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This study was conducted to provide evidence, using in vitro and in silico testing methods, regarding the adverse effects of iprodione, a representative dichlorophenyl dicarboxamide fungicide, on the endocrine system. In the present study, we used the HeLa9903 stably transfected transactivation assay (OECD TG 455), 22Rv1/MMTV_GR‒KO androgen receptor transcriptional activation assay (OECD TG 458), and toxicity prediction using VEGA QSAR. Our results showed that iprodione had no estrogen receptor antagonistic or androgen receptor agonistic effects; however, iprodione was determined to be an estrogen receptor agonist (log PC10 value is less than − 9) and androgen receptor antagonist (log IC30 value is − 4.58) without intrinsic toxicity against the human cell lines used in this study. VEGA QSAR was used to evaluate five substances with structures similar to that of iprodione. Among them, four chemicals were found to have positive androgen receptor and aromatase activities and have been observed to be developmental toxicants. These results suggest that iprodione regulates steroid hormone receptor interactions and is a potential reproductive toxicant. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder that primarily manifests itself by progressive memory loss and cognitive decline, thus significantly affecting memory functions and quality of life. In this review, we proceed from the understanding that the canonical amyloid‐β hypothesis, while significant, has faced setbacks, highlighting the need to adopt a broader perspective considering the intricate interplay of diverse pathological pathways for effective AD treatments. Sex differences in AD offer valuable insights into a better understanding of its pathophysiology. Fluctuation of the levels of ovarian sex hormones during perimenopause is associated with changes in glucose metabolism, as a possible window of opportunity to further understand the roles of sex steroid hormones and their associated receptors in the pathophysiology of AD. We review these dimensions, emphasizing the potential of estrogen receptors (ERs) to reveal mitochondrial functions in the search for further research and therapeutic strategies for AD pharmacotherapy. Understanding and addressing the intricate interactions of mitochondrial dysfunction and ERs potentially pave the way for more effective approaches to AD therapy. [ABSTRACT FROM AUTHOR]

Introduction: The prognostic significance of steroid receptors in bladder cancer remains controversial. This study was designed to determine the expression status of androgen receptor (AR), estrogen receptors (ERα and Erβ), and its potential role in predicting survival in patients with nonmuscle invasive bladder cancer (NMIBC). Methods: Sixty patients of NMIBC were screened and 57 (41 males and 16 females) were included in our study. The tissue microarray slides were evaluated by pathologists blinded to the clinical information. Association of distribution of steroid receptors with stage, grade, progression, and recurrence was seen. Results: The mean age of the population was 60.9 ± 9.3 years. Pathologically, majority of the patients were Ta (Ta: T1 stage 61.4% vs. 38.6%). Nine (15.8%) of the tumors stained positive for AR while one (1.8%) tumor stained positive for ERβ and 36 (63.2%) tumors stained for ERβ. A higher proportion of male NMIBC stained positive for AR (19.5% vs. 6.2%, P = 0.420) while ERβ positivity was higher in females (58.5% vs. and 75%,P = 0.247). AR-negative tumors showed higher recurrence (20/48%-42%) as compared to AR-positive tumors (2/9%-22%). ERβ-positive tumors showed higher recurrence (15/36%-42% vs. 7/21%-33%, P = 0.179). Progression free survival (PFS) was found to be significantly lower for ERβ-negative group (log-rank test P = 0.035). Conclusion: AR and ERβ positivity is found in NMIBC patients while ERα shows minimal staining in NMIBC patients. Although it did not reach a statistical significance, a higher proportion of AR-negative and ERβ-positive tumors recurred as compared to AR-positive and ERβ-negative patients. PFS was significantly lower in ERβ-negative group. Further exploratory studies on larger sample sizes are required to validate these findings in NMIBC patients. [ABSTRACT FROM AUTHOR]

