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Small molecule inhibitors of the mono (ADP) ribosyl transferase PARP7 are being evaluated as a monotherapy for tumors overexpressing PARP7 and in combination with immune checkpoint blockade. We previously showed that sensitivity to the PARP7 inhibitor (PARP7i) RBN-2397 could be enhanced by co-treatment with agonists of the Aryl Hydrocarbon Receptor (AHRa) in cell lines that show strong intrinsic sensitivity to RBN-2397. Here we demonstrate that a range of tumor cell lines that are relatively insensitive to PARP7i or AHRa as individual agents are unexpectedly profoundly sensitive to the combination. Our data show that this synergistic response is dependent on AHR/ARNT and is associated with increased levels of nuclear AHR and increased transcription of AHR target genes. In some hormone receptor-positive cell lines, we find that combination treatment is associated with proteasomal turnover of the steroid hormone receptors, androgen receptor and estrogen receptor. Both wildtype and hormone-resistant mutant forms of these receptors are degraded upon treatment with AHRa and PARP7i in breast and prostate cancer models. These results suggest that combining PARP7i with AHRa may extend the utility of these drugs to a wider range of tumors, including those that are refractory to hormone therapy.

Only a handful of somatic alterations have been linked to endocrine therapy resistance in hormone-dependent breast cancer, potentially explaining ∼40% of relapses. If other mechanisms underlie the evolution of hormone-dependent breast cancer under adjuvant therapy is currently unknown. In this work, we employ functional genomics to dissect the contribution of cis-regulatory elements (CRE) to cancer evolution by focusing on 12 megabases of noncoding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Parallel epigenetic perturbation (CRISPRi) in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies a limited set of noncoding changes potentially involved in therapy resistance. Overall, our data uncover how endocrine therapies trigger the emergence of transient features which could ultimately be exploited to hinder the adaptive process. Significance: This study shows that cells adapting to endocrine therapies undergo changes in the usage or regulatory regions. Dormant cells are less vulnerable to regulatory perturbation but gain transient dependencies which can be exploited to decrease the formation of dormant persisters.

Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER+) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER+ human epidermal growth factor receptor-negative (HER2-) metastatic breast cancer (mBC). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as monotherapy and in combination with fulvestrant, were met. Secondary endpoints included characterization of PK and evaluation of antitumor activity, including objective response rate (ORR) and progression-free survival (PFS). Common treatment-related adverse events (any grade; grades 3-4) included dysgeusia (83.2%, 0%), neutropenia (59.8%, 35.5%) and anemia (48.6%, 13.1%). Exposure was approximately dose proportional. Antitumor activity was observed as monotherapy. For the PF-07248144-fulvestrant combination (n = 43), the ORR (95% confidence interval (CI)) was 30.2% (95% CI = 17.2-46.1%) and the median PFS was 10.7 (5.3-not evaluable) months. PF-07248144 demonstrated a tolerable safety profile and durable antitumor activity in heavily pretreated ER+HER2- mBC. These findings establish KAT6A and KAT6B as druggable cancer targets, provide clinical proof of concept and reveal a potential avenue to treat mBC. clinicaltrial.gov registration: NCT04606446 .

The prevalence and progression of cancer differ in males and females, and thus, sexual dimorphism in tumor development directly impacts clinical research and medicine. Long non-coding RNAs (lncRNAs) are increasingly recognized as important players in gene expression and various cellular processes, including cancer development and progression. In recent years, lncRNAs have been implicated in the differences observed in cancer incidence, progression, and treatment responses between men and women. Here, we present a brief overview of the current knowledge regarding the role of lncRNAs in cancer sex dimorphism, focusing on how they affect epigenetic processes in male and female mammalian cells. We discuss the potential mechanisms by which lncRNAs may contribute to sex differences in cancer, including transcriptional control of sex chromosomes, hormonal signaling pathways, and immune responses. We also propose strategies for studying lncRNA functions in cancer sex dimorphism. Furthermore, we emphasize the importance of considering sex as a biological variable in cancer research and the need to investigate the role lncRNAs play in mediating these sex differences. In summary, we highlight the emerging link between lncRNAs and cancer sex dimorphism and their potential as therapeutic targets.

