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Objectives: To investigate whether hormone replacement therapy (HRT) impacts health care resource utilization in the management of chronic rhinosinusitis (CRS) in older women. Methods: Using the TriNetX US health record database, women 55 years or older with a diagnosis of CRS were included and followed for 3 years. The cohort was stratified into two groups: women who received HRT at the beginning of the study were compared to women who did not receive HRT. The groups were matched by age, race, ethnicity, history of asthma, and history of nasal polyps. Outcomes included whether the patient underwent endoscopic sinus surgery (ESS) and frequency of antibiotic use. Measures of association, Kaplan–Meier analysis, and cohort descriptive statistics were calculated. Results: Of the 65,400 women included, the mean age was 66.9 years. 27.0% and 3.6% of patients had a history of asthma or nasal polyps, respectively. Overall, 2.0% of CRS patients underwent ESS, with the HRT group less likely to undergo ESS [OR: 0.28; 95% CI: (0.25–0.32)] compared to patients who did not receive HRT. When stratified by polyp status, HRT patients with nasal polyps had a greater decrease in ESS rates compared to control than HRT patients without nasal polyps. The HRT group had a higher mean number of antibiotic prescriptions compared to the non‐HRT group. Conclusion: HRT is associated with decreased utilization of ESS to treat CRS, with a greater effect size for ESS among CRSwNP patients. However, HRT was associated with higher antibiotic utilization. Level of Evidence: 3 Laryngoscope, 134:3921–3926, 2024 [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the effects of the estrogen depression during orthodontic tooth movement on alveolar bone microarchitecture and periodontal ligament. Female Wistar rats were divided into two groups, one consisting of non‐ovariectomized animals subjected to orthodontic tooth movement, and one comprising ovariectomized animals subjected to orthodontic tooth movement. Micro‐CT assessment of bone volume to total volume (BV/TV), total porosity, trabecular thickness (Tb.Th), trabecular number (Tb.N), and trabecular separation (Tb.Sp) in the alveolar bone of the orthodontically moved tooth was performed. Histomorphometric analyses were made in the periodontal ligament, and immunoexpression of RANK, RANKL, OPG, and TUNEL were quantified. Orthodontic tooth movement in the group of ovariectomized rats was faster than in non‐ovariectomized animals. The alveolar bone area showed lower values of BV/TV and trabecular thickness, and higher bone porosity and trabeculae numbers in the ovariectomized rats. Histological analyses in the ovariectomized group revealed an increase in collagen fibers in the periodontal ligament. The apoptotic cell counts in the periodontal ligament were higher in the group of ovariectomized rats than in the sham‐operated rats. Ovariectomy resulted in an increase in tooth movement and alteration of the alveolar bone microstructure in the first 7 day of orthodontic tooth movement, and in the presence of apoptotic cells in the periodontal ligament. [ABSTRACT FROM AUTHOR]

Dysfunctional RNA‐binding proteins (RBPs) have been implicated in several geriatric diseases, including Alzheimer's disease (AD). However, little is known about the nuclear molecular actions and cooperative functions mediated by RBPs that affect gene regulation in sporadic AD or aging. In the present study, we investigated aging‐ and AD‐associated changes in the expression of PSF and G3BP2, which are representative RBPs associated with sex hormone activity. We determined that both PSF and G3BP2 levels were decreased in aged brains compared to young brains of mice. RNA sequencing (RNA‐seq) analysis of human neuronal cells has shown that PSF is responsible for neuron‐specific functions and sustains cell viability. In addition, we showed that PSF interacted with G3BP2 in the nucleus and stress granules (SGs) at the protein level. Moreover, PSF–mediated gene regulation at the RNA level correlated with G3BP2. Interestingly, PSF and G3BP2 target genes are associated with AD development. Mechanistically, quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR) analysis demonstrated that the interaction of RBPs with the pre‐mRNA of target genes enhanced post‐transcriptional mRNA stability, suggesting a possible role for these RBPs in preserving neuronal cell viability. Notably, in the brains of patients with sporadic AD, decreased expression of PSF and G3BP2 in neurons was observed compared to non‐AD patients. Overall, our findings suggest that the cooperative action of PSF and G3BP2 in the nucleus is important for preventing aging and AD development. [ABSTRACT FROM AUTHOR]

Estrogens produced in peripheral tissues and locally in the brain are potent neuromodulators. The function of the hippocampus, a brain region essential for episodic memory and spatial navigation, relies on the activity of ensembles of excitatory neurons whose activity is temporally and spatially coordinated by a wide diversity of inhibitory neurons (INs) types. Over the last years, we have accumulated evidence that indicates that estrogens regulate the function of hippocampal INs through different mechanisms, including transcriptional regulation and rapid nongenomic signaling. Here, we argue that the well‐documented influence of estrogens on episodic memory may be related to the actions of local and peripheral estrogens on the heterogenous populations of hippocampal INs. We discuss how physiological changes in peripheral sex hormone levels throughout lifespan may interact with local brain sources to regulate IN function at different stages of life, from early hippocampal development to the aging brain. We conclude that considering INs as mediators of sex hormone actions in the hippocampus across the healthy life span will benefit our understanding of sex‐biased neurodevelopmental disorders and physiological aging. [ABSTRACT FROM AUTHOR]

We examined performance across one menstrual cycle (MC) and 3 weeks of hormonal contraceptives (HC) use to identify whether known fluctuations in estrogen and progesterone/progestin are associated with functional performance changes. National Rugby League Indigenous Women's Academy athletes [n = 11 naturally menstruating (NM), n = 13 using HC] completed performance tests [countermovement jump (CMJ), squat jump (SJ), isometric mid‐thigh pull, 20 m sprint, power pass and Stroop test] during three phases of a MC or three weeks of HC usage, confirmed through ovulation tests alongside serum estrogen and progesterone concentrations. MC phase or HC use did not influence jump height, peak force, sprint time, distance thrown or Stroop effect. However, there were small variations in kinetic and kinematic CMJ/SJ outputs. NM athletes produced greater mean concentric power in MC phase four than one [+0.41 W·kg−1 (+16.8%), p = 0.021] during the CMJ, alongside greater impulse at 50 ms at phase one than four [+1.7 N·s (+4.7%), p = 0.031] during the SJ, without differences between tests for HC users. Among NM athletes, estradiol negatively correlated with mean velocity and power (r = −0.44 to −0.50, p < 0.047), progesterone positively correlated with contraction time (r = 0.45, p = 0.045), and both negatively correlated with the rate of force development and impulse (r = −0.45 to −0.64, p < 0.043) during the SJ. During the CMJ, estradiol positively correlated to 200 ms impulse (r = 0.45, p = 0.049) and progesterone to mean power (r = 0.51, p = 0.021). Evidence of changes in testing performance across a MC, or during active HC use, is insufficient to justify "phase‐based testing"; however, kinetic or kinematic outputs may be altered in NM athletes. Highlights: Evidence of changes in testing performance across a menstrual cycle, or during active hormonal contraceptives use, is insufficient to justify "phase‐based testing" at a group or team‐based level among female rugby league athletes.Kinetic or kinematic outputs in jumping movements may be altered in naturally menstruating athletes; however it could not be determined if the observed alterations exceeded between‐day variability. [ABSTRACT FROM AUTHOR]

Women are more prone to develop rheumatoid arthritis, with peak incidence occurring around menopause. Estrogen has major effects on the immune system and is protective against arthritis. We have previously shown that treatment with estrogen inhibits inflammation and joint destruction in murine models of arthritis, although the mechanisms involved remain unclear. Fibroblastic reticular cells (FRCs) are specialized stromal cells that generate the three‐dimensional structure of lymph nodes (LNs). FRCs are vital for coordinating immune responses from within LNs and are characterized by the expression of the chemokine CCL19, which attracts immune cells. The aim of this study was to determine whether the influence of estrogen on innate and adaptive immune cells in arthritis is mediated by estrogen signaling in FRCs. Conditional knockout mice lacking estrogen receptor α (ERα) in CCL19‐expressing cells (Ccl19‐CreERαfl/fl) were generated and tested. Ccl19‐CreERαfl/fl mice and littermate controls were ovariectomized, treated with vehicle or estradiol and subjected to the 28‐day‐long antigen‐induced arthritis model to enable analyses of differentiated T‐ and B‐cell populations and innate cells in LNs by flow cytometry. The results reveal that while the response to estradiol treatment in numbers of FRCs per LN is significantly reduced in mice lacking ERα in FRCs, estrogen does not inhibit joint inflammation or markedly affect immune responses in this arthritis model. Thus, this study validates the Ccl19‐CreERαfl/fl strain for studying estrogen signaling in FRCs within inflammatory diseases, although the chosen arthritis model is deemed unsuitable for addressing this question. [ABSTRACT FROM AUTHOR]

The association of hormonal contraception with increased risk of inflammatory bowel disease (IBD) observed in females suggests involvement of ovarian hormones, such as estradiol, and the estrogen receptors in the progression of intestinal inflammation. Here, we investigated the effects of prophylactic SERM2 and estradiol supplementation in dextran sulfate sodium‐induced colitis using mice with intact ovaries and ovariectomized (OVX) female mice. We found that graded colitis score was threefold reduced in the OVX mice, compared to mice with intact ovaries. Estradiol supplementation, however, aggravated the colitis in OVX mice, increasing the colitis score to a similar level than what was observed in the intact mice. Further, we observed that immune infiltration and gene expression of inflammatory interleukins Il1b, Il6, and Il17a were up to 200‐fold increased in estradiol supplemented OVX colitis mice, while a mild but consistent decrease was observed by SERM2 treatment in intact animals. Additionally, cyclo‐oxygenase 2 induction was increased in the colon of colitis mice, in correlation with increased serum estradiol levels. Measured antagonist properties of SERM2, together with the other results presented here, indicates an exaggerating role of ERα signaling in colitis. Our results contribute to the knowledge of ovarian hormone effects in colitis and encourage further research on the potential use of ER antagonists in the colon, in order to alleviate inflammation. [ABSTRACT FROM AUTHOR]