The primary objective of this study was to forecast the core targets of formononetin through network pharmacology and to assess its potential anti-benign prostatic hyperplasia (BPH) effects using molecular docking and animal experimentation. Active compounds were filtered from the Swiss ADME database, while drug targets were extrapolated from TTD, GeneCards, and DrugBank databases. Targets overlapping between drug and disease were pinpointed, and PPI networks were subsequently developed. Both GO and KEGG enrichment analyses were executed. The AutodockVina software facilitated molecular docking to examine formononetin's estrogen activity. Mice diagnosed with BPH were grouped into control, TP, 2.5 mg/kg, 5 mg/kg, 10 mg/kg, 5 mg/kg + fulvestrant (20 mg/kg/week), and 10 mg/kg + fulvestrant (20 mg/kg/week) groups. Pathological deviations were discerned through H&E and Masson staining. Estrogen receptor and cell cycle gene expressions were quantified by qPCR. Our findings pinpointed 35 potential protein targets bridging formononetin and BPH, with ER-α, EGFR, ER-β, CYP19A1, AChE, and PPARA being the focal targets. The GO and KEGG enrichment analyses indicated that formononetin's targets predominantly revolved around cellular responses to estradiol stimulation, estrogen biosynthesis, steroid hormone receptor activity, steroid binding, and other related processes. These extended to pathways like steroid hormone biosynthesis and estrogen signaling. Molecular docking deduced a stronger affinity of formononetin for ER-β than for ER-α. Examination of pathological sections in formononetin-treated BPH mice demonstrated its significant inhibitory effect on BPH. Concurrently, the estrogen receptor inhibitor, fulvestrant, markedly dampened formononetin's therapeutic efficacy. qPCR assessments revealed that formononetin effectively curtailed ER-β expression within hyperplastic prostate tissues. Moreover, post-formononetin treatment led to a decline in expression levels of cell cycle-related genes, such as CDK1, cyclin A2, CDK2, and cyclin B1. However, this trend was notably stunted with the introduction of an estrogen receptor inhibitor. In summation, through the combined insights of network pharmacology and animal testing, we ascertained that formononetin mitigated cell cycle progression via the estrogen receptor when addressing prostatic hyperplasia. [ABSTRACT FROM AUTHOR]

Estrogen actions are mediated by both nuclear (n) and membrane (m) localized estrogen receptor 1 (ESR1). Male Esr1 knockout (Esr1 KO) mice lacking functional Esr1 are infertile, with reproductive tract abnormalities. Male mice expressing nESR1 but lacking mESR1 (nuclear-only estrogen receptor 1 mice) are progressively infertile due to testicular, rete testis, and efferent ductule abnormalities similar to Esr1 KO males, indicating a role for mESR1 in male reproduction. The H2NES mouse expresses only mESR1 but lacks nESR1. The goal of this study was to identify the functions of mESR1 alone in mice where nESR1 was absent. Breeding trials showed that H2NES males are fertile, with decreased litter numbers but normal pup numbers/litter. In contrast to Esr1 KO mice, H2NES testicular, and epididymal weights were not reduced, and seminiferous tubule abnormalities were less pronounced. However, Esr1 KO and H2NES males both had decreased sperm motility and a high incidence of abnormal sperm morphology. Seminiferous tubule and rete testis dilation and decreased efferent ductule epithelial height characteristic of Esr1 KO males were reduced in H2NES. Consistent with this, expression of genes involved in fluid transport and ion movement that were reduced in Esr1 KO (Aqp1 , Car2 , Car14 , Cftr) were partially or fully restored to wild-type levels in H2NES. In summary, in contrast to Esr1 KO males, H2NES males are fertile and have reduced phenotypic and functional abnormalities in the testis and efferent ductules. Thus, mESR1 alone, in the absence of nESR1, can partially regulate male reproductive tract structure and function, emphasizing its importance for overall estrogen action. [ABSTRACT FROM AUTHOR]

