinical and experimental studies. The new approaches to the treatment of this disease may be developed on the basis of the biological and genetic mechanisms underlying the occurrence and development of leiomyomas. The use of ulipristal acetate in patients with uterine leiomyoma may be a promising method for preparing them to the surgical procedures, but also for avoiding surgical treatment and related hypoestrogenic conditions, which results in the improvement of the women’s quality of life.

Purpose The purpose of this study was to investigate the non-inferiority of omitting radiotherapy (RT) after breast-conserving surgery (BCS) for hormone receptor (HR)‒positive T1N0 breast cancer in elderly women. Materials and methods From 2004 to 2014, HR-positive T1N0 breast cancer patients aged 50 years or older and receiving BCS were retrieved from the Surveillance, Epidemiology, and End results 18 database. After propensity score matching between the no-RT and RT groups, univariate and multivariate analyses were performed. Identified prognostic factors were used to stratify the risk groups. In each risk group, 10-year cancer-specific survival (CSS) rates were compared between the no-RT and RT groups. Results After propensity score matching, the numbers of patients in the no-RT and RT groups were both 18,586. For patients who satisfied both a tumor size of 1-10 mm and a tumor grade of 1-2, omitting RT did not decrease the CSS rate at any age group, ranging from ≥ 50 to ≥ 85 years; for patients aged ≥ 50 years, the 10-year CSS rates in the no-RT and RT groups were 97.2% and 96.8%, respectively (adjusted hazard ratio, 0.862; p=0.312). However, for patients with a tumor size of 11-20 mm or tumor grade of 3-4, RT significantly increased the CSS rate irrespective of age. Conclusion RT after BCS for HR-positive T1N0 breast cancer in elderly women might be omitted without causing a decrease in the CSS rate, but only in patients who satisfy both a small tumor size (≤ 10 mm) and low tumor grade (1-2).

Among Chinese soft-shelled turtles, Pelodiscus sinensis, males have a richer nutritional value and higher market price than females. All-male offspring were obtained by 17β-estradiol (E2). However, the molecular mechanisms of E2 inducing sexual reversal remain unclear. In this study, we cloned estrogen nuclear receptors (ERs) from P. sinensis and investigated their expression profiles. We examined the responses of ERα and ERβ after treatment with different concentrations of 1.0, 5.0, and 10 mg/mL E2. ERs showed abundant expressions in the adult gonad, ERα for ovary, and ERβ for testis. E2 can up-regulate the expression of ERα, which showed a remarkable increase while the promotion of ERβ was unobvious. They reached a high level at stage 17 after the treatment of E2, genes of the female-related genes Rspo1, Wnt4, β-catenin, Foxl2, Cyp19a1, and Sox3 exhibited a significant raise at stage 17 with the increase in the concentration of E2 while the male-related genes Sox9, Dmrt1, and Amh were significantly inhibited. Our study cloned the full length of ERs and analyzed their structures and expressions, laying a foundation for the further study of the effect of estrogen on sex determination.

Pulmonary hypertension (PH) includes multiple diseases that share as common characteristic an elevated pulmonary artery pressure and right ventricular involvement. Sex differences are observed in practically all causes of PH. The most studied type is pulmonary arterial hypertension (PAH) which presents a gender bias regarding its prevalence, prognosis, and response to treatment. Although this disease is more frequent in women, once affected they present a better prognosis compared to men. Even if estrogens seem to be the key to understand these differences, animal models have shown contradictory results leading to the birth of the estrogen paradox. In this review we will summarize the evidence regarding sex differences in experimental animal models and, very specially, in patients suffering from PAH or PH from other etiologies.