Background: Breast cancer, a leading cause of female mortality, is closely linked to mutations in estrogen receptor beta (ESR2), particularly in the ligand‐binding domain, which contributed to altered signaling pathways and uncontrolled cell growth. Objectives/Aims: This study investigates the molecular and structural aspects of ESR2 mutant proteins to identify shared pharmacophoric regions of ESR2 mutant proteins and potential therapeutic targets aligned within the pharmacophore model. Methods: This study was initiated by establishing a common pharmacophore model among three mutant ESR2 proteins (PDB ID: 2FSZ, 7XVZ, and 7XWR). The generated shared feature pharmacophore (SFP) includes four primary binding interactions: Hydrogen bond donors (HBD), hydrogen bond acceptors (HBA), hydrophobic interactions (HPho), and Aromatic interactions (Ar), along with halogen bond donors (XBD) and totalling 11 features (HBD: 2, HBA: 3, HPho: 3, Ar: 2, XBD: 1). By employing an in‐house Python script, these 11 features distributed into 336 combinations, which were used as query to isolate a drug library of 41,248 compounds and subjected to virtual screening through the generated SFP. Results: The virtual screening demonstrated 33 hits showing potential pharmacophoric fit scores and low RMSD value. The top four compounds: ZINC94272748, ZINC79046938, ZINC05925939, and ZINC59928516 showed a fit score of more than 86% and satisfied the Lipinski rule of five. These four compounds and a control underwent molecular (XP Glide mode) docking analysis against wild‐type ESR2 protein (PDB ID: 1QKM), resulting in binding affinity of −8.26, −5.73, −10.80, and −8.42 kcal/mol, respectively, along with the control −7.2 kcal/mol. Furthermore, the stability of the selected candidates was determined through molecular dynamics (MD) simulations of 200 ns and MM‐GBSA analysis. Conclusion: Based on MD simulations and MM‐GBSA analysis, our study identified ZINC05925939 as a promising ESR2 inhibitor among the top four hits. However, it is essential to conduct further wet lab evaluation to assess its efficacy. [ABSTRACT FROM AUTHOR]

Objectives: 17β‐estradiol (E2) is a steroidal hormone with immunomodulatory functions that play a role in infectious and inflammatory diseases. E2 was recently identified as the leading upstream regulator of differentially expressed genes in a comparative RNA sequencing study of pediatric patients with otitis media (OM) versus OM‐free counterparts and may therefore play a role in the inflammatory response to bacterial otopathogens during pediatric OM. This study examined the effect of E2 on bacterial‐induced inflammatory cytokine expression in an in vitro pediatric OM model. Methods: An immortalized middle ear (ME) epithelial cell line, ROM‐SV40, was developed from a pediatric recurrent OM patient. The culture was exposed to E2 at physiological levels for 1–48 h prior to 6 h‐stimulation with nontypeable Haemophilus influenzae (NTHi) whole cell lysate. TNFA, IL1B, IL6, and IL8 were assayed by qPCR and ELISA. Results: E2 pretreatment (24 h) abrogated NTHi induction of IL6; a longer pretreatment (1–10 nM, 48 h) abrogated IL1B induction (p < 0.05). E2 pretreatment (5 nM, 48 h) abrogated NTHi‐induced IL8 secretion (p = 0.017). Conclusion: E2 pretreatment partially rescued NTHi‐induced cytokine production by ME epithelia. These data support a role for E2 in moderating the excessive inflammatory response to middle ear infection that contributes to OM pathophysiology. Levels of Evidence: NA Laryngoscope, 134:3815–3819, 2024 [ABSTRACT FROM AUTHOR]

It is well established that pyruvate kinase M2 (PKM2) activity contributes to metabolic reprogramming in various cancers, including colorectal cancer (CRC). Estrogen or 17β‐estradiol (E2) signaling is also known to modulate glycolysis markers in cancer cells. However, whether the inhibition of PKM2 combined with E2 treatment could adversely affect glucose metabolism in CRC cells remains to be investigated. First, we confirmed the metabolic plasticity of CRC cells under varying environmental conditions. Next, we identified glycolysis markers that were upregulated in CRC patients and assessed in vitro mRNA levels following E2 treatment. We found that PKM2 expression, which is highly upregulated in CRC clinical samples, is not altered by E2 treatment in CRC cells. In this study, glucose uptake, generation of reactive oxygen species (ROS), lactate production, cell viability, and apoptosis were evaluated in CRC cells following E2 treatment, PKM2 silencing, or a combination of both. Compared to individual treatments, combination therapy resulted in a significant reduction in cell viability and enhanced apoptosis. Glucose uptake and ROS production were markedly reduced in PKM2‐silenced E2‐treated cells. The data presented here suggest that E2 signaling combined with PKM2 inhibition cumulatively targets glucose metabolism in a manner that negatively impacts CRC cell growth. These findings hold promise for novel therapeutic strategies targeting altered metabolic pathways in CRC. Highlights: Colorectal cancer (CRC) cells exhibit a versatile metabolic profile that is responsive to changes in the tumor microenvironment.Estrogen (E2) signaling modulates glycolysis and reduces CRC cell growth and survival.Pyruvate kinase M2 (PKM2) inhibition also modulates glycolysis and reduces CRC cell growth.Combining E2 treatment with PKM2 inhibition precipitates significant cumulative antitumor effects in CRC cells. [ABSTRACT FROM AUTHOR]

The enteric nervous system (ENS) orchestrates intricate and autonomous functions throughout the gastrointestinal (GI) tract. Disruptions in ENS function are associated GI disorders. This mini review focuses on the past decade's research, utilizing rodent models, with an emphasis on protecting enteric neurons from loss. The review specifically looks at efforts to reduce oxidative stress, limit inflammation, and enhance neuronal resilience. Protective interventions including administration of antioxidants and compounds targeting cellular redox buffer systems, are evaluated for their effectiveness in preventing loss of enteric neurons in the ischemia–reperfusion model and streptozotocin‐induced diabetes model. Interventions such as engrafting mesenchymal stem cells and targeting inflammatory signaling pathways in enteric neurons and glial cells are evaluated in inflammatory bowel disease models including the Winnie mouse, DSS‐, and DNBS/TNBS‐induced colitis models. The review also touches upon neuronal resilience, particularly in the context of Parkinson's disease models. Including estrogen's neuroprotective role, and the influence of metal ions on enteric neuronal protection. Understanding the dynamic interplay within the ENS and its role in disease pathogenesis holds promise for developing targeted therapies to effectively manage and treat various GI ailments. [ABSTRACT FROM AUTHOR]

In females, Alzheimer's disease (AD) incidences increases as compared to males due to estrogen deficiency after menopause. Estrogen therapy is the mainstay therapy for menopause and associated complications. Estrogen, a hormone with multifaceted physiological functions, has been implicated in AD pathophysiology. Estrogen plays a crucial role in amyloid precursor protein (APP) processing and overall neuronal health by regulating various factors such as brain‐derived neurotrophic factor (BDNF), intracellular calcium signalling, death domain‐associated protein (Daxx) translocation, glutamatergic excitotoxicity, Voltage‐Dependent Anion Channel, Insulin‐Like Growth Factor 1 Receptor, estrogen‐metabolising enzymes and apolipoprotein E (ApoE) protein polymorphisms. All these factors impact the physiology of postmenopausal women. Estrogen replacement therapies play an important treatment strategy to prevent AD after menopause. However, use of these therapies may lead to increased risks of breast cancer, venous thromboembolism and cardiovascular disease. Various therapeutic approaches have been used to mitigate the effects of estrogen on AD. These include hormone replacement therapy, Selective Estrogen Receptor Modulators (SERMs), Estrogen Receptor Beta (ERβ)‐Selective Agonists, Transdermal Estrogen Delivery, Localised Estrogen Delivery, Combination Therapies, Estrogen Metabolism Modulation and Alternative Estrogenic Compounds like genistein from soy, a notable phytoestrogen from plant sources. However, mechanism via which these approaches modulate AD in postmenopausal women has not been explained earlier thoroughly. Present review will enlighten all the molecular mechanisms of estrogen and estrogen replacement therapies in AD. Along‐with this, the association between estrogen, estrogen‐metabolising enzymes and ApoE protein polymorphisms will also be discussed in postmenopausal AD. [ABSTRACT FROM AUTHOR]

The article titled "Correction to 'Impact of estrogens on resting energy expenditure: A systematic review'" discusses an error in Table 2 of the published article. The table contained mixed-up data and misplaced cell contents in two studies. The correct table is provided in the correction. The article presents a systematic review on the impact of estrogens on resting energy expenditure, examining various studies on the topic. The given text appears to be a table with various measurements and calculations related to resting energy expenditure (REE) in different groups of individuals. The table includes information on hormonal contraception users, hormonal contraception non-users, and oral contraceptive (OC) users. The measurements and calculations include baseline REE, energy expenditure during different phases of the menstrual cycle, and the comparison of REE between different groups. The table also mentions the abbreviations used in the text. [Extracted from the article]