Silver nanoparticles (AgNPs) are a popular engineered nanomaterial widely used in industry. Despite the benefits they bring to society, AgNPs are not neutral to human health. The aim of this study was to evaluate the effects of a single intravenous dose (5 mg/kg body weight) of 20 nm AgNPs on steroid metabolism and redox balance in the testes of adult rats. The effects were evaluated 1 day or 28 days after intervention and compared with saline-treated animals. Decreased aromatase and estrogen receptor α levels (by 21% and 27%, respectively) were observed 1 day after AgNPs administration, while increased testosterone, increased dihydrotestosterone levels, higher androgen receptors and higher aromatase expression in Leydig cells (by 43%, 50%, 20% and 32%, respectively) as well as lower (by 35%) androgen receptor protein levels were observed 28 days after exposure to AgNPs compared to control groups. The AgNPs treatment resulted in decreased superoxide dismutase activity, decreased GSH/GSSG ratio, and increased glutathione reductase activity (by 23%, 63% and 28%, respectively) compared to control animals, irrespective of the time of measurement. Increased (by 28%) intratesticular lipid hydroperoxides level was observed 1 day after AgNPs exposure, while decreased (by 70%) GSH and increased (by 43%) 7-ketocholesterol levels were observed 28 days after treatment compared to control animals. Conclusions: AgNPs exposure caused redox imbalance in the gonads shortly after AgNPs administration, while a longer perspective AgNPs exposure was associated with impaired androgen metabolism, probably due to increased oxidative stress. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is one of the most commonly diagnosed malignancies in women and is also a leading cause of cancer related death. Estrogens play crucial roles in the development and progression of breast cancer, and estrogen signaling is generally mediated by estrogen receptors. Steroid receptor co-activator protein family members are transcriptional activators that interact with steroid receptors, including estrogen receptors. SRC-3 is a member of this family and has been shown to be overexpressed and/or amplified in breast cancer. Here, we review and discuss the versatile effects of SRC-3 in breast malignancy and its potential as a therapeutic target. Breast cancer (BCa) is the most frequently diagnosed malignant tumor in women and is also one of the leading causes of cancer-related death. Most breast tumors are hormone-dependent and estrogen signaling plays a critical role in promoting the survival and malignant behaviors of these cells. Estrogen signaling involves ligand-activated cytoplasmic estrogen receptors that translocate to the nucleus with various co-regulators, such as steroid receptor co-activator (SRC) family members, and bind to the promoters of target genes and regulate their expression. SRC-3 is a member of this family that interacts with, and enhances, the transcriptional activity of the ligand activated estrogen receptor. Although SRC-3 has important roles in normal homeostasis and developmental processes, it has been shown to be amplified and overexpressed in breast cancer and to promote malignancy. The malignancy-promoting potential of SRC-3 is diverse and involves both promoting malignant behavior of tumor cells and creating a tumor microenvironment that has an immunosuppressive phenotype. SRC-3 also inhibits the recruitment of tumor-infiltrating lymphocytes with effector function and promotes stemness. Furthermore, SRC-3 is also involved in the development of resistance to hormone therapy and immunotherapy during breast cancer treatment. The versatility of SRC-3 in promoting breast cancer malignancy in this way makes it a good target, and methodical targeting of SRC-3 probably will be important for the success of breast cancer treatment. [ABSTRACT FROM AUTHOR]

Sex steroids and antioxidant enzymes modulate uterine and placental physiology. Failures in the expression, signaling, and/or secretion of these mediators are associated with female infertility and gestational problems. However, there is no data on the expression profile of receptors for sex steroids and antioxidant enzymes in the maternal-fetal interface of domestic cats. Uterus and placenta samples from non-pregnant diestrus cats and cats in mid- and late pregnancy were used to analyze the protein and gene expression of the receptors for estrogen alpha (ERα), progesterone (PR), and androgen (AR) and the antioxidant enzymes superoxide dismutase 1 (SOD1), catalase, and glutathione peroxidase 1 (GPX1) by immunohistochemistry and qPCR. Higher uterine expression of ERα, Pr , and Sod1 was observed in the pregnant cats, especially in mid-pregnancy, compared to non-pregnant diestrus cats, as well as reduced endometrial catalase immunostaining. In the placenta, the mRNA expression of Erα, Pr, Ar , and Gpx1 was higher in late pregnancy in relation to mid-pregnancy. Moreover, weak or no placental expression was observed for catalase in mid- and late pregnancy, while strong immunostaining was observed for AR in trophoblasts and decidual cells in mid-pregnancy. The findings of this study demonstrated that pregnancy in female cats increases the uterine expression of sex steroid receptors and antioxidant enzymes, and that the placental expression of these mediators varies according to gestational age. • Pregnancy increases the uterine expression of ERα and Pr in domestic cats. • Pregnancy alters the uterine epithelial expression of AR in domestic cats. • Pregnancy modulates uterine expression of antioxidant enzymes in domestic cats. • Placental Gpx1 expression increases during late pregnancy in domestic cats. [ABSTRACT FROM AUTHOR]

To investigate the relationship between polyamine metabolism and reproductive hormones in ovarian follicles of Sichuan white geese, follicle polyamine content and reproductive hormone levels and gene expressions related to polyamine metabolism, steroidogenesis and steroid hormone receptors were detected by HPLC, ELISA and RT-qPCR. The results showed that the overall trend of spermidine and spermine levels increased first and then decreased as increasing follicle size, with the highest level in F3 and F5 follicles (P < 0.05). Putrescine and 17β-estradiol (E2) levels in hierarchical follicles were significantly lower than those in prehierarchical follicles (P < 0.05). Progesterone (P4) first increased and then decreased, with the highest level in the F5 follicle (P < 0.05). The expression levels of estrogen receptor 1 (ER1) showed an overall increase as increasing follicle size (except in F3 follicles), while estrogen receptor 2 (ER2) in hierarchical follicles was significantly lower than that in the prehierarchical follicles (P < 0.05). In addition, the overall expression level of progesterone receptor (PR) decreased, with no significant differences among F1, F2 and F3 follicles (P > 0.05). Yolk putrescine contents were positively correlated with yolk E2 concentrations and PR expression levels (P < 0.05), A significant positive correlation of spermidine levels with yolk P4 concentrations and PR expressions was also observed, as well as the spermine levels with yolk P4 concentrations (P < 0.05). In summary, polyamines were involved in the regulation of follicular development in geese, and this regulation played a role in affecting steroidogenesis and the expression of genes related to hormone receptors. • Polyamine affects the steroidogenesis. • Polyamine contents show a specific change during goose follicular development. • Polyamine affects the expression of genes related to reproductive hormones. [ABSTRACT FROM AUTHOR]