PurposeThe inhibition of estrogen receptor alpha (ERα) or the activation of ERβ can inhibit papillary thyroid cancer (PTC), but the precise mechanism is not known. We aimed to explore the role of ERα and ERβ on the production of endogenous peroxisome proliferator-activated receptor gamma (PPARγ) ligands in PTC.Methods2 PTC cell lines, 32 pairs of PTC tissues and matched normal thyroid tissues were used in this study. The levels of endogenous PPARγ ligands 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE), 13-S-hydroxyoctadecadienoic acid (13(S)-HODE), and15-deoxy-Δ12,14-prostaglandin J2 (PGJ2) were measured by ELISA.ResultsThe levels of PGJ2 and 15(S)-HETE were significantly reduced in PTC, but 13(S)-HODE was not changed. Activation of ERα or inhibition of ERβ significantly downregulated the production of PGJ2, 15(S)-HETE and 13(S)-HODE, whereas inhibition of ERα or activation of ERβ markedly upregulated the production of these three ligands. Application of endogenous PPARγ ligands inhibited growth, induced apoptosis of cancer cells, and promoted the efficacy of chemotherapy.ConclusionThe levels of endogenous PPARγ ligands PGJ2 and 15(S)-HETE are significantly decreased in PTC. The inhibition of ERα or activation of ERβ can inhibit PTC by stimulating the production of endogenous PPARγ ligands to induce apoptosis in cancer cells.

Progesterone (Pg) and estrogen (E) receptors (PgRs and ERs) are expressed in normal and neoplastic adrenal cortex, but their role is not fully understood. In literature, Pg demonstrated cytotoxic activity on AdrenoCortical Carcinoma (ACC) cells, while tamoxifen is cytotoxic in NCI-H295R cells. Here, we demonstrated that in ACC cell models, ERs were expressed in NCI-H295R cells with a prevalence of ER-β over the ER-α.Metastasis-derived MUC-1 and ACC115m cells displayed a very weak ER-α/β signal, while PgR cells were expressed, although at low level. Accordingly, these latter were resistant to the SERM tamoxifen and scarcely sensitive to Pg, as we observed a lower potency compared to NCI-H295R cells in cytotoxicity (IC50: MUC-1 cells: 67.58 µM (95%CI: 63.22–73.04), ACC115m cells: 51.76 µM (95%CI: 46.45–57.67) and cell proliferation rate. Exposure of NCI-H295R cells to tamoxifen induced cytotoxicity (IC50: 5.43 µM (95%CI: 5.18–5.69 µM) mainly involving ER-β, as their nuclear localization increased after tamoxifen: Δ A.U. treated vs untreated: 12 h: +27.04% (p < 0.01); 24 h: +36.46% (p < 0.0001). This effect involved the SF-1 protein reduction: Pg: −36.34 ± 9.26%; tamoxifen: −46.25 ± 15.68% (p < 0.01). Finally, in a cohort of 36 ACC samples, immunohistochemistry showed undetectable/low level of ERs, while PgR demonstrated a higher expression. In conclusion, ACC experimental cell models expressed PgR and low levels of ER in line with data obtained in patient tissues, thus limiting the possibility of a clinical approach targeting ER. Interestingly, Pg exerted cytotoxicity also in metastatic ACC cells, although with low potency.

The main estrogens: estradiol, estrone, and their acyl-esters have been studied essentially related to their classical estrogenic and pharmacologic functions. However, their main effect in the body is probably the sustained control of core energy metabolism. Estrogen nuclear and membrane receptors show an extraordinary flexibility in the modulation of metabolic responses, and largely explain gender and age differences in energy metabolism: part of these mechanisms is already sufficiently known to justify both. With regard to energy, the estrogen molecular species act essentially through four key functions: (1) Facilitation of insulin secretion and control of glucose availability; (2) Modulation of energy partition, favoring the use of lipid as the main energy substrate when more available than carbohydrates; (3) Functional protection through antioxidant mechanisms; and (4) Central effects (largely through neural modulation) on whole body energy management. Analyzing the different actions of estrone, estradiol and their acyl esters, a tentative classification based on structure/effects has been postulated. Either separately or as a group, estrogens provide a comprehensive explanation that not all their quite diverse actions are related solely to specific molecules. As a group, they constitute a powerful synergic action complex. In consequence, estrogens may be considered wardens of energy homeostasis.

Estradiol exerts neuroprotective actions that are mediated by the regulation of a variety of signaling pathways and homeostatic molecules. Among these is neuroglobin, which is upregulated by estradiol and translocated to the mitochondria to sustain neuronal and glial cell adaptation to injury. In this paper, we will discuss the role of neuroglobin in the neuroprotective mechanisms elicited by estradiol acting on neurons, astrocytes and microglia. We will also consider the role of neuroglobin in the neuroprotective actions of clinically relevant synthetic steroids, such as tibolone. Finally, the possible contribution of the estrogenic regulation of neuroglobin to the generation of sex differences in brain pathology and the potential application of neuroglobin as therapy against neurological diseases will be examined. This research received no external funding.