BACKGROUND: A bioactive myelin basic protein (MBP) fragment, comprising MBP84-104, is released in sciatic nerve after chronic constriction injury (CCI). Intraneural injection (IN) of MBP84-104 in an intact sciatic nerve is sufficient to induce persistent neuropathic pain-like behavior via robust transcriptional remodeling at the injection site and ipsilateral dorsal root ganglia (DRG) and spinal cord. The sex (female)-specific pronociceptive activity of MBP84-104 associates with sex-specific changes in cholesterol metabolism and activation of estrogen receptor (ESR)1 signaling. METHODS: In male and female normal and post-CCI rat sciatic nerves, we assessed: (i) cholesterol precursor and metabolite levels by lipidomics; (ii) MBP84-104 interactors by mass spectrometry of MBP84-104 pull-down; and (iii) liver X receptor (LXR)α protein expression by immunoblotting. To test the effect of LXRα stimulation on IN MBP84-104-induced mechanical hypersensitivity, the LXRα expression was confirmed along the segmental neuraxis, in DRG and spinal cord, followed by von Frey testing of the effect of intrathecally administered synthetic LXR agonist, GW3965. In cultured male and female rat DRGs exposed to MBP84-104 and/or estrogen treatments, transcriptional effect of LXR stimulation by GW3965 was assessed on downstream cholesterol transporter Abc, interleukin (IL)-6, and pronociceptive Cacna2d1 gene expression. RESULTS: CCI regulated LXRα ligand and receptor levels in nerves of both sexes, with cholesterol precursors, desmosterol and 7-DHC, and oxysterol elevated in females relative to males. MBP84-104 interacted with nuclear receptor coactivator (Ncoa)1, known to activate LXRα, injury-specific in nerves of both sexes. LXR stimulation suppressed ESR1-induced IL-6 and Cacna2d1 expression in cultured DRGs of both sexes and attenuated MBP84-104-induced pain in females. CONCLUSION: The injury-released bioactive MBP fragments induce pronociceptive changes by selective inactivation of nuclear transcription factors, including LXRα. By Ncoa1 sequestration, bioactive MBP fragments render LXRα function to counteract pronociceptive activity of estrogen/ESR1 in sensory neurons. This effect of MBP fragments is prevalent in females due to high circulating estrogen levels in females relative to males. Restoring LXR activity presents a promising therapeutic strategy in management of neuropathic pain induced by bioactive MBP.

PURPOSE: Treatment guidelines for gender-affirming hormone therapy with estrogen (GAHT-E) recommend specific dosing regimens based on limited data. Well-controlled efficacy trials are essential to tailoring treatment to patient goals as the guidelines recommend. The goal of this study was to take a foundational step toward designing community-centered effectiveness trials for gender-diverse individuals seeking GAHT-E. METHODS: Our team developed a cross-sectional survey based on broad clinical experience and consultation with our community advisory board. The survey included 60 items covering demographics, transition history, goals and priorities for treatment, indicators of treatment success, sexual function goals, and future research priorities. The survey was distributed during the summer of 2021, primarily through social networks designed for gender-expansive individuals seeking treatment with estrogen. RESULTS: A total of 1270 individuals completed the survey. Overall treatment goals most frequently rated extremely important or very important were the following: (1) improved satisfaction with life (81%), (2) appearing more feminine (80%), (3) appearing less masculine (77%), (4) improved mental health (76%), and (5) being seen as your true gender by others (75%). The three body characteristics most frequently rated highest priority or high priority among changes were the following: (1) facial hair (85%), (2) breast shape or size (84%), and (3) body shape (80%). The highest-rated research priority was comparing feminization with different routes of estrogen administration. CONCLUSION: The goals and experiences of individuals seeking GAHT-E are diverse. Future clinical trials of GAHT-E should be grounded in the needs and priorities of community stakeholders.