Simple Summary: The presence of estrogen receptor beta, the androgen receptor, and the glucocorticoid receptor on triple-negative breast cancer cells has opened the possibility for the development of new treatment approaches against this disease. This review summarizes the current knowledge and development regarding the presence and function of these receptors in triple-negative breast cancer. Key data from current and previous clinical trials targeting these receptors are also described in detail. Triple-negative breast cancer (TNBC) is considered one of the most aggressive forms of breast cancer with poor survival rates compared to other breast cancer subtypes. TNBC is characterized by the absence of the estrogen receptor alpha, progesterone receptor, and the human epidermal growth factor receptor 2, limiting those viable treatment options available to patients with other breast cancer subtypes. Furthermore, due to the particularly high heterogeneity of TNBC, conventional treatments such as chemotherapy are not universally effective, leading to drug resistance and intolerable side effects. Thus, there is a pressing need to discover new therapies beneficial to TNBC patients. This review highlights current findings regarding the roles of three steroid hormone receptors, estrogen receptor beta, the androgen receptor, and the glucocorticoid receptor, in the progression of TNBC. In addition, we discussed several ongoing and completed clinical trials targeting these hormone receptors in TNBC patients. [ABSTRACT FROM AUTHOR]

The estrogen receptor alpha (ER ) is a steroid receptor that is pivotal in the initiation and progression of most breast cancers. ER regulates gene transcription through recruitment of essential coregulators, including the steroid receptor coactivator AIB1 (Amplified in Breast Cancer 1). AIB1 itself is an oncogene that is overexpressed in a subset of breast cancers and is known to play a role in tumor progression and resistance to endocrine therapy through multiple mechanisms. Here we review the normal and pathological functions of AIB1 in regard to its ER α-dependent and ER α-independent actions, as well as its genomic conservation and protein evolution.We also outline the efforts to target AIB1 in the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

The androgen pathway via androgen receptor (AR) has received the most attention for development of male reproductive tracts. The estrogen pathway through estrogen receptor (ESR1) is also a major contributor to rete testis and efferent duct formation, but the role of progesterone via progesterone receptor (PGR) has largely been overlooked. Expression patterns of these receptors in the mesonephric tubules (MTs) and Wolffian duct (WD), which differentiate into the efferent ductules and epididymis, respectively, remain unclear because of the difficulty in distinguishing each region of the tracts. This study investigated AR, ESR1, and PGR expressions in the murine mesonephros using three-dimensional (3-D) reconstruction. The receptors were localized in serial paraffin sections of the mouse testis and mesonephros by immunohistochemistry on embryonic days (E) 12.5, 15.5, and 18.5. Specific regions of the developing MTs and WD were determined by 3-D reconstruction using Amira software. AR was found first in the specific portion of the MTs near the MT-rete junction at E12.5, and the epithelial expression showed increasing strength from cranial to the caudal regions. Epithelial expression of ESR1 was found in the cranial WD and MTs near the WD first at E15.5. PGR was weakly positive only in the MTs and cranial WD starting on E15.5. This 3-D analysis suggests that gonadal androgen acts first on the MTs near the MT-rete junction but that estrogen is the first to influence MTs near the WD, while potential PGR activity is delayed and limited to the epithelium. [ABSTRACT FROM AUTHOR]

Background: To compare the efficacy of CO2 fractional laser with that of topical estriol for treating genitourinary syndrome of menopause and to investigate the relationship between epithelial thickness and vaginal atrophy. Methods: Twenty-five menopausal women were randomized to receive either laser or estrogen treatment. Vaginal biopsies before and after treatment were compared to assess the amount and distribution of estrogen and progesterone receptors. Results: Estrogen receptor levels were statistically similar between groups before and after treatment. Although there was no change over time in the estrogen group, an increase in receptor levels was confirmed in the laser group. Changes in estrogen receptor levels showed no association with treatment. Progesterone receptor levels were statistically similar between groups throughout treatment. There was no change over time in both groups. These changes displayed no association with the type of treatment. There was no significant correlation between epithelium thickness and estrogen or progesterone receptor levels. Conclusions: Estrogen and progesterone receptor levels increased and were maintained, respectively, in the vaginal epithelium in both groups. There was no significant relationship between epithelium thickness and receptor density. Laser therapy had similar outcomes to the gold standard without involving the disadvantages of hormone therapy. [ABSTRACT FROM AUTHOR]