Objective: The Visiopharm artificial intelligence (AI) algorithm for oestrogen receptor (ER) immunohistochemistry (IHC) in whole slide images (WSIs) has been successfully validated in surgical pathology. This study aimed to assess its efficacy in cytology specimens. Methods: The study cohort comprised 105 consecutive cytology specimens with metastatic breast carcinoma. ER IHC WSIs were seamlessly integrated into the Visiopharm platform from the Image Management System (IMS) during our routine digital workflow, and an AI algorithm was employed for analysis. ER AI scores were compared with pathologists' manual consensus scores. Optimization steps were implemented and evaluated to reduce discordance. Results: The overall concordance between pathologists' scores and AI scores was excellent (99/105, 94.3%). Six cases exhibited discordant results, including two false‐negative (FN) cases due to abundant histiocytes incorrectly counted as negatively stained tumour cells by AI, two FN cases owing to weak staining, and two false‐positive (FP) cases where pigmented macrophages were erroneously counted as positively stained tumour cells by AI. The Pearson correlation coefficient of ER‐positive percentages between pathologists' and AI scores was 0.8483. Optimization steps, such as lowering the cut‐off threshold and additional training using higher input magnification, significantly improved accuracy. Conclusions: The automated ER AI algorithm demonstrated excellent concordance with pathologists' assessments and accurately differentiated ER‐positive from ER‐negative metastatic breast carcinoma cytology cases. However, precision in identifying tumour cells in cytology specimens requires further enhancement. [ABSTRACT FROM AUTHOR]

Endometriosis is defined as an oestrogen‐dependent and inflammatory gynaecological disease of which the pathogenesis remains unclear. This study aimed to investigate the cellular heterogeneity and reveal the effect of CD8+ T cells on the progress of endometriosis. Three ovarian endometriosis patients were collected, and single‐cell RNA sequencing (scRNA‐seq) progressed and delineated the cellular landscape of endometriosis containing five cell clusters. The endometrial cells (EMCs) were the major component, of which the mesenchymal cells were preponderant and characterized with increased inflammation and oestrogen synthesis in endometriosis. The proportion of T cells, mainly CD8+ T cells rather than CD4+, was reduced in endometriotic lesions, and the cytokines and cytotoxicity of ectopic T cells were depressed. CD8+ T cells depressed the proliferation of ESCs through inhibiting CDK1/CCNB1 pathway to arrest the cell cycle and triggered inflammation through activating STAT1 pathway. Correspondingly, the coculture with ESCs resulted in the dysfunction of CD8+ T cells through upregulating STAT1/PDCD1 pathway and glycolysis‐promoted metabolism reprogramming. The endometriotic lesions were larger in nude mouse models with T‐cell deficiency than the normal mouse models. The inhibition of T cells via CD90.2 or CD8A antibody increased the endometriotic lesions in mouse models, and the supplement of T cells to nude mouse models diminished the lesion sizes. In conclusion, this study revealed the global cellular variation of endometriosis among which the cellular count and physiology of EMCs and T cells were significantly changed. The depressed cytotoxicity and aberrant metabolism of CD8+ T cells were induced by ESCs with the activation of STAT1/PDCD1 pathway resulting in immune survival to promote endometriosis. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Premenopausal bilateral oophorectomy (PBO) is associated with later‐life cognition, but the underlying brain changes remain unclear. We assessed the impact of PBO and PBO age on white matter integrity. METHODS: Female participants with regional diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA) and mean diffusivity (MD) were included (22 with PBO < 40 years; 43 with PBO 40‐45 years; 39 with PBO 46‐49 years; 907 referents without PBO < 50 years). Linear regression models adjusted for age and apolipoprotein E (APOE) genotype. RESULTS: Females with PBO < 40 years, compared to referents, had lower FA and higher MD in the anterior corona radiata, genu of the corpus collosum, inferior fronto‐occipital fasciculus, superior occipital, and superior temporal white matter. Females who underwent PBO between 45 and 49 also had some changes in white matter integrity. DISCUSSION: Females who underwent PBO < 40 years had reduced white matter integrity across multiple regions in later‐life. These results are important for females considering PBO for noncancerous conditions. Highlights: Females with premenopausal bilateral oophorectomy (PBO) < 40 years had lower FA versus referents.Females with PBO < 40 years had higher MD in many regions versus referents.Adjusting for estrogen replacement therapy use did not attenuate results.Females with PBO 45‐49 years also had some white matter changes versus referents. [ABSTRACT FROM AUTHOR]

Context: Meditation and related relaxation techniques are good means of alleviating stress and maintaining good health. Osho dynamic meditation decreases several psychopathological variables such as anxious‐depressive syndrome, aggressive behaviors, and depression which is practiced in Nepal and all over the world. Various studies have shown alteration in different hormone levels due to meditation by strengthening adaptive mechanisms. Aim: The aim of this study was to evaluate the effect of Osho meditation on serum hormonal levels in pre‐ and postmeditation participants. Methods: A pre–post study was conducted among 70 healthy volunteers (42 male and 28 female) where various types of Osho dynamic meditation techniques were incorporated together to understand their combined effects on serum hormone levels in participants attending the 7 days meditation camp. Serum hormones such as cortisol, estrogen, progesterone, free triiodothyronine (fT3), free thyroxine (fT4), thyroid‐stimulating hormone (TSH), testosterone, and growth hormone were measured by chemiluminescence immunoassay. Results: Out of 70 participants, 68 participants (97%) had subjective opinion of Osho dynamic meditation being effective in alleviating stress, depression, and anger. Also, there was a significant decline in body weight and body mass index in both male and female populations after a strict vegetarian diet and meditation. Likewise, a significant rise in the level of estrogen (p < 0.001), progesterone (p < 0.001), growth hormone (p < 0.001), testosterone (p = 0.002), and fT3 (p = 0.049) in postmeditation male participants indicates the importance of Osho dynamic meditation on elevating sex hormones such as estrogen, progesterone, testosterone as well as fT3, and growth hormones among Osho meditation practicing participants. Conclusion: Our findings suggest significant changes in the hormonal levels and improvement in stress and depression in participants undergoing Osho meditation. [ABSTRACT FROM AUTHOR]

Female carriers of a Duchenne muscular dystrophy (DMD) gene mutation manifest exercise intolerance and metabolic anomalies that may be exacerbated following menopause due to the loss of estrogen, a known regulator of skeletal muscle function and metabolism. Here, we studied the impact of estrogen depletion (via ovariectomy) on exercise tolerance and muscle mitochondrial metabolism in female mdx mice and the potential of estrogen replacement therapy (using estradiol) to protect against functional and metabolic perturbations. We also investigated the effect of estrogen depletion, and replacement, on the skeletal muscle proteome through an untargeted proteomic approach with TMT‐labelling. Our study confirms that loss of estrogen in female mdx mice reduces exercise capacity, tricarboxylic acid cycle intermediates, and citrate synthase activity but that these deficits are offset through estrogen replacement therapy. Furthermore, ovariectomy downregulated protein expression of RNA‐binding motif factor 20 (Rbm20), a critical regulator of sarcomeric and muscle homeostasis gene splicing, which impacted pathways involving ribosomal and mitochondrial translation. Estrogen replacement modulated Rbm20 protein expression and promoted metabolic processes and the upregulation of proteins involved in mitochondrial dynamics and metabolism. Our data suggest that estrogen mitigates dystrophinopathic features in female mdx mice and that estrogen replacement may be a potential therapy for post‐menopausal DMD carriers. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusions Emerging evidence suggests that the endometrial microbiome plays important roles in the development of endometrial cancer (EC). Here, we evaluate stage‐specific roles of microbial dysbiosis and metabolic disorders in patients with EC, patients with endometrial hyperplasia (EH), and patients afflicted with benign uterine conditions (CK).This prospective cohort study included 33 women with EC, 15 women with endometrial EH, and 15 women with benign uterine conditions (CK) from November 2022 to September 2023. Different typical endometrial samples were imaged with a scanning electron microscope and a transmission electron microscope. The endometrial microbiome was assessed by sequencing the V3–V4 region of the 16S rRNA gene and the ITS1 to fill the gap in relation to the study of the uterine fungal microbiome. Moreover, liquid chromatography‐mass spectrometry‐based metabolomics was used to identify and quantify metabolic changes among these groups.The endometrial microbiome revealed that there is a structural microbiome shift and an increase in the α‐diversity in the EC and EH cases, distinguishable from the benign cases, especially the fungal community structure. The fungal microbiome from patients with EC and EH was altered relative to controls and dominated by Penicillium sp. By contrast, Sarocladium was more abundant in controls. Significant differences were observed in the composition and content of compounds between benign cases and EC, especially estradiol‐like metabolism‐related substances. Altered microbiota was correlated with the concentrations of interleukin‐6 (IL‐6), IL‐11, transforming growth factor‐beta, and β‐glucuronidase activity especially the relative abundance increase of Penicillium sp.This study suggested that the endometrial microbiome is complicit in modulating the development of EC such as estrogen activity and a pro‐inflammatory response. Our work provides a new insight into the endometrial microbiome from a perspective of stages, which opens up new avenues for EC prognosis and therapy. [ABSTRACT FROM AUTHOR]

Proanthocyanidin‐rich grape seed extract (GSE) has been shown to have the potential to protect bones, although the underlying mechanism remains unknown. The current study aims to explore GSE's preventive and therapeutic impact on bone loss induced by oestrogen deficiency and the underlying mechanism through the gut microbiota (GM) and metabolomic responses. In oestrogen‐deficient ovariectomized (OVX) mice, GSE ameliorated bone loss by inhibiting the expansion of bone marrow adipose tissue (BMAT), restoring BMAT lipolysis and promoting bone formation. GSE regulated OVX‐induced GM dysbiosis by reducing the abundance of opportunistic pathogenic bacteria, such as Alistipes, Turicibacter and Romboutsia, while elevating the abundance of beneficial bacteria, such as Bifidobacterium. The modified GM primarily impacted lipid and amino acid metabolism. Furthermore, the serum metabolites of GSE exhibited a significant enrichment in lipid metabolism. In summary, GSE shows potential as a functional food for preventing oestrogen deficiency‐induced bone loss by modulating GM and metabolite‐mediated lipid metabolism. [ABSTRACT FROM AUTHOR]