IntroductionReproductive health history may contribute to cognitive aging and risk for Alzheimer's disease, but this is understudied among Hispanic/Latina women.MethodsParticipants included 2126 Hispanic/Latina postmenopausal women (44 to 75 years) from the Study of Latinos-Investigation of Neurocognitive Aging. Survey linear regressions separately modeled the associations between reproductive health measures (age at menarche, history of oral contraceptive use, number of pregnancies, number of live births, age at menopause, female hormone use at Visit 1, and reproductive span) with cognitive outcomes at Visit 2 (performance, 7-year change, and mild cognitive impairment [MCI] prevalence).ResultsYounger age at menarche, oral contraceptive use, lower pregnancies, lower live births, and older age at menopause were associated with better cognitive performance. Older age at menarche was protective against cognitive change. Hormone use was linked to lower MCI prevalence.DiscussionSeveral aspects of reproductive health appear to impact cognitive aging among Hispanic/Latina women.

Aster proteins mediate the nonvesicular transport of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER). However, the importance of nonvesicular sterol movement for physiology and pathophysiology in various tissues is incompletely understood. Here we show that loss of Aster-B leads to diet-induced obesity in female but not in male mice, and that this sex difference is abolished by ovariectomy. We further demonstrate that Aster-B deficiency impairs nonvesicular cholesterol transport from the PM to the ER in ovaries in vivo, leading to hypogonadism and reduced estradiol synthesis. Female Aster-B-deficient mice exhibit reduced locomotor activity and energy expenditure, consistent with established effects of estrogens on systemic metabolism. Administration of exogenous estradiol ameliorates the diet-induced obesity phenotype of Aster-B-deficient female mice. These findings highlight the key role of Aster-B-dependent nonvesicular cholesterol transport in regulating estradiol production and protecting females from obesity.

BACKGROUND: The most aggressive form of breast cancer is triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER) and progesterone receptor (PR), and does not have overexpression of the human epidermal growth factor receptor 2 (HER2). Treatment options for women with TNBC tumors are limited, unlike those with ER-positive tumors that can be treated with hormone therapy, or those with HER2-positive tumors that can be treated with anti-HER2 therapy. Therefore, we have sought to identify novel targeted therapies for TNBC. In this study, we investigated the potential of a novel phosphatase, NUDT5, as a potential therapeutic target for TNBC. METHODS: The mRNA expression levels of NUDT5 in breast cancers were investigated using TCGA and METABRIC (Curtis) datasets. NUDT5 ablation was achieved through siRNA targeting and NUDT5 inhibition with the small molecule inhibitor TH5427. Xenograft TNBC animal models were employed to assess the effect of NUDT5 inhibition on in vivo tumor growth. Proliferation, death, and DNA replication assays were conducted to investigate the cellular biological effects of NUDT5 loss or inhibition. The accumulation of 8-oxo-guanine (8-oxoG) and the induction of γH2AX after NUDT5 loss was determined by immunofluorescence staining. The impact of NUDT5 loss on replication fork was assessed by measuring DNA fiber length. RESULTS: In this study, we demonstrated the significant role of an overexpressed phosphatase, NUDT5, in regulating oxidative DNA damage in TNBCs. Our findings indicate that loss of NUDT5 results in suppressed growth of TNBC both in vitro and in vivo. This growth inhibition is not attributed to cell death, but rather to the suppression of proliferation. The loss or inhibition of NUDT5 led to an increase in the oxidative DNA lesion 8-oxoG, and triggered the DNA damage response in the nucleus. The interference with DNA replication ultimately inhibited proliferation. CONCLUSIONS: NUDT5 plays a crucial role in preventing oxidative DNA damage in TNBC cells. The loss or inhibition of NUDT5 significantly suppresses the growth of TNBCs. These biological and mechanistic studies provide the groundwork for future research and the potential development of NUDT5 inhibitors as a promising therapeutic approach for TNBC patients.