Summary: Estradiol and progesterone have been recognized as important mediators of reproductive events in the female mainly via binding to their receptors. This study aimed to characterize the immunolocalization of the estrogen receptor alfa (ERα), estrogen receptor beta (ERβ) and progesterone receptor (PR) in the ovarian follicles of the lizard Sceloporus torquatus. The localization of steroid receptors has a spatio-temporal pattern that depends on the stage of follicular development. The immunostaining intensity of the three receptors was high in the pyriform cells and the cortex of the oocyte of previtellogenic follicles. During the vitellogenic phase, the granulosa and theca immunostaining was intense even with the modification of the follicular layer. In the preovulatory follicles, the receptors were found in yolk and additionally, ERα was also located in the theca. These observations suggest a role for sex steroids in regulating follicular development in lizards, like other vertebrates. [ABSTRACT FROM AUTHOR]

Oral disorders including non-homogeneous leukoplakia, erythroplakia, erosive lichen planus, and many others can potentially progress to oral squamous cell carcinoma (OSCC). Currently, the late diagnosis of OSCC contributes to high mortality rates, emphasizing the need for specific markers and early intervention. In this study, we present a novel, quick, sensitive, and non-invasive method for the early detection and screening of oral cancer, enabling the qualitative assessment of neoplastic forms even before the onset of symptoms. Our method directly examines the expression of oral cancer biomarkers, such as the epithelial growth factor receptor (EGFR), and steroid receptors, including the androgen receptor (AR) and the estrogen receptor (ER). The crosstalk between sexual hormones and the EGF receptor plays a crucial role in the progression of different types of cancers, including head and neck squamous cell carcinoma. To implement our method, we developed a kit box comprising nine wells or stations, each containing buffers, lysis systems, and dried/lyophilized antibodies stored at room temperature. The kit includes instruments for sample collection and a PVDF strip (Immobilon) with specific primary antibodies immobilized on it. These antibodies capture the target proteins from cytological samples. Additionally, complementary tools are provided to ensure efficient utilization and optimal test performance. The technique can be performed outside the laboratory, either "patient side" with an instant chemocolorimetric response or with a digital reader utilizing the enzyme-linked immunosorbent assay (ELISA) method. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The androgen receptor (AR) is a steroid hormone receptor widely detected in breast cancer. Evidence suggests that the AR might be a tumor suppressor in estrogen receptor alpha-positive (ERα+ve) breast cancer but a tumor promoter in estrogen receptor alpha-negative (ERα-ve) breast cancer. Modulating AR activity could be a potential strategy for treating breast cancer. For ERα+ve breast cancer, activation of the AR had been demonstrated to suppress the disease. In contrast, for ERα-ve breast cancer, blocking the AR could confer better prognosis to patients. These studies support the feasibility of utilizing AR modulators as anti-cancer drugs for different subtypes of breast cancer patients. Nevertheless, several issues still need to be addressed, such as the lack of standardization in the determination of AR positivity and the presence of AR splice variants. In future, the inclusion of the AR status in the breast cancer report at the time of diagnosis might help improve disease classification and treatment decision, thereby providing additional treatment strategies for breast cancer. [ABSTRACT FROM AUTHOR]