The cervix is an important organ that has to dilate sufficiently at delivery to allow the foetus to transition to extrauterine life. Insufficient dilatation of the cervix (IDC) is a frequent cause of dystocia in cattle. The mechanisms underlying cervical opening and the pathogenesis of IDC are still widely unclear. Systematic studies on the relationship between IDC and steroid hormones have been limited and have yielded inconsistent findings. This study aimed to measure oestrogen and progesterone (P4) concentrations in intrapartum cows presented with dystocia due to IDC and in a comparison (C) group of cows with eutocic delivery. Before any obstetrical procedures, and right after the initial evaluation, blood samples were taken from IDC and C animals. Concentrations of P4, oestradiol‐17β (E2), free total oestrogens (FTE) and conjugated total oestrogens (CTE) were measured by established radioimmunoassays. Concentrations of P4 (p =.538), FTE (p =.065) and CTE (p =.605) were not statistically different between C and IDC groups. However, E2 levels in group C were significantly lower when compared to those in the IDC group (p =.013), which is inconsistent with the function of oestrogens in cervical dilatation. The correlation analysis demonstrated significant positive correlations between the pairs P4 versus FTE, P4 versus E2 and FTE versus E2 in group C and between the pair FTE versus E2 in group IDC. In conclusion, the results suggest that local activities of steroids relevant to the aetiology of IDC are not reflected by concentrations in the systemic circulation or that other factors are clearly more important. [ABSTRACT FROM AUTHOR]

Background: Most fractures occur in women aged ≥80 years but competing mortality unrelated to fracture may limit the benefit of osteoporosis drug therapy for some women in late life. Our primary aim was to develop separate prediction models for non‐spine fracture (NSF) and mortality before fracture to identify subsets of women with varying fracture versus mortality risks. Methods: Separate prediction models were developed for NSF and mortality before NSF for 4895 women aged ≥80 years enrolled in the Study of Osteoporotic Fractures (SOF) or the Health Aging and Body Composition (HABC) study. Proportional hazards models modified to account for competing mortality were used to identify candidate risk factors for each outcome. Predictors associated with NSF or mortality (p < 0.2) were included in separate competing risk models to estimate the cumulative incidence of NSF and mortality before NSF during 5 years of follow‐up. This process was repeated to develop separate prediction models for hip fracture and mortality before hip fracture. Results: Significant predictors of NSF (race, total hip BMD, grip strength, prior fracture, falls, and use of selective serotonin reuptake inhibitors, benzodiazepines, or oral/transdermal estrogen) differed from predictors of mortality before NSF (age, walking speed, multimorbidity, weight change, shrinking, smoking, self‐rated health, dementia, and use of warfarin). Within nine subsets of women defined by tertiles of risk, 5‐year outcomes varied from 28% NSF and 8% mortality in the high‐risk NSF/low‐risk mortality subset, to 9% NSF and 22% mortality in the low‐risk NSF/high‐risk mortality subset. Similar results were seen for predictors of hip fracture and mortality before hip fracture. Conclusion: Considerable variation in 5‐year competing mortality risk is present among women in late life with similar 5‐year NSF risk. Both fracture risk and life expectancy should inform shared clinical decision‐making regarding initiation or continuation of osteoporosis drug therapy for women aged ≥80 years. [ABSTRACT FROM AUTHOR]

To observe developmental changes in the ovarian tissue structure and distribution characteristics of oestrogen receptors (ERs) in the ovaries of Huanghuai goats at different ages, we selected healthy Huanghuai goats ewes and divided them into five groups (i.e. 3‐, 30‐, 60‐, 90‐ and 120‐day‐old groups), with 10 animals in each group. The serum was separated after blood collection through the jugular vein, and the contents of oestrogen (E) and progesterone (P) in the serum of Huanghuai goats at each age were determined. Three goats were randomly selected from each group and sacrificed after anaesthesia, and the ovarian tissue was quickly obtained and placed in 4% paraformaldehyde fixative to prepare the tissue sections. Using HE, oestrogen receptors were immunohistochemically stained and observed. These results showed many primordial follicles and occasional secondary follicles in the ovaries of 3‐day‐old Huanghuai goats. Ovarian reticular structures were observed in 30‐day‐old ovarian medulla, with occasional near‐mature growing follicles. Mature follicles and corpus luteum were occasionally detected in 60‐day‐old ovarian cortex. The 90–120‐day‐old ovarian cortices contained growing and mature follicles, and the number of mature follicles and corpora lutea increased, implying a significant luteal involution period. The E and P contents in the 120‐day‐old group were significantly higher than those in the 3‐, 30‐, 60‐ and 90‐day‐old groups. The levels of ERα and ERβ in the 3‐ and 30‐day‐old groups were mainly distributed in the granulosa cells of ovarian reproductive epithelial cells, primordial follicles, atretic follicles, and primary and secondary follicles. The ERα and ERβ levels of the 60‐, 90‐ and 120‐day‐old groups were also distributed in the granulosa cells and luteal cells of mature follicles, especially in the 120‐day‐old endometrial cells of mature follicles, where ERβ was distributed significantly. The overall expression of ERβ in the ovary was higher than that of ERα. The results of this study provide basic data on the ovarian development and the specific expression of ERs and PRs in the ovaries of Huanghuai white goats, which play an important role in ovarian development and precocity. [ABSTRACT FROM AUTHOR]

In this study, we examined whether the frequency of exogenous oestrogen treatment affects the induction of artificial lactation and milk production. Furthermore, we analysed changes in milk components obtained from artificially lactating sows. Pseudopregnant induced by treatment with 30 mg of estradiol dipropionate (EDP) on Day 10 (Day 0 = the last day of estrus) were divided into three groups: those administered 5 mg of EDP once on Day 39 (n = 5), twice on Days 32 and 39 (n = 5) and three times on Days 25, 32 and 39 (n = 6). All animals were treated with prostaglandin F2α (PGF2α) on Day 46 for induced lactation. Artificial lactation was induced in 66.7%–80.0% of sows, and the EDP treatment frequency before PGF2α administration had no significant effect on either the induction rate of artificial lactation or the milk yield during the experimental period. The milk composition (levels of crude protein, crude fat, crude ash, lactose and immunoglobulin) did not differ among the groups. In conclusion, the number of EDP treatments prior to PGF2α administration had no effect on either the efficiency of artificial lactation induction or milk production. [ABSTRACT FROM AUTHOR]

Oestrogen is known to be strongly associated with ovarian cancer. There was much work to show the importance of lncRNA SNHG17 in ovarian cancer. However, no study has revealed the molecular regulatory mechanism and functional effects between oestrogen and SNHG17 in the development and metastasis of ovarian cancer. In this study, we found that SNHG17 expression was significantly increased in ovarian cancer and positively correlated with oestrogen treatment. Oestrogen could promote M2 macrophage polarization as well as ovarian cancer cells SKOV3 and ES2 cell exosomal SNHG17 expression. When exposure to oestrogen, exosomal SNHG17 promoted ovarian cancer cell proliferation, migration, invasion and epithelial‐mesenchymal transition (EMT) in vitro, and tumour growth and lung metastasis in vivo by accelerating M2‐like phenotype of macrophages. Mechanically, exosomal SNHG17 could facilitate the release of CCL13 from M2 macrophage via the PI3K‐Akt signalling pathway. Moreover, CCL13‐CCR2 axis was identified to be involved in ovarian cancer tumour behaviours driven by oestrogen. There results demonstrate a novel mechanism that exosomal SNHG17 exerts an oncogenic effect on ovarian cancer via the CCL13–CCR2–M2 macrophage axis upon oestrogen treatment, of which SNHG17 may be a potential biomarker and therapeutic target for ovarian cancer responded to oestrogen. [ABSTRACT FROM AUTHOR]