Cardiometabolic disorders (CMD) are a growing public health problem across the world. Among the known cardiometabolic risk factors are compounds that induce endocrine and metabolic dysfunctions, such as endocrine disrupting chemicals (EDCs). To date, how EDCs influence molecular programs and cardiometabolic risks has yet to be fully elucidated, especially considering the complexity contributed by species-, chemical-, and dose-specific effects. Moreover, different experimental and analytical methodologies employed by different studies pose challenges when comparing findings across studies. To explore the molecular mechanisms of EDCs in a systematic manner, we established a data-driven computational approach to meta-analyze 30 human, mouse, and rat liver transcriptomic datasets for 4 EDCs, namely bisphenol A (BPA), bis(2-ethylhexyl) phthalate (DEHP), tributyltin (TBT), and perfluorooctanoic acid (PFOA). Our computational pipeline uniformly re-analyzed pre-processed quality-controlled microarray data and raw RNAseq data, derived differentially expressed genes (DEGs) and biological pathways, modeled gene regulatory networks and regulators, and determined CMD associations based on gene overlap analysis. Our approach revealed that DEHP and PFOA shared stable transcriptomic signatures that are enriched for genes associated with CMDs, suggesting similar mechanisms of action such as perturbations of peroxisome proliferator-activated receptor gamma (PPARγ) signaling and liver gene network regulators VNN1 and ACOT2. In contrast, TBT exhibited highly divergent gene signatures, pathways, network regulators, and disease associations from the other EDCs. In addition, we found that the rat, mouse, and human BPA studies showed highly variable transcriptomic patterns, providing molecular support for the variability in BPA responses. Our work offers insights into the commonality and differences in the molecular mechanisms of various EDCs and establishes a streamlined data-driven workflow to compare molecular mechanisms of environmental substances to elucidate the underlying connections between chemical exposure and disease risks.

Purpose: In East Asia, the incidence of breast cancer has been increasing rapidly, particularly among premenopausal women. An elevated ratio of estrogen-DNA adducts was linked to a higher risk of breast cancer. The present study explored the influence of the interaction between base excision repair (BER) gene polymorphisms and estrogen-DNA adducts on breast cancer risk. Methods: We conducted a case–control study comprising healthy volunteers and individuals with benign breast disease (control arm, n = 176) and patients with invasive carcinoma or carcinoma in situ (case arm, n = 177). Genotyping for BER-related genes, including SMUG1, OGG1, ERCC5, and APEX1, was performed. A logistic regression model, incorporating interactions between gene polymorphisms, estrogen-DNA adduct ratio, and clinical variables, was used to identify the risk factors for breast cancer. Results: Univariate analysis indicated marginal associations between breast cancer risk and APEX1 rs1130409 T > G (P = 0.057) and APEX1 rs1760944 T > G (P = 0.065). Multivariate regression analysis revealed significant associations with increased breast cancer risk for APEX1_rs1130409 (GT/GG versus TT) combined with a natural logarithmic value of the estrogen-DNA adduct ratio (estimated OR 1.164, P = 0.023) and premenopausal status with an estrogen-DNA adduct ratio > 2.93 (estimated OR 2.433, P = 0.001). Conclusion: APEX1_rs1130409 (GT/GG versus TT) polymorphisms, which are related to decreased BER activity, combined with an increased ratio of estrogen-DNA adducts, increase the risk of breast cancer in East Asian women. [ABSTRACT FROM AUTHOR]