Introduction: Rapid histopathological processing of neoplastic biopsies is crucial for initiating early therapy in patients. Microwave processing shortens the time to diagnosis and is less labour intensive. Aim: To compare the quality of immunohistochemical staining of Estrogen Receptors (ER) and Progesterone Receptors (PR) on paired breast samples using microwave processing versus conventional processing. Materials and Methods: A cross-sectional study was conducted at a tertiary care hospital in Kerala, India, from February 2014 to September 2015. A total of 44 paired samples from breast carcinoma patients were taken. Baseline characteristics of the patients such as age and type of carcinoma were noted. Haematoxylin and Eosin (H&E) stain was used. One slide of the pair was processed conventionally and the other using a microwave. The stained slides were observed by three pathologists. The validity of ER and PR receptor status was evaluated with sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV). Kappa statistics and Spearman’s correlation test was used to denote the agreement between them. Results: The mean age was 51.32±11.16 years. There was agreement (Cohen k=0.902) between the microwave processed and conventionally processed paired breast samples for ER. The sensitivity and specificity of microwave processing in ER evaluation was 87.5% and 100% while that of PR evaluation was 92.9% and 100% respectively. The PPV was 100% and NPV was 93.3% for ER evaluation by microwave processing. Conclusion: Microwave aided tissue processing had significant advantages over conventional methods for providing a rapid diagnosis, being less laborious and had effective staining, which makes it a better choice.

Bisphenol-S (BPS) and Bisphenol-F (BPF) are current Bisphenol-A (BPA) substitutes. Here we used pancreatic beta-cells from wild type (WT) and estrogen receptor beta (ER beta) knockout (BERKO) mice to investigate the effects of BPS and BPF on insulin secretion, and the expression and activity of ion channels involved in beta-cell function. BPS or BPF rapidly increased insulin release and diminished ATP-sensitive K+ (K-ATP) channel activity. Similarly, 48 h treatment with BPS or BPF enhanced insulin release and decreased the expression of several ion channel subunits in beta-cells from WT mice, yet no effects were observed in cells from BERKO mice. PaPE-1, a ligand designed to preferentially trigger extranuclear-initiated ER pathways, mimicked the effects of bisphenols, suggesting the involvement of extranuclear-initiated ER beta pathways. Molecular dynamics simulations indicated differences in ER beta ligand-binding domain dimer stabilization and solvation free energy among different bisphenols and PaPE-1. Our data suggest a mode of action involving ER beta whose activation alters three key cellular events in beta-cell, namely ion channel expression and activity, and insulin release. These results may help to improve the hazard identification of bisphenols. (C) 2020 Elsevier Ltd. All rights reserved.

Wound healing is a dynamic biological process achieved through four sequential, overlapping phases; hemostasis, inflammation, tissue proliferation and remodeling. For effective wound healing, all four phases must occur in the appropriate order and time frame. It is well accepted that the wound healing process becomes disrupted in the elderly, increasing the propensity of non-healing wound states that can lead to substantial patient morbidity and an enormous financial burden on healthcare systems. Estrogen deprivation in the elderly has been identified as the key driver of age-related delayed wound healing in both genders, with topical and systemic estrogen replacement reversing the detrimental effects of aging on wound repair. Evidence suggests estrogen deprivation may contribute to the development of chronic wound healing states in the elderly but research in this area is somewhat limited, warranting further investigations. Moreover, although the beneficial effects of estrogen on cutaneous healing have been widely explored, the development of estrogen-based treatments to enhance wound repair in the elderly have yet to be widely exploited. This review explores the critical role of estrogen in reversing age-related impaired healing and evaluates the prospect of developing more focused novel therapeutic strategies that enhance wound repair in the elderly via activation of specific estrogen signaling pathways in regenerating tissues, whilst leaving non-target tissues largely unaffected., EXCLI Journal; 20:Doc99; ISSN 1611-2156