Triple–negative breast cancer (TNBC) is thought to be an estradiol–independent, hormone therapy–resistant cancer because of lack of estrogen receptor alpha 66 (ERα66). We identified a membrane–bound splice variant, ERα36, in TNBC cells that responds to estrogen (E2) and may contribute to bone osteolysis. We demonstrated that the MDA-MB-231 TNBC cell line, which expresses ERα36 similarly to MCF7 cells, is responsive to E2, forming osteolytic tumors in vivo. MDA-MB-231 cells activate osteoclasts in a paracrine manner. Conditioned media (CM) from MDA-MB-231 cells treated with bovine serum albumin–bound E2 (E2-BSA) increased activation of human osteoclast precursor cells; this was blocked by addition of anti–ERα36 antibody to the MDA-MB-231 cultures. Osteoclast activation and bone resorption genes were elevated in RAW 264.7 murine macrophages following treatment with E2-BSA–stimulated MDA-MB-231 CM. E2 and E2-BSA increased phospholipase C (PLC) and protein kinase C (PKC) activity in MDA-MB-231 cells. To examine the role of ERα36 signaling in bone osteolysis in TNBC, we used our bone–cancer interface mouse model in female athymic homozygous Foxn1nu mice. Mice with MDA-MB-231 tumors and treated with tamoxifen (TAM), E2, or TAM/E2 exhibited increased osteolysis, cortical bone breakdown, pathologic fracture, and tumor volume; the combined E2/TAM group also had reduced bone volume. These results suggest that E2 increased osteolytic lesions in TNBC through a membrane–mediated PLC/PKC pathway involving ERα36, which was enhanced by TAM, demonstrating the role of ERα36 and its membrane–associated signaling pathway in bone tumors. This work suggests that ERα36 may be a potential therapeutic target in patients with TNBC. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a common and highly metastatic cancer affecting people worldwide. Drug resistance and unwanted side effects are some of the limitations of current treatments for CRC. Naringenin (NAR) is a naturally occurring compound found in abundance in various citrus fruits such as oranges, grapefruits, and tomatoes. It possesses a diverse range of pharmacological and biological properties that are beneficial for human health. Numerous studies have highlighted its antioxidant, anticancer, and anti‐inflammatory activities, making it a subject of interest in scientific research. This review provides a comprehensive overview of the effects of NAR on CRC. The study's findings indicated that NAR: (1) interacts with estrogen receptors, (2) regulates the expression of genes related to the p53 signaling pathway, (3) promotes apoptosis by increasing the expression of proapoptotic genes (Bax, caspase9, and p53) and downregulation of the antiapoptotic gene Bcl2, (4) inhibits the activity of enzymes involved in cell survival and proliferation, (5) decreases cyclin D1 levels, (6) reduces the expression of cyclin‐dependent kinases (Cdk4, Cdk6, and Cdk7) and antiapoptotic genes (Bcl2, x‐IAP, and c‐IAP‐2) in CRC cells. In vitro CDK2 binding assay was also performed, showing that the NAR derivatives had better inhibitory activities on CDK2 than NAR. Based on the findings of this study, NAR is a potential therapeutic agent for CRC. Additional pharmacology and pharmacokinetics studies are required to fully elucidate the mechanisms of action of NAR and establish the most suitable dose for subsequent clinical investigations. Significance statement: The review discusses the molecular and biochemical processes related to naringenin (NAR's) effects on colorectal cancer (CRC), emphasizing its diverse pharmacological and biological properties. NAR interacts with estrogen receptors, regulates gene expression related to the p53 signaling pathway, promotes apoptosis, inhibits enzymes involved in cell survival and proliferation, decreases cyclin D1 levels, and reduces the expression of cyclin‐dependent kinases and antiapoptotic genes in CRC cells. In vitro studies demonstrate that NAR derivatives have better inhibitory activities on CDK2 than NAR, suggesting their potential as therapeutic agents for CRC. [ABSTRACT FROM AUTHOR]

About 70% of cases of breast cancer are compromised by Estrogen‐positive breast cancer. Through its regulation of several processes, including cell proliferation, cell cycle progression, and apoptosis, Estrogen signaling plays a pivotal role in the genesis and progression of this particular kind of breast cancer. One of the best treatment strategies for treating Estrogen‐positive breast cancer is blocking Estrogen signaling. However, patients' treatment failure is mainly caused by the emergence of resistance and metastases, necessitating the development of novel therapeutic targets. Numerous studies have shown long noncoding RNAs (lncRNAs) to play a role in Estrogen‐mediated carcinogenesis. These lncRNAs interact with co‐regulators and the Estrogen signaling cascade components, primarily due to Estrogen activation. Vimentin and E‐cadherin are examples of epithelial‐to‐mesenchymal transition markers, and they regulate genes involved in cell cycle progression, such as Cyclins, to affect the growth, proliferation, and metastasis of Estrogen‐positive breast cancer. Furthermore, a few of these lncRNAs contribute to developing resistance to chemotherapy, making them more desirable targets for enhancing results. Thus, to shed light on the creation of fresh approaches for treating this cancer, this review attempts to compile recently conducted studies on the relationship between lncRNAs and the advancement of Estrogen‐positive breast cancer. Significance Statement: Long noncoding RNAs (lncRNAs) correlated to Estrogen Receptor (ER)‐related cellular stress, suggesting that they could potentially have a role in the pathogenesis of breast cancer.LncRNAs regulate the growth, proliferation, and metastasis of ER‐positive breast cancer by controlling epithelial‐to‐mesenchymal transition signals and possibly cell cycle‐related genes.Since lncRNAs are involved in chemoresistance, they could be appealing prognostic, diagnostic, as well as therapeutic targets for ER‐positive breast cancer. [ABSTRACT FROM AUTHOR]

The circadian clock orchestrates many physiological and behavioural rhythms in mammals with 24‐h periodicity, through a hierarchical organisation, with the central clock located in the suprachiasmatic nucleus (SCN) in the hypothalamus. The circuits of the SCN generate circadian rhythms with precision, relying on intrinsic coupling mechanisms, for example, neurotransmitters like arginine vasopressin (AVP), vasoactive intestinal peptide (VIP), neuronal gamma‐aminobutyric acid (GABA) signalling and astrocytes connected by gap junctions composed of connexins (Cx). In female rodents, the presence of estrogen receptors (ERs) in the dorsal SCN suggests an influence of estrogen (E2) on the circuit timekeeping that could regulate circadian rhythm and coupling. To investigate this, we used SCN explants together with hypothalamic neurons and astrocytes. First, we showed that E2 stabilised the circadian amplitude in the SCN when rAVPs (receptor‐associated vasopressin peptides) were inhibited. However, the phase delay induced by VIPAC2 (VIP receptors) inhibition remained unaffected by E2. We then showed that E2 exerted its effects in the SCN via ERβ (estrogen receptor beta), resulting in increased expression of Cx36 and Cx43. Notably, specific inhibition of both connexins resulted in a significant reduction in circadian amplitude within the SCN. Remarkably, E2 restored the period with inhibited Cx36 but not with Cx43 inhibition. This implies that the network between astrocytes and neurons, responsible for coupling in the SCN, can be reinforced through E2. In conclusion, these findings provide new insights into how E2 regulates circadian rhythms ex vivo in an ERβ‐dependent manner, underscoring its crucial role in fortifying the SCN's rhythm. [ABSTRACT FROM AUTHOR]

Aim: To characterize the effects of CO2 laser treatment and estrogen treatment on vaginal microbiota in patients with genitourinary syndrome of menopause (GSM). Methods: Sixty‐four patients with genitourinary syndrome were divided into the estrogen group, the CO2 laser group, and the control group. The control group did not receive any treatment. Vaginal mucosa was collected after 3 and 12 months of treatment. The former was used for 16S rRNA sequencing, and the latter was used for pathological evaluation. Vaginal health and voiding function were assessed using the vaginal health index (VHI) scale and the UDI‐6 scale at 3 and 12 months after treatment. Results: The results showed that both treatments reduced alpha diversity in the vaginal flora. Additionally, the abundance of 65 genera differed significantly between the treatment and control groups, with an increase in potentially beneficial bacteria such as Lactobacillus, IheB3_7, Mycoplasma urealyticum, and Streptococcus. In addition, the VHI and UDI‐6 scores improved in both treatment groups compared to the control group after 3 months. Whereas VHI and UDI‐6 scores were close to baseline in the estrogen group, and remained significantly improved in the CO2 laser group after 12 months. Pathological results showed that both methods improved the vaginal health status of patients with GSM after 12 months of treatment. However, the CO2 group exhibited a more significant increase in type III collagen. Conclusions: Both CO2 laser and estrogen therapies can regulate the vaginal flora imbalance of GSM and improve the corresponding symptoms. However, the long‐term efficacy of CO2 laser therapy is superior compared to estrogen therapy. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a complex disease of multifactorial origin. While registries have demonstrated that women are more susceptible to the disease, females with PAH have superior right ventricle (RV) function and a better prognosis than their male counterparts, a phenomenon referred to as the 'estrogen paradox'. Numerous pre‐clinical studies have investigated the involvement of sex hormones in PAH pathobiology, often with conflicting results. However, recent advances suggest that abnormal estrogen synthesis, metabolism and signalling underpin the sexual dimorphism of this disease. Other sex hormones, such as progesterone, testosterone and dehydroepiandrosterone may also play a role. Several non‐hormonal factor including sex chromosomes and epigenetics have also been implicated. Though the underlying pathophysiological mechanisms are complex, several compounds that modulate sex hormones levels and signalling are under investigation in PAH patients. Further elucidation of the estrogen paradox will set the stage for the identification of additional therapeutic targets for this disease. [ABSTRACT FROM AUTHOR]