Nowadays, the use of food additives, such as Sunset Yellow (SY), is growing, which attracted attention to the potential relationship between some diseases and food additives. The study aimed to investigate the role of Sunset Yellow during chemically-induced mammary gland carcinogenesis in Sprague–Dawley rats. Three groups of female rats were intraperitoneally administered with N-methyl-N-nitrosourea (MNU). Group 1 was set on a basal diet. Group 2 was treated with 161.4 mg\kg\day Sunset Yellow (SY). Group 3 was given SY at 80.7 mg\kg\day. Groups 4–6 were not administered MNU; Group 4 received vehicles only. Groups 5 and 6 were administered SY similarly to groups 2 and 3 respectively. Sunset Yellow at both doses exerted a significant dose-dependent increase in tumor incidences, multiplicities, volumes, and decreased tumor latency as compared with control. Immunolabeling indexes of the proliferating cell nuclear antigen, estrogen receptor alpha, and progesterone receptor were significantly increased after SY treatment. Oxidative stress markers, serum estrogen, progesterone, and prolactin levels were significantly modified by SY treatment. The mRNA expression of estrogen receptor alpha and epidermal growth factor was up-regulated in SY groups versus control. Collectively, SY has significantly promoted MNU-induced mammary tumors in rats with underlying mechanisms correlating SY consumption with estrogen disruption and subsequent antioxidative stress discrepancy. [Display omitted] • Sunset Yellow (SY) is a food coloring dye. • SY has significantly promoted MNU-induced mammary tumors in rats. • SY exaggerated tumor growth via estrogen disruption and subsequent antioxidative stress discrepancy. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder responsible for over half of dementia cases, with two-thirds being women. Growing evidence from preclinical and clinical studies underscores the significance of sex-specific biological mechanisms in shaping AD risk. While older age is the greatest risk factor for AD, other distinct biological mechanisms increase the risk and progression of AD in women including sex hormones, brain structural differences, genetic background, immunomodulation and vascular disorders. Research indicates a correlation between declining estrogen levels during menopause and an increased risk of developing AD, highlighting a possible link with AD pathogenesis. The neuroprotective effects of estrogen vary with the age of treatment initiation, menopause stage, and type. This review assesses clinical and observational studies conducted in women, examining the influence of estrogen on cognitive function or addressing the ongoing question regarding the potential use of hormone replacement therapy (HRT) as a preventive or therapeutic option for AD. This review covers recent literature and discusses the working hypothesis, current use, controversies and challenges regarding HRT in preventing and treating age-related cognitive decline and AD. The available evidence indicates that estrogen plays a significant role in influencing dementia risk, with studies demonstrating both beneficial and detrimental effects of HRT. Recommendations regarding HRT usage should carefully consider the age when the hormonal supplementation is initiated, baseline characteristics such as genotype and cardiovascular health, and treatment duration until this approach can be more thoroughly investigated or progress in the development of alternative treatments can be made. [ABSTRACT FROM AUTHOR]

Background: There is a continued debate on whether menopausal hormone therapy (MHT) protects women against Alzheimer's disease (AD). It is also unclear whether phytoestrogen could be an alternative treatment for AD. Objective: To investigate whether mixed study findings may be due to differences in age at initiation of MHT and duration of prescription of different types of MHT using meta-analyses. Methods: After a systematic literature search, meta-analyses were carried out using Cochrane Revman 5.4.1.software including data from large nationwide studies of registered medically diagnosed AD and prescribed MHT. These analyses were stratified for duration and type of treatment, by age at start of prescription of therapy. Insufficient quality data were available for phytoestrogen treatment and AD meta-analyses. Results: A total of 912,157 women were included from five registries, of whom 278,495 had developed AD during follow-up. Meta-analyses suggested a small increased AD risk after 5–10 years prescription of combination MHT regardless of age, and over 10 years only in women younger than 60 years of age. No association was seen for estrogen alone for women younger than 60 years of age, but AD risk did increase for women over 60 years of age for up to 5 years of MHT prescriptions. Conclusions: Combination MHT should probably be prescribed for less than 5 years after menopause to reduce risk for AD, while estrogen alone should not be prescribed to women over 60. For phytoestrogen, small treatment trials suggested some benefit of tempeh (fermented soy), which should be investigated further. [ABSTRACT FROM AUTHOR]

Objective: 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). Methods: 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. Results: 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. Conclusions: 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. Synopsis: This study suggested that the endometrial microbiome is complicit in modulating the development of endometrial cancer. [ABSTRACT FROM AUTHOR]

Female hypogonadism (FH) is a relatively common endocrine disorder in women of premenopausal age, but there are significant uncertainties and wide variation in its management. Most current guidelines are monospecialty and only address premature ovarian insufficiency (POI); some allude to management in very brief and general terms, and most rely upon the extrapolation of evidence from the studies relating to physiological estrogen deficiency in postmenopausal women. The Society for Endocrinology commissioned new guidance to provide all care providers with a multidisciplinary perspective on managing patients with all forms of FH. It has been compiled using expertise from Endocrinology, Primary Care, Gynaecology and Reproductive Health practices, with contributions from expert patients and a patient support group, to help clinicians best manage FH resulting from both POI and hypothalamo‐pituitary disorders, whether organic or functional. [ABSTRACT FROM AUTHOR]