Background: Scoparia dulcis Linn. is reported to be used by women of Assam and Arunachal Pradesh in northeast India for treating menstrual disorders. Scoparia dulcis contains compounds that bind with estrogen receptors (ERα and ERβ) evidenced by increased PCNA in endometrial epithelium. Methods: Crude extract was orally administered at the dose of 500 mg/kg body weight/day to the female mice (60–70 days old) in five different groups. Each group containing six females included: (I) cyclic control, (II) cyclic extract treated, (III) Ovariectomized (OVX)-vehicle treated (Control), (IV) OVX-E2 treated (V) OVX- extract treated. Extract was administered for eight days to the cyclic groups and three days to the OVX groups. PCNA was detected immunohistochemically in uterine tissues and signals were analyzed by Image J software (NIH, USA). Compounds were separated by GC-MS and identified using NIST. In silico molecular docking studies was performed with human estrogen receptors (ERα and ERβ). Molecular dynamics (MD) simulations of the best interacting compound was done using gromacs. Results: The results showed cell proliferation in the uterine endometrium evidenced by PCNA. Two phytocompounds, Octadecanoic acid and methyl stearate showed binding affinity with ERα and ERβ. Conclusion: Scoparia dulcis contains compounds having binding affinity with ERα and ERβ. The present study is the first report on compounds from Scoparia dulcis showing binding affinity with human estrogen receptors which may have biological effect on female reproduction.

There are gender differences between men and women in many physiological functions and diseases, which indicates that female sex hormones may be important. Traditionally, estrogen exerts its biological activities by activating two classical nuclear estrogen receptors, ESR1 and ESR2. However, the roles of estrogen in the regulation of physiological functions and the pathogenesis of diseases become more complicated with the identification of the G protein-coupled estrogen receptor (GPER1). Although many GPER1-specific ligands have been developed, the therapeutic mechanisms of exclusively targeting GPER1 are not yet well understood. Translational applications and clinical trial efforts for the identified GPER1 ligands have been focused primarily on the reproductive, cardiovascular, nervous, endocrine, and immune systems. More recently, research found that GPER1 may play an important role in regulating the digestive system. Cholesterol gallstone disease, a major biliary disease, has a higher prevalence in women than in men worldwide. Emerging evidence implies that GPER1 could play an important role, independent of the classical ESR1, in the pathophysiology of cholesterol gallstones in women. This review discusses the complex signaling pathways of three estrogen receptors, highlights the development of GPER1-specific ligands, and summarizes the latest advances in the role of GPER1 in the pathogenesis of gallstone formation.

The peri-menopause or menopausal transition—the time period that surrounds the final years of a woman’s reproductive life—is associated with profound reproductive and hormonal changes in a woman’s body and exponentially increases a woman’s risk of cerebral ischemia and Alzheimer’s disease. Although our understanding of the exact timeline or definition of peri-menopause is limited, it is clear that there are two stages to the peri-menopause. These are the early menopausal transition, where menstrual cycles are mostly regular, with relatively few interruptions, and the late transition, where amenorrhea becomes more prolonged and lasts for at least 60 days, up to the final menstrual period. Emerging evidence is showing that peri-menopause is pro-inflammatory and disrupts estrogen-regulated neurological systems. Estrogen is a master regulator that functions through a network of estrogen receptors subtypes alpha (ER-α) and beta (ER-β). Estrogen receptor-beta has been shown to regulate a key component of the innate immune response known as the inflammasome, and it also is involved in regulation of neuronal mitochondrial function. This review will present an overview of the menopausal transition as an inflammatory event, with associated systemic and central nervous system inflammation, plus regulation of the innate immune response by ER-β-mediated mechanisms.

The current therapeutic approach for the treatment of hormone dependent breast cancer includes interference with estrogen receptors via either selective modulators or estrogens deprivation, by preventing their biosynthesis with aromatase inhibitors. Severe side effects and acquired resistance are drawbacks of both drug classes, and the efforts to overcome these issues still allow for research in this field to be animated. This review reports on recent findings that have opened new avenues for reconsidering the role of aromatase enzymes (and estrogen receptors) leading to the possibility of looking at well-known targets in a new perspective.