Endometrioid adenocarcinoma (EEC) is one of the most common cancers of the female reproductive system. In recent years, much emphasis has been placed on early diagnosis and treatment. PAX2 (Paired box 2) inactivation is reportedly an important biomarker for endometrioid intraepithelial neoplasia (EIN) and EEC. However, the role of PAX2 in EEC carcinogenesis remains unclear. PAX2 expression and associated clinical characteristics were analyzed via The Cancer Genome Atlas, Gene Expression Omnibus, and Cancer Cell Line Encyclopedia databases and clinical paired EIN/EEC tissue samples. Bioinformatic analysis was conducted to identify the putative molecular function and mechanism of PAX2. Cell proliferation, colony formation, cell migration, and invasion assays in vitro, and mouse xenograft models were utilized to study the biological functions of PAX2 in vivo. Pyrosequencing and the demethylating drug 5‐Aza‐dc were used to verify promoter methylation in clinical tissues and cell lines, respectively. The mechanism underlying the regulatory effect of estrogen (E2) and progesterone (P4) on PAX2 expression was investigated by receptor block assay and double luciferase reporter assay. PAX2 expression was found to be significantly downregulated in EIN and EEC tissues, its overexpression inhibited EEC cell malignant behaviors in vivo and in vitro and inhibited the AKT/mTOR signaling pathway. PAX2 inactivation in EEC was related to promoter methylation, and its expression was regulated by E2 and P4 through their receptors via promoter methylation. Our findings elucidated the expression and function of PAX2 in EEC and have provided hitherto undocumented evidence of the underlying molecular mechanisms. PAX2 expression is suppressed by estrogen prompting its methylation through estrogen receptor. Furthermore, PAX2 regulates the AKT/mTOR signaling pathway to influence EEC progression. © 2024 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Malic enzyme (ME) genes are key functional metabolic enzymes playing a crucial role in carcinogenesis. However, the detailed effects of ME gene expression on breast cancer progression remain unclear. Here, our results revealed ME1 expression was significantly upregulated in breast cancer, especially in patients with oestrogen receptor/progesterone receptor‐negative and human epidermal growth factor receptor 2‐positive breast cancer. Furthermore, upregulation of ME1 was significantly associated with more advanced pathological stages (p < 0.001), pT stage (p < 0.001) and tumour grade (p < 0.001). Kaplan–Meier analysis revealed ME1 upregulation was associated with poor disease‐specific survival (DSS: p = 0.002) and disease‐free survival (DFS: p = 0.003). Multivariate Cox regression analysis revealed ME1 upregulation was significantly correlated with poor DSS (adjusted hazard ratio [AHR] = 1.65; 95% CI: 1.08–2.52; p = 0.021) and DFS (AHR, 1.57; 95% CI: 1.03–2.41; p = 0.038). Stratification analysis indicated ME1 upregulation was significantly associated with poor DSS (p = 0.039) and DFS (p = 0.038) in patients with non‐triple‐negative breast cancer (TNBC). However, ME1 expression did not affect the DSS of patients with TNBC. Biological function analysis revealed ME1 knockdown could significantly suppress the growth of breast cancer cells and influence its migration ability. Furthermore, the infiltration of immune cells was significantly reduced when they were co‐cultured with breast cancer cells with ME1 knockdown. In summary, ME1 plays an oncogenic role in the growth of breast cancer; it may serve as a potential biomarker of progression and constitute a therapeutic target in patients with breast cancer. [ABSTRACT FROM AUTHOR]

Aims: Serum sex hormones have been linked to cardiovascular disease risk. However, their roles in the pathogenesis of heart failure (HF) in both men and women are unclear. We investigated the associations between free androgen, testosterone, and estradiol, and future risk of HF. Methods and results: This prospective cohort study evaluated UK Biobank participants free of prevalent cardiovascular disease and HF at baseline. Unitless free androgen, testosterone, and estradiol indices were generated using serum concentrations of total testosterone (nmol/L), estradiol (pmol/L), sex hormone binding globulin (SHBG, nmol/L), and albumin (g/L) in blood collected at enrolment. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident HF in relation to quartiles (Q) of free androgen (FAI), testosterone (FTI), estradiol (FEI) indices, and potential confounders. There were 180 712 men (including 5585 HF cases with FAI and 571 HF cases with FEI), and 177 324 women (including 2858 HF cases with FAI and 314 HF cases with FEI) with complete data. Increased FAI was associated with decreased HF risk in both men (HRQ4 vs. Q1: 0.86, 95% CI 0.79–0.94, p‐trendcontinuous < 0.0001) and post‐menopausal women (HRQ4 vs. Q1: 0.83, 95% CI 0.73–0.95). Similar inverse associations were observed for FTI only in men (HRQ4 vs. Q1: 0.91, 95% CI 0.83–0.98). Higher FEI was significantly associated with decreased HF risk among men (HRQ4 vs. Q1: 0.76, 95% CI 0.59–0.98), but was positively associated among pre‐menopausal women (HRQ4 vs. Q1: 2.16, 95% CI 1.11–4.18). Conclusions: Sex hormones potentially influence HF pathogenesis and may offer pathways for interventions. [ABSTRACT FROM AUTHOR]

Objective: Previvor is a term applied to a person with an identified, elevated lifetime cancer risk but without an actual cancer diagnosis. Previvorship entails the selection of risk management strategies. For women with a genetic mutation that increases their predisposition for a breast cancer diagnosis, bilateral risk‐reducing mastectomy (BRRM) is the most effective prevention strategy. However, BRRM can change a woman's breast appearance and function. The purpose of this qualitative metasynthesis (QMS) was to better understand the decision‐making process for BRRM among previvors. Methods: A theory‐generating QMS approach was used to analyze and synthesize qualitative findings. Research reports were considered for inclusion if: (1) women over 18 years of age possessed a genetic mutation increasing lifetime breast cancer risk or a strong family history of breast cancer; (2) the sample was considering, or had completed, BRRM; (3) the results reported qualitative findings. Exclusion criteria were male gender, personal history of breast cancer, and research reports which did not separate findings based on cancer diagnosis and/or risk‐reduction surgery. Results: A theory and corresponding model emerged, comprised of seven themes addressing the decision‐making process for or against BRRM. While some factors to decision‐making were decisive for surgery, others were more indefinite and contributed to women changing, processing, or suspending their decision‐making for a period of time. Conclusions: Regardless of the decision previvors make about BRRM, physical and psychosocial well‐being should be considered and promoted through shared decision‐making in the clinical setting. [ABSTRACT FROM AUTHOR]

Background: Experts define the Genitourinary Syndrome of Menopause (GSM) as a collection of signs and symptoms associated with decreased oestrogen levels. Its prevalence ranges between 13% and 87% in postmenopausal women. Objective: We aimed to describe the main pathophysiology mechanisms of GSM affecting the lower urinary tract and the manifestations and treatment options for lower urinary tract dysfunction in GSM. Results: Several treatments and recommendations have been proposed to enhance patients' ability to manage their symptoms, such as regular sexual activity or masturbation, to increase this physiological response and reduce the severity of GSM. Conclusion: GSM is a multifactorial and complex syndrome that affects postmenopausal women. Impairment of urogenital structures implies diverse manifestations of genital atrophy and lower urinary tract symptoms. [ABSTRACT FROM AUTHOR]

Background: Selective oestrogen receptor modulators and aromatase inhibitors stimulate endogenous gonadotrophins and testosterone in men with hypogonadism. There are no systematic reviews/meta‐analyses assessing the effects of selective oestrogen receptor modulators/aromatase inhibitors on semen parameters in men with secondary hypogonadism. Objectives: To assess the effect of monotherapy or a combination of selective oestrogen receptor modulators/aromatase inhibitors on sperm parameters and/or fertility in men with secondary hypogonadism. Materials and methods: A systematic search was conducted in PubMed, MEDLINE, Cochrane Library and ClinicalTrials.gov. Study selection and data extraction were performed by two reviewers independently. Randomised controlled trials and non‐randomised studies of interventions reporting effects of selective oestrogen receptor modulators and/or aromatase inhibitors on semen parameters or fertility in men with low testosterone with low/normal gonadotrophins were selected. The risk of bias was assessed using ROB‐2 and ROBINS‐I tools. The results of randomised controlled trials were summarised using vote counting while summarising effect estimates where available. Non‐randomised studies of intervention meta‐analysis were conducted using the random‐effect model. The certainty of evidence was assessed using GRADE. Results: Five non‐randomised studies of interventions (n = 105) of selective oestrogen receptor modulators showed an increase in sperm concentration (pooled mean difference 6.64 million/mL; 95% confidence interval 1.54, 11.74, I2 = 0%) and three non‐randomised studies of interventions (n = 83) of selective oestrogen receptor modulators showed an increase in total motile sperm count (pooled mean difference 10.52; 95% confidence interval 1.46–19.59, I2 = 0%), with very low certainty of evidence. The mean body mass index of participants was >30 kg/m2. Four randomised controlled trials (n = 591) comparing selective oestrogen receptor modulators to placebo showed a heterogeneous effect on sperm concentration. Three included men with overweight or obesity. The results were of very low certainty of evidence. Limited pregnancy or live birth data were available. No studies comparing aromatase inhibitors with placebo or testosterone were found. Discussion and conclusion: Current studies are of limited size and quality but suggest that selective oestrogen receptor modulators may improve semen parameters in those patients, particularly when associated with obesity. [ABSTRACT FROM AUTHOR]

Failure of healing after rotator cuff repair (RCR) is common. The purpose of the current study was to evaluate the effect of systemic estrogen or testosterone supplementation on tendon healing after RCR. Seventy‐two adult male mice were utilized for all experiments. The supraspinatus tendon was transected and repaired with 6‐0 Prolene suture on the left shoulder of 51 animals. Mice were segregated into three groups postoperative: (1) vehicle group (VG; n = 18), (2) estrogen group (EST; n = 17), and (3) testosterone group (TST; n = 16). An unrepaired control group (unrepaired, n = 21) did not have surgery. Utilizing these animals, histological analysis, activity testing, biomechanical testing and RNA sequencing (RNA‐seq) was performed. At 8 weeks post‐RCR, TST, and EST supplementation improved the overall histologic structure of the repaired enthesis site. No differences in ultimate failure loads or stiffness were detected between VG, EST, and TST groups after biomechanical testing. RCR caused a reduction in wheel activity compared to unrepaired controls and supplementation with TST restored wheel activity. RNA‐seq analysis indicated that estrogen and testosterone regulated different pathways associated with enthesis healing, including a suppression of inflammatory signaling. Supplementation with sex hormones improved the structure of the repaired tendon enthesis and significantly regulated expression of diverse pathways regulating multiple biological processes. Testosterone administration following RCR restored wheel activity without having a detrimental impact on biomechanical strength. Future human studies of sex hormone supplementation after RCR are warranted as supplementation in an animal model may improve tendon enthesis healing. [ABSTRACT FROM AUTHOR]