The management of haematuria, in patients with a palliative diagnosis, refractory to standard measures presents a significant challenge for multidisciplinary teams. Our experiences with two cases led us to review the literature and highlighted the limited evidence base. We describe the cases here and propose options for medical approaches to management. We also report on successful use of a nonconjugated oestrogen which has a lower VTE risk compared to conjugated oestrogens. We aim to help support clinicians manage other palliative patients with this challenging symptom in future. Relevant references for this review were identified through searches of PubMed using the terms "haematuria," "hematuria," "palliative," "antifibrinolytic," "tranexamic acid," "etamsylate" "glucocorticoid," "oestrogen," "estrogen," "estradiol," "somatostatin," "thalidomide," hyperbaric oxygen" and "intravesical hyaluronic acid." Other references were suggested by the authors. [ABSTRACT FROM AUTHOR]

There are studies revealing the effects of estrogen receptors alpha (α) and beta (β) on hair follicles. However, the effects of G protein-coupled estrogen receptors (GPER-1) on hair follicles have not been elucidated. This study aims to evaluate the relationship between serum GPER-1 levels and the severity and duration of the disease in patients with androgenetic alopecia (AGA). The study included 81 patients with AGA aged 18 to 50 years (22 men and 19 women with an onset of AGA more than 5 years, and 20 men and 20 women with an onset of AGA less than 5 years) and 40 healthy controls (20 men, 20 women). The mean age of participants with AGA was 29.12 ± 8.15 (18-50), and the mean age of the control group was 25.21± 4.71 (19-42). Serum GPER-1 levels were measured, and the relationship between GPER-1 levels and duration of the disease, severity of the disease, and sex was statistically evaluated. The serum level of GPER-1 was significantly higher in patients with AGA as compared to the control group (p < 0.001). A negative correlation was found between serum GPER-1 levels and the duration of the disease in both men and women (p < 0.001, r = 0.793; p < 0.001, r = 0.711, respectively). There was a significant relationship between serum GPER-1 levels and the severity of the disease in both men and women (p = 0.003; p = 0.002, respectively). Additionally, a significant difference in GPER-1 levels was noted between male and female patients with AGA (p = 0.001). However, no statistically significant relationship was identified between GPER-1 levels and estrogen levels (p = 0.097). The higher levels of GPER-1 in patients with AGA compared to the control group, and the significant relationship between GPER-1 levels and both the duration and severity of the disease, suggest an estrogen-independent role of GPER-1 in the pathogenesis of AGA. The fact that GPER-1 levels are high in the early stages of AGA when inflammation is prominent suggests that treatments targeting these receptors may be effective at this stage. [ABSTRACT FROM AUTHOR]

Myocardial structural and functional abnormalities are hallmarks of diabetic cardiomyopathy (DCM), a chronic consequence of diabetes mellitus (DM). Maternal DM affects and increases the risk of heart defects in diabetic mothers compared with nondiabetic mothers. Momordica charantia exhibits antidiabetic effects due to various bioactive compounds that are phytochemicals, a broad group that includes phenolic compounds, alkaloids, proteins, steroids, inorganic compounds, and lipids. Pregnant maternal rats were split into four groups: control (C), M. charantia‐treated (MC), type 2 diabetes mellitus (T2DM) (DM), and diabetic (MC + DM) groups. Diabetes mothers had increased serum glucose, insulin, total cholesterol, triglyceride, and low‐density lipoprotein cholesterol levels and reduced high‐density lipoprotein cholesterol levels. Cardiac biomarkers such as cardiac troponin T (cTnT), creatine kinase‐myocardial band (CK‐MB), and lactate dehydrogenase were increased. Hormone levels of follicle‐stimulating hormone, luteinizing hormone, progesterone, and estrogen decreased significantly. Inflammatory markers such as interleukin 6 (IL‐6), tumor necrosis factor‐alpha (TNF‐α), and vascular adhesion molecule‐1 (VCAM‐1) were elevated in diabetic mothers. Oxidative stress markers indicated increased malondialdehyde and nitric oxide levels, while antioxidants such as glutathione, superoxide dismutase, and catalase were decreased in maternal heart tissue. The levels of apoptotic markers such as tumor suppressor 53 (P53) and cysteine aspartic protease‐3 (caspase‐3) were significantly greater in diabetic maternal heart tissue. Histopathological analysis revealed heart tissue abnormalities in diabetic maternal rats. M. charantia extract improved maternal diabetes‐induced changes in inflammation, antioxidant levels, and heart tissue structure. Research Highlights: Diabetes is characterized by a malfunction of glucose metabolism.Gestational diabetes increases maternal and fetal complications.Cardiovascular defects are linked to maternal gestational diabetes.Momordica charantia has antidiabetic effects on pregnant rats. [ABSTRACT FROM AUTHOR]