Context: Dairy cattle experience stressful environmental situations that affect production. Heat stress during gestation can influence the intrauterine development of offspring, resulting in long-term damage that can affect the reproductive life of the adult offspring. Aim: The aim of the present study was to evaluate changes in the expression and regulation of steroid hormone receptors in the ovary of Holstein cows gestated under different temperature-humidity index (THI) during their in utero development. Methods: Animals were classified by their exposure to temperature-humidity index (THI) ≥72 during their development in utero according to date of birth or date of effective service of their mother. This study was not carried out under controlled conditions, but the conditions to which the cows were naturally exposed during their development were considered retrospectively, controlling the variables in the statistical analyses (age as a covariate, dairy farm as a random factor). Gestation was divided into two periods (P1 = days 0–150; and P2 = day 151 to calving) and three trimesters (T1 = days 0–90; T2 = days 91–180; and T3 = day 181 to calving), and the exposure to THI ≥72 was calculated in each one. The following characteristics were evaluated: gene expression of estrogen receptor (ESR) 1, ESR2 and progesterone receptor (PGR), CpG methylation in the 5′UTR of ESR1 and ESR2, and protein expression of ESR1, ESR2, PGR and coregulatory proteins in the dominant follicles of daughter cows in adulthood. Key results: We found associations between heat stress variables during gestation and the methylation status of CpG sites in the 5′UTR of ESR1 and ESR2 in dominant follicles. Results also showed association between exposure to high THI values during intrauterine development and expression of ESR1, ESR2 and PGR and coregulatory proteins in dominant follicles of adult cows. Conclusions: These results provide novel information about the impact of prenatal heat stress on molecular aspects at the ovary level in the offspring, during their adult life, which probably impacts the reproductive aspects of the herd. It has been widely demonstrated that heat stress affects fertility in dairy cattle in geographic regions that have high temperature-humidity indices. This is one of the first studies that indicates that adverse environmental conditions, like heat, suffered by pregnant cows, are associated with ovarian modifications at the molecular level of the daughters when they are adults. The results obtained emphasise the need to control the environmental and management conditions of the females during pregnancy, considering the possible effects on the fertility of the progeny. [ABSTRACT FROM AUTHOR]

In patients with high serum E2 embryo transfer is often postponed, as high E2 levels adversely affect embryo transfer outcome. We aimed to determine if stratified serum oestradiol (E2) and progesterone (P4) levels differentially affect endometrial histology and endometrial oestrogen and progesterone receptor protein levels. Endometrial biopsies were collected from oocyte donors. Samples were divided based on peak serum E2 levels into three groups: (i) low-E2 (n = 33) E2≤2999pg/mL; (ii) mid-E2 (n = 40) E2 3000–4999 pg/mL; and (iii) high-E2 (n = 15) E2≥5000 pg/mL. Oestrogen receptor alpha (ERα) and progesterone receptors A and B (PR) protein levels in endometrial stroma (S), glandular (GE) and luminal (LE) epithelia were assessed by immunohistochemistry. Samples in high-E2 group demonstrated strongest association with accelerated endometrial maturation (2 (1–2); 2 (1–3); and 3 (2.8–3) median days of advancement of endometrial maturation respectively in low, mid, high-E2 groups, p = 0.046). There were significant differences in ERα and PR immunoexpression in S, GE and LE among the groups (p < 0.05). Higher E2 levels were associated with decreased ERα expression (p < 0.017) in GE and LE, and increased PR expression in S and GE (p < 0.011 and p < 0.0001, respectively). Higher serum E2 levels were associated with impaired endometrial steroid hormone receptor expression, higher serum P4 and more advancement of endometrial maturation. [ABSTRACT FROM AUTHOR]

The mineralocorticoid receptor (MR/NR3C2) is a member of the family of steroid receptors (SR) which also includes the estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR) and glucocorticoid receptor (GR). They function primarily as nuclear receptors to regulate gene expression. While the other steroid hormone receptors are known to play important roles in the pathogenesis and progression of many cancers, relatively little is understood about the role of MR in cancer biology. This review focuses on examining new insights into the potential roles and mechanisms of action of MR in cancers. • The mineralocorticoid receptor (MR) is an essential regulator of salt homeostasis. • We review the evidence for a role of MR in cancer development and progression. • MR expression is frequently disrupted in cancer. • Decreased expression of MR is a marker of poor outcome in several cancer types. • MR is implicated in regulation of a range of cancer associated processes. [ABSTRACT FROM AUTHOR]