Estrogen receptor is an important target in breast cancer. Serotonin receptors (5‐HT2A and 5‐HT2C, in particular) were investigated for a potential role in development and progression of breast cancer. Ligands that interact with estrogenic receptors influence the emotional state of females. Thus, designing selective estrogen receptor modulator (SERM) analogs with potential serotonergic activity is a plausible approach. The dual ligands can augment cytotoxic effect of SERMs, help in both physical and emotional menopausal symptom relief, enhance cognitive function and support bone health. Herein, we report triarylethylene analogs as potential candidates for treatment of breast cancer. Compound 2e showed (ERα relative β‐ galactosidase activity = 0.70), 5‐HT2A (Ki = 0.97 µM), and 5‐HT2C (Ki = 3.86 µM). It was more potent on both MCF‐7 (GI50 = 0.27 µM) and on MDA‐MB‐231 (GI50 = 1.86 µM) compared to tamoxifen (TAM). Compound 4e showed 40 times higher antiproliferative activity on MCF‐7 and 15 times on MDA‐MBA compared to TAM. Compound 4e had higher average potency than TAM on all nine tested cell line panels. Our in‐silico model revealed the binding interactions of compounds 2 and 2e in the three receptors; further structural modifications are suggested to optimize binding to the ERα, 5‐HT2A, and 5‐HT2C. [ABSTRACT FROM AUTHOR]

Cartilage is frequently used as a scaffolds for repairing and reconstructing body surface organs. However, after successful plastic surgery, transplanted cartilage scaffolds often exhibit deformation and absorption over time. To enhance the shaping stability of cartilage scaffolds and improve patients' satisfaction after reconstructions, we employed the ear folding models in New Zealand rabbits to confirm whether the 1064nm neodymium‐doped yttrium aluminum garnet (Nd:YAG) laser could promote cartilage reshaping. There was an increase in collagen and aromatase (Cyp19) expression within the ear cartilage after laser treatment. Moreover, we have found that the Cyp19 inhibitor can inhibit the laser's effect on cartilage shaping and reduce collagen and Cyp19 expression. The overall findings suggest that treatment with 1064nm Nd:YAG laser irradiation can enhance estrogen levels in local cartilage tissues by upregulating Cyp19 expression in chondrocytes through photobiomodulation, thereby promoting the proliferation and collagen secretion of chondrocytes to improve cartilage reshaping and stability. [ABSTRACT FROM AUTHOR]

Proteolysis‐targeting chimeras (PROTACs) are essential bifunctional molecules that target proteins of interest (POIs) for degradation by cellular ubiquitination machinery. Despite significant progress made in understanding PROTACs' functions, their therapeutic potential remains largely untapped. As a result of the success of highly flexible, scalable, and low‐cost mRNA therapies, as well as the advantages of the first generation of peptide PROTACs (p‐PROTACs), we present for the first time an engineering mRNA PROTACs (m‐PROTACs) strategy. This design combines von Hippel–Lindau (VHL) recruiting peptide encoding mRNA and POI‐binding peptide encoding mRNA to form m‐PROTAC and promote cellular POI degradation. We then performed proof‐of‐concept experiments using two m‐PROTACs targeting two cancer‐related proteins, estrogen receptor alpha and B‐cell lymphoma‐extra large protein. Our results demonstrated that m‐PROTACs could successfully degrade the POIs in different cell lines and more effectively inhibit cell proliferation than the traditional p‐PROTACs. Moreover, the in vivo experiment demonstrated that m‐PROTAC led to significant tumor regression in the 4T1 mouse xenograft model. This finding highlights the enormous potential of m‐PROTAC as a promising approach for targeted protein degradation therapy. [ABSTRACT FROM AUTHOR]

Objectives: Endocrinal variations within an individual impact the electrolyte composition, pH, and flow‐rate (FR) of saliva. The aim of this study was to evaluate the gender‐specific differences and the effect of combined estrogen‐progestin oral contraceptives (COCs) on FR, pH, and electrolyte concentrations in the parotid saliva (PS) of a group of healthy adults. Material and Methods: Stimulated PS was collected from 20 healthy adults using a Lashley cup; 11 males, 8 females, and 1 female undertaking combined contraceptive therapy (levonorgestrel/ethinyloestradiol 0.1 mg + 0.02 mg). FR and pH were recorded for each saliva sample. Electrolytes concentrations (Na+, Ca2+, K+, Mg2+) were measured using inductively coupled plasma optical emission spectrometer (ICP‐OES). Statistical analysis was performed, and the significance level was set at p <.05. Results: PS FR varied from 0.13 to 0.42 mL/min in females not taking any medication and from 0.08 to 0.5 mL/min in males not taking any medication. PS pH of females and males not taking any medication ranged from 6.23 to 7.50 and from 6.15 to 7.55. PS pH and FR of the female taking COCs were 6.5 and 0.1 mL/min. PS pH, FR, and electrolytes concentrations (Ca2+, Na+, K+, Mg2+) were not statistically significantly different between females and males not taking any medication. PS concentrations of Ca2+ and Na+ were significantly higher in the females taking COCs than in the females not taking any medication. Whereas, concentrations of K+ and Mg2+ did not differ significantly between the females taking COCs and the females not taking any medication. Conclusions: There are no significant gender‐specific differences in PS flow rate, pH, and electrolyte concentrations of Na+, Ca2+, Mg2+, and K+. Combined hormonal oral contraceptive has a significant effect on PS flow rate, pH, Ca2+, and Na+ concentrations. Whereas the PS concentration of K+ and Mg2+ are not influenced by COCs. These results warrant further investigation. [ABSTRACT FROM AUTHOR]

Objective: Mandibular condylar cartilage (MCC) of the rat was examined with the Fourier‐transform infrared (FITR) spectroscopic imaging to study the effects of ageing, oestrogen level and altered dietary loading on the structure of MCC. Materials and Methods: The Sprague–Dawley rats (n = 96) aged 5 and 14 months were divided into 12 subgroups according to age, oestrogen status (ovariectomized [OVX], non‐ovariectomized [non‐OVX)]) and diet (hard, normal, soft). Specimens of the MCC were examined with FTIR spectroscopic imaging to quantify the distribution of collagens and proteoglycans. MCC was divided sagittally into three segments: anterior, most superior and posterior. From each segment, the collagen and proteoglycan contents at different depths of cartilage were statistically compared between the groups using an N‐way analysis of variance (ANOVA). Results: The amount of collagen content was significantly associated with old age in the deep layer of the anterior segment and in the middle layer of the posterior segment of MCC. In the deep layer of the most superior segment, the collagen content also increased with ageing. The amount of proteoglycan content increased significantly when dietary loading increased, and the oestrogen level decreased in the deep layer of the most superior segment of MCC. Conclusion: Ageing, oestrogen level and altered dietary loading have a significant effect on the location and content of collagens and proteoglycans of rat MCC. Ageing significantly increased the amount of collagen content in the superior and posterior segments, being highest in the older soft‐diet rats. Decreased oestrogen levels and increased dietary loading increased the amount of proteoglycan content. [ABSTRACT FROM AUTHOR]

Objective: Idiopathic subglottic stenosis (iSGS) is a rare, recurrent, fibroinflammatory disease affecting the larynx and proximal trachea. Given it occurs primarily in adult females, estrogen is speculated to play a central pathophysiological role. This study aimed to evaluate relationships between estrogen exposure, disease progression, and recurrence. Methods: North American Airway Collaborative (NoAAC) data of adults with iSGS obstructive airway lesions, who underwent index endoscopic airway dilation, were used to identify associations between estrogen exposure, disease characteristics, and time to recurrence (TTR), and interventions were analyzed using Kruskal–Wallis test and Pearson coefficient. Cox proportional hazards regression models compared hazard ratios by estrogen exposure. Kaplan–Meier curves were plotted for TTR based on menopausal status. Results: In all, 533 females had complete estrogen data (33% premenopausal, 17% perimenopausal, 50% postmenopausal). Median estrogen exposure was 28 years. Overall, there was no dose–response relationship between estrogen exposure and disease recurrence. Premenopausal patients had significantly shorter time from symptom manifestation to diagnosis (1.17 vs. 1.42 years perimenopausal vs. 2.08 years postmenopausal, p < 0.001), shorter time from diagnosis to index endoscopic airway dilation (1.90 vs. 2.50 vs. 3.76 years, p = 0.005), and higher number of procedures (1.73 vs. 1.20 vs. 1.08 procedures, p < 0.001). Conclusions: We demonstrate premenopausal patients may have a more aggressive disease variant than their peri‐ and postmenopausal counterparts. However, it is unclear as to whether this is related to reduced estrogen in the peri‐ and postmenopausal states or the age‐related physiology of wound healing and inflammation, regardless of estrogen. Level of Evidence: 3 Laryngoscope, 134:825–830, 2024 [ABSTRACT FROM AUTHOR]