HOXA5 is a homeobox-containing gene associated with the development of the lung, gastrointestinal tract, and vertebrae. Here, we investigate potential roles and the gene regulatory mechanism in HOXA5 in breast cancer cells. Our studies demonstrate that HOXA5 expression is elevated in breast cancer tissues and in estrogen receptor (ER)-positive breast cancer cells. HOXA5 expression is critical for breast cancer cell viability. Biochemical studies show that estradiol (E2) regulates HOXA5 gene expression in cultured breast cancer cellsin vitro. HOXA5 expression is also upregulatedin vivoin the mammary tissues of ovariectomized female rats. E2-induced HOXA5 expression is coordinated by ERs. Knockdown of either ERα or ERβ downregulated E2-induced HOXA5 expression. Additionally, ER co-regulators, including CBP/p300 (histone acetylases) and MLL-histone methylases (MLL2, MLL3), histone acetylation-, and H3K4 trimethylation levels are enriched at the HOXA5 promoter in present E2. In summary, our studies demonstrate that HOXA5 is overexpressed in breast cancer and is transcriptionally regulated via estradiol in breast cancer cells.

Estrogen receptor α (ERα) functions as a ligand dependent transcription factor that directly binds specific estrogen responsive elements, thus regulating the transcription of estrogen sensitive genes. ERα has also been shown to be associated with the plasma membrane (membrane associated ERα, mERα), concentrated in lipid rafts, plasma membrane microdomains with a distinct lipid composition, where it transduces membrane-initiated estrogen-dependent activation of the mitogen-activated protein (MAP) kinase signaling pathway. Two isoforms of ERα have been described: the “traditional” ERα66 (66 kDa) and a lower molecular weight variant: the ERα46 (46 kDa). More recently, a novel ERα variant with a molecular mass of 36 kDa (ERα36) has been discovered. Notably, ERα36 has been found expressed in different human tumor cells, including both ER- positive and ER- negative breast cancer cells. Estrogen signaling at the cell membrane via ERα36 appears as capable of activating multiple pathways of importance for cancer aggressiveness and metastatic potential. The presence of serum autoantibodies reacting with mERα (anti-ERα Abs) in a large percentage of patients with breast cancer has recently been reported by our group. These anti-ERα Abs seem to act as estrogen agonists rapidly triggering MAP kinase pathway activation thus inducing tumor cell proliferation and overcoming cell resistance to anti-estrogen drug tamoxifen. In this review, we describe the involvement of ERα36 in different tumors. We also report the potential pathogenetic activity of anti-ERα Abs and their implication in drug resistance.

The mechanism of gender disparity in cutaneous melanoma incidence remains unclear. Steroid hormones including estrogens have long been implicated in the course of melanoma, but the conclusion is controversial. Estrogen receptors (ERs) and insulin-like growth factor 1 receptor (IGF1R) show extensive crosstalk in cancer development, but how the ER/IGF1R network impacts melanoma is currently unclear. Here we studied the melanoma associations of selected SNPs from the ER/IGF1R network. Part of the International Genes, Environment, and Melanoma (GEM) cohort was used as a discovery set, and the Gene Environment Association Studies Initiative (GENEVA) dataset served as a validation set. Based on the associations with other malignant disease conditions, thirteen single nucleotide polymorphism (SNP) variants in ESR1, ESR2, IGF1, and IGF1R were selected for candidate gene association analyses. The rs1520220 in IGF1 and rs2229765 in IGF1R variants were significantly associated with melanoma risk in the GEM dataset after Benjamini-Hochberg multiple comparison correction, although they were not validated in the GENEVA set. The discrepancy may be caused by the multiple melanoma characteristics in the GEM patients. Further analysis of gender disparity was carried out for IGF1 and IGF1R SNPs in the GEM dataset. The GG phenotype in IGF1 rs1520220 (recessive model) presented an increased risk of melanoma (OR = 8.11, 95% CI: 2.20, 52.5, p = 0.006) in men but a significant opposite effect in women (OR = 0.15, 95% CI: 0.018, 0.86, p = 0.045). The AA genotype in IGF1R rs2229765 (recessive model) showed a significant protective effect in men (OR = 0.24, 95% CI: 0.07, 0.64, p = 0.008) and no effect in women. Results from the current study are warranted for further validation.