• Evidence for estrogen receptor signaling in lophotrochozoans is reviewed. • Lophotrochozoans of particular interest are annelids and rotifers. • Estrogen receptors are present and ligand activation in some lineages. • De novo synthesis of estradiol is not clearly established due to large data gaps. • Expression patterns for ER suggest roles in development, reproduction, digestion. Estrogen receptors (ERs) are thought to be the ancestor of all steroid receptors and are present in most lophotrochozoans studied to date, including molluscs, annelids, and rotifers. A number of studies have investigated the functional role of estrogen receptors in invertebrate species, although most are in molluscs, where the receptor is constitutively active. In vitro experiments provided evidence for ligand-activated estrogen receptors in annelids, raising important questions about the role of estrogen signalling in lophotrochozoan lineages. Here, we review the concordant and discordant evidence of estradiol receptor signalling in lophotrochozoans, with a focus on annelids and rotifers. We explore the de novo synthesis of estrogens, the evolution and expression of estrogen receptors, and physiological responses to activation of estrogen receptors in the lophotrochozoan phyla Annelida and Rotifera. Key data are missing to determine if de novo biosynthesis of estradiol in non-molluscan lophotrochozoans is likely. For example, an ortholog for the CYP11 gene is present, but confirmation of substrate conversion and measured tissue products is lacking. Orthologs CYP17 and CYP19 are lacking, yet intermediates or products (e.g. estradiol) in tissues have been measured. Estrogen receptors are present in multiple species, and for a limited number, in vitro data show agonist binding of estradiol and/or transcriptional activation. The expression patterns of the lophotrochozoan ERs suggest developmental, reproductive, and digestive roles but are highly species dependent. E 2 exposures suggest that lophotrochozoan ERs may play a role in reproduction, but no strong dose–response relationship has been established. Therefore, we expect most lophotrochozoan species, outside of perhaps platyhelminths, to have an ER but their physiological role remains elusive. Mining genomes for orthologs gene families responsible for steroidogenesis, coupled with in vitro and in vivo studies of the steroid pathway are needed to better assess whether lophotrochozoans are capable of estradiol biosynthesis. One major challenge is that much of the data are divided across a diversity of species. We propose that the polychaetes Capitella teleta or Platyneris dumerilii, and rotifer Brachionus manjavacas may be strong species choices for studies of estrogen receptor signalling, because of available genomic data, established laboratory culture techniques, and gene knockout potential. [ABSTRACT FROM AUTHOR]

The androgen receptor (AR) and estrogen receptor alpha (ERα) are steroid receptor transcription factors with critical roles in the development and progression of prostate and breast cancers. Advances in the understanding of mechanisms underlying the ligand-dependent activation of these transcription factors have contributed to the development of small molecule inhibitors that block AR and ERα actions. These inhibitors include competitive antagonists and degraders that directly bind the ligand binding domains of these receptors, luteinizing hormone releasing hormone (LHRH) analogs that suppress gonadal synthesis of testosterone or estrogen, and drugs that block specific enzymes required for biosynthesis of testosterone or estrogen. However, resistance to these therapies is frequent, and is often driven by selection for tumor cells with alterations in the AR or ESR1 genes and/or alternatively spliced AR or ESR1 mRNAs that encode variant forms AR or ERα. While most investigations involving AR have been within the context of prostate cancer, and the majority of investigations involving ERα have been within the context of breast cancer, important roles for AR have been elucidated in breast cancer, and important roles for ERα have been elucidated in prostate cancer. Here, we will discuss the roles of AR and ERα in breast and prostate cancers, outline the effects of gene- and mRNA-level alterations in AR and ESR1 on progression of these diseases, and identify strategies that are being developed to target these alterations therapeutically. • Androgen receptor splice variants in breast and prostate cancers. • Estrogen receptor splice variants in breast and prostate cancers. • AR gene alterations in breast and prostate cancers. • ESR1 gene alterations in breast and prostate cancers. [ABSTRACT FROM AUTHOR]

Women are subject to constitutional changes after menopause, which increases conditions and diseases prone to cardiovascular risks such as obesity and diabetes mellitus. Both estrogens and androgens influence the individual’s metabolic mechanism, which controls the fat distribution and the hypothalamic organization of the regulatory centers of hunger and satiety. While androgens tend to accumulate fat in the splanchnic and the visceral region with an increase in cardiovascular risk, estrogens generate more subcutaneous and extremity distribution of adipose tissue. The absence of estrogen during menopause seems to be the main factor that gives rise to the greater predisposition of women to suffer cardiovascular alterations. However, the mechanisms by which estrogens regulate the energy condition of people are not recognized. Estrogens have several mechanisms of action, which mainly include the modification of specific receptors that belong to the steroid receptor superfamily. The alpha estrogen receptors (ERα) and the beta receptors (ERβ) have a fundamental role in the metabolic control of the individual, with a very characteristic corporal distribution that exerts an influence on the metabolism of lipids and glucose. Despite the significant amount of knowledge in this field, many of the regulatory mechanisms exerted by estrogens and ER continue to be clarified. This review will discuss the role of estrogens and their receptors on the central regulation of caloric expenditure and the influence they exert on the differentiation and function of adipocytes. Furthermore, chemical substances with a hormonal activity that cause endocrine disruption with affectation on estrogen receptors will be considered. Finally, the different medical therapies for the vasomotor manifestations of menopause and their role in reducing obesity, diabetes, and cardiovascular risk will be analyzed. [ABSTRACT FROM AUTHOR]