Polycystic ovarian syndrome (PCOS) is an endocrinological disorder aroused due to hormonal disturbances. It is characterized by anovulation due to an excess of androgen and estrogen hormones, thus leading to the formation of multiple cysts, imposing life‐threatening conditions. This manuscript aimed to introduce a natural estrogen receptor (ESR) inhibitors that can provide protection against PCOS. The computational analysis of Linum usitatissimum seeds compounds against ESR alpha receptor was performed, and the binding affinities of the ligand compounds and receptor proteins were scrutinized. Nine lignin compounds were docked, and the results were compared with that of reference estrogen receptor inhibitors, clomiphene, and tamoxifen. The binding affinity scores for pinoresinol, lariciresinol, secoisolariciresinol, and matairesinol were −10.67, −10.66, −10.91, and −10.60 kcal mol−1, respectively. These were comparable to the binding affinity score of reference compounds −11.406 kcal mol−1 for clomiphene and −10.666 kcal mol−1 for tamoxifen. Prime MM‐GBSA studies showcased that Linum usitatissimum seeds compounds exhibit significant efficacy and efficiency towards receptor protein. Moreover, MD‐simulation studies were performed and the results depict that the lignin compounds form stable complexes at 300 K throughout the simulation time. For further clarity, in‐vitro experiments were carried out. The results exhibit the decline in cell proliferation in a concentration‐dependent manner by extract 1 (ethyl acetate) EX1 and extract 2 (petroleum ether) EX2. Hence, providing evidence regarding the anti‐estrogenic activity of the sample extracts. Collectively, these results showed that flax seed can reduce the levels of estrogen, which can induce ovulation and prevent cyst formation, and ultimately can provide protection against PCOS. Significance statement: The Linum usitatissimum (flax seeds) plant has been traditionally used in the past for treating different diseases. In this study, natural estrogen receptor inhibitors were analyzed, and they were proven to show the desired results for the management of polycystic ovarian syndrome (PCOS). Herein the affinity of naturally occurring compounds, lignin from flax seeds as natural estrogen inhibitors for estrogen receptor (ESR) alpha, was determined using the in silico and in vitro approaches. In this regard, four lignin compounds from flax seeds, pinoresinol (1), lariciresinol (2), secoisolariciresinol (3), and matairesinol (4), were considered and studied against ESR alpha protein by molecular docking, prime MM‐GBSA calculations and Molecular‐dynamic simulations. The in silico and in vitro study of lignans in flax seeds provided evidence that besides their antioxidant effect on the body, they can also inhibit ESRs. The results of both these studies opened a gateway and provided a convenient approach for the management of PCOS and better ovulation. Thus, this manuscript focuses on outlining the affinity, stability, efficacy, toxicity, and potential of the flax seed compounds, under analysis, to assess how well they could emerge as a viable natural therapy for PCOS in the future. These natural inhibitors have the benefit of being less hazardous, and have comparable inhibitory action against ESR than synthetic medicines available commercially. Moreover, they not only protect against PCOS but also help to alleviate the harmful effects resulting from PCOS. Additionally, plant‐based medicines are more affordable and readily available than commercial medications in countries with less developed healthcare systems. [ABSTRACT FROM AUTHOR]

Lung diseases characterized by type 2 inflammation are reported to occur with a female bias in prevalence/severity in both humans and mice. This includes previous work examining multi‐walled carbon nanotube (MWCNT)‐induced eosinophilic inflammation, in which a more exaggerated M2a phenotype was observed in female alveolar macrophages (AMs) compared to males. The mechanisms responsible for this sex difference in AM phenotype are still unclear, but estrogen receptor (ER) signaling is a likely contributor. Accordingly, male AMs downregulated ERα expression after MWCNT exposure while female AMs did not. Thus, ER antagonist Fulvestrant was administered prior to MWCNT instillation. In females, Fulvestrant significantly attenuated MWCNT‐induced M2a gene expression and eosinophilia without affecting IL‐33. In males, Fulvestrant did not affect eosinophil recruitment but reduced IL‐33 and M2a genes compared to controls. Regulation of cholesterol efflux and oxysterol synthesis is a potential mechanism through which estrogen promotes the M2a phenotype. Levels of oxysterols 25‐OHC and 7α,25‐OHC were higher in the airways of MWCNT‐exposed males compared to MWCNT‐females, which corresponds with the lower IL‐1β production and greater macrophage recruitment previously observed in males. Sex‐based changes in cholesterol efflux transporters Abca1 and Abcg1 were also observed after MWCNT exposure with or without Fulvestrant. In vitro culture with estrogen decreased cellular cholesterol and increased the M2a response in female AMs, but did not affect cholesterol content in male AMs and reduced M2a polarization. These results reveal the modulation of (oxy)sterols as a potential mechanism through which estrogen signaling may regulate AM phenotype resulting in sex differences in downstream respiratory inflammation. [ABSTRACT FROM AUTHOR]

Characterization of the interleukin (IL)‐10 knockout (KO) mouse with chronic gut inflammation, cardiovascular dysfunction, and bone loss suggests a critical role for this cytokine in interorgan communication within the gut, bone, and cardiovascular axis. We sought to understand the role of IL‐10 in the cross‐talk between these systems. Six‐week‐old IL‐10 KO mice and their wild type (WT) counterparts were maintained on a standard rodent diet for 3 or 6 months. Gene expression of proinflammatory markers and Fgf23, serum 17β‐estradiol (E2), and cardiac protein expression were assessed. Ileal Il17a and Tnf mRNA increased while Il6 mRNA increased in the bone and heart by at least 2‐fold in IL‐10 KO mice. Bone Dmp1 and Phex mRNA were repressed at 6 months in IL‐10 KO mice, resulting in increased Fgf23 mRNA (~4‐fold) that contributed to increased fibrosis. In the IL‐10 KO mice, gut bacterial β‐glucuronidase activity and ovarian Cyp19a1 mRNA were lower (p < 0.05), consistent with reduced serum E2 and reduced cardiac pNOS3 (Ser1119) in these mice. Treatment of ileal lymphocytes with E2 reduced gut inflammation in WT but not IL‐10 KO mice. In conclusion, our data suggest that diminished estrogen and defective bone mineralization increased FGF23 which contributed to cardiac fibrosis in the IL‐10 KO mouse. [ABSTRACT FROM AUTHOR]

Background: Adult women with Turner syndrome (TS) have high rates of miscarriage, presumably due to the abnormal size and shape of the uterus. There is a paucity of data regarding the determinants of uterine volume (UtVol) in young girls with TS before the initiation of oestrogen replacement therapy (ERT). Methods: We performed a cross‐sectional study on premenarchal girls with TS, aged 5–15 years, pubertal stage B1–B3, not having received ERT (n = 73) and 50 age‐matched healthy controls. Anthropometric parameters and a history of growth hormone (GH) therapy (≥1 year) were noted. Uterine length (UtL), UtVol, and mean‐ovarian‐volume (MOV) standard‐deviation scores (SDS) were determined from transabdominal ultrasonography data. Results: Girls with TS had lower median UtVol‐SDS (−1.07 vs. 0.86; p <.001), UtL‐SDS (−3.72 vs. −0.41; p <.001) and MOV‐SDS (−5.53 vs. 1.96; p <.001) compared to age‐matched controls. Among TS girls, recipients of GH (n = 38) had higher UtVol‐SDS (−0.63 vs. −1.39; p =.0001), UtL‐SDS (−1.73 vs. −6.49; p <.0001) but similar MOV‐SDS compared to nonrecipients (n = 35). Those with normal uterine volume for age (NUVA, n = 29) had earlier initiation (7.8 vs. 9.3 years; p =.03) and a longer duration of GH (3.71 vs. 2.14 years; p =.002) than those with low UtVol for age (n = 44). UtVol‐SDS correlated with duration of GH (ρ = 0.411, p =.01) and negatively with age at GH initiation (ρ = −0.479, p =.003). In a model adjusted for pubertal status, karyotype and height‐SDS, GH use could independently predict having NUVA (odds ratio: 5.09, confidence interval: 1.63–15.94, p =.005). Conclusion: GH therapy has a stimulatory effect on uterine dimensions in pre‐and peripubertal girls with TS. Earlier initiation and longer duration of GH is important in TS girls before ERT. [ABSTRACT FROM AUTHOR]

Background: Intratumour heterogeneity is a hallmark of most solid tumours, including breast cancers. We applied spatial transcriptomics and single‐cell RNA‐sequencing on patient‐derived xenografts (PDXs) to profile spatially resolved cell populations within oestrogen receptor‐positive (ER+) breast cancer and to elucidate their importance in oestrogen‐dependent tumour growth. Methods: Two PDXs of 'ER‐high' breast cancers with opposite oestrogen‐mediated growth responses were investigated: oestrogen‐suppressed GS3 (80–100% ER) and oestrogen‐dependent SC31 (40–90% ER) models. The observation was validated via single‐cell analyses on an 'ER‐low' PDX, GS1 (5% ER). The results from our spatial and single‐cell analyses were further supported by a public ER+ breast cancer single‐cell dataset and protein‐based dual immunohistochemistry (IHC) of SC31 examining important luminal cancer markers (i.e., ER, progesterone receptor and Ki67). The translational implication of our findings was assessed by clinical outcome analyses on publicly available cohorts. Results: Our space‐gene‐function study revealed four spatially distinct compartments within ER+ breast cancers. These compartments showed functional diversity (oestrogen‐responsive, proliferative, hypoxia‐induced and inflammation‐related). The 'proliferative' population, rather than the 'oestrogen‐responsive' compartment, was crucial for oestrogen‐dependent tumour growth, leading to the acquisition of luminal B‐like features. The cells expressing typical oestrogen‐responsive genes like PGR were not directly linked to oestrogen‐dependent proliferation. Dual IHC analyses demonstrated the distinct contribution of the Ki67+ proliferative cells toward oestrogen‐mediated growth and their response to a CDK4/6 inhibitor. The gene signatures derived from the proliferative, hypoxia‐induced and inflammation‐related compartments were significantly correlated with worse clinical outcomes, while patients with the oestrogen‐responsive signature showed better prognoses, suggesting that this compartment would not be directly associated with oestrogen‐dependent tumour progression. Conclusions: Our study identified the gene signature in our 'proliferative' compartment as an important determinant of luminal cancer subtypes. This 'proliferative' cell population is a causative feature of luminal B breast cancer, contributing toward its aggressive behaviours. [ABSTRACT FROM AUTHOR]