Adenomyosis is a common gynaecological disease associated with the presence of endometrial lesions in the uterine myometrium. Estrogens have been proven to be the crucial hormones driving the growth of adenomyosis. Little is known about the distinct mechanisms of progesterone action in adenomyosis. Hence, in this study, we decided to characterize the expression of all nuclear and membrane estrogen and progesterone receptors. Additionally, as a functional investigation, we monitored prolactin production and cell proliferation after estradiol and progesterone treatments. We confirmed the presence of all nuclear and membrane estrogen and progesterone receptors in adenomyotic lesions at gene and protein levels. The expression of membrane progesterone receptors α and β (mPRα, mPRβ) as well as estrogen receptor β (ERβ) was upregulated in adenomyosis compared to normal myometrium. Estradiol significantly increased adenomyotic cell proliferation. Progesterone and cAMP upregulated prolactin secretion in adenomyosis in the same pattern as in the normal endometrium. In the present study, we showed the functional link between estradiol action and adenomyotic cell proliferation, as well as progesterone and prolactin production. Our findings provide novel insights into the sex steroid receptor expression pattern and potential regulated pathways in adenomyosis, suggesting that all receptors play an important role in adenomyosis pathophysiology. [ABSTRACT FROM AUTHOR]

Simple Summary: There is worldwide interest in understanding the cancerous diseases that are causing increasing deaths in humans. In recent years, interest has grown in finding suitable models of different types of cancer in animals to lead the scientific community to a better understanding of the disease, in order to win the battle against cancer. The aim of this investigation was to compare breast cancer samples and canine mammary tumors from a hormonal point of view to validate the canine species as a model to study human breast cancer. There was a close similarity between premenopausal human breast cancer and canine mammary cancer in terms of hormonal receptors. In both species, all hormones assayed were increased in tumors compared to normal mammary gland samples. This research not only further supports canine mammary cancer as a spontaneous model for the study of human breast cancer but is also important in providing a deeper understanding of the hormonal pathogenesis of breast/mammary cancer in each independent species. The validity of spontaneous canine mammary cancer (CMC) as a natural model for the study of human breast cancer (HBC) from a hormonal point of view has never been thoroughly investigated. In this study, we analyzed the immunohistochemical expression of aromatase (Arom) and steroid receptors [estrogen receptor α (ER α), estrogen receptor β (ER β), progesterone receptor (PR) and androgen receptor (AR)] and intratumor steroid hormone levels of 17β-estradiol (E2), estrone sulfate (SO4E1), progesterone (P4), androstenedione (A4), dehydroepiandrosterone (DHEA), and testosterone (T) in 78 samples of mammary cancer—51 human breast cancer (HBC) and 27 canine mammary cancer (CMC)—and corresponding controls. Frequency of tumors expressing Arom, ERβ, PR, and AR was similar in both species, whereas ERα+ tumors were less frequent in the canine species. There was a closer similarity between premenopausal HBC and CMC. In HBC and CMC, all hormones assayed were increased in tumors compared to control samples. Intratumor androgen levels were similar in the two species, although levels of progesterone and estrogens were higher in the HBC samples than the CMC samples. Statistical associations among Arom, receptors, and hormones analyzed suggest that the major hormonal influence in both species is estrogenic through the ER, being the α isoform predominant in the human samples. Our findings further support CMC as a spontaneous model for the study of HBC, especially premenopausal HBC, although several differences, such as the more prevalent ERα immunoexpression and higher intratumor levels of estrogens and P4 in HBC, should be taken into account in comparative hormonal studies. [ABSTRACT FROM AUTHOR]

The wide variety of sex hormone actions underlie bone growth and health, and their actions mediate gene regulation by the cognate nuclear receptors. Nuclear androgen and estrogen receptors (AR, and ERα/ERβ) are hormone-dependent and DNA binding- transcription regulatory factors, and gene regulation by sex hormones often accompany with chromatin remodeling under aid of a number of co-regulators. As sex hormone biosynthesis is under highly regulated systemic and local regulations, the skeletal actions of sex hormones could be inferred from only the phenotypic abnormalities in skeleton in mouse genetic models deficient of nuclear receptors selectively in specific types of bone cells as well as at specific cell differentiation stages. Anabolic androgen actions and anti-bone resorptive estrogen actions are discussed here from the phenotypic abnormalities in such model mice. Though rapid gene regulation by sex hormones may not require chromatin reorganization, dynamic chromatin reconfiguration looks to facilitate profound and long-term hormonal actions. In this review, we focus the recent findings in gene regulation at a chromatin level, particularly of the function of enhancer RNAs transcribed from strong enhancers, and in the role of liquid–liquid phase separation state in transcription initiation through chromatin reconfiguration. [ABSTRACT FROM AUTHOR]