Physical debilitation and other health risks such as cardiovascular disease and osteoporosis often accompany decreased estrogen production in postmenopausal women. Phytoestrogens, natural compounds that functionally mimic estrogens, have emerged as a potential treatment method for hormonal dysregulation during menopause. Among these, chaga (Inonotus obliquus) extract has gained attention for its various health benefits, including anti-cancer and antioxidant properties. The aim of this study was to investigate the bone metabolic efficacy of lactic acid bacteria derived from I. obliquus in ovariectomized C57BL/6J female mice. The results demonstrated the estrogenic activity of probiotics derived from I. obliquus and its potential to alleviate osteoporosis symptoms by improving bone microstructure and density. Furthermore, probiotics derived from I. obliquus favored biochemical markers associated with a reduction in bone resorption. Additionally, effects on brain neurotransmitters and serum estradiol levels suggested its regulatory role in estrogen mimicry. These findings underscore the therapeutic potential of probiotics derived from I. obliquus in managing menopausal symptoms and thus warrant potential human investigation in improving bone health in postmenopausal women. [ABSTRACT FROM AUTHOR]

Background: Epigenetic dysregulation affecting oncogenic transcription and DNA damage response is a hallmark of cancer. The histone demethylase KDM4B, a factor regulating these processes, plays important roles in estrogen receptor-mediated transcription and DNA repair in breast cancer. However, how oncogenic phospho-signal transduction affects epigenetic regulation is not fully understood. Here we found that KDM4B phosphorylation by ribosomal S6 kinase (RSK), a downstream effector of the Ras/MAPK pathway, is critical for the function of KDM4B in response to DNA damage. Methods: KDM4B-knockout breast cancer cell lines were generated via CRISPR/Cas9-mediated gene editing. Re-expression of wild-type or phospho-site mutated KDM4B in knockout cells was performed by lentivirus-mediated gene transfer. Gene knockdown was achieved by RNA interference. DNA double-strand breaks (DSBs) were induced by ionizing radiation or laser-microirradiation. Protein accumulation at DSB sites was analyzed by immunofluorescence. KDM4B phosphorylation by RSK was assessed by in vitro and in vivo kinase assays. Gene and protein expression levels were analyzed by RT‒PCR and western blotting. The sensitivity of cells to ionizing radiation was examined by a clonogenic survival assay. Results: RSK phosphorylated KDM4B at Ser666, and inhibition of the phosphorylation by RSK depletion or RSK inhibitors abrogated KDM4B accumulation at the sites of DNA double-strand breaks (DSBs). DSB repair was significantly delayed in KDM4B-knockout cells or cells treated with RSK inhibitors. The replacement of endogenous KDM4B with the phosphomimetic mutant S666D restored KDM4B accumulation and DSB repair that had been inhibited by RSK inhibitors, suggesting a critical role for RSK at the specific serine residue of KDM4B in the effect of RSK inhibitors on DSB repair. As a consequence of these aberrant responses, inhibition of KDM4B phosphorylation increased the sensitivity of the cells to ionizing radiation. Conclusions: Overall, the present study uncovered a novel function of RSK on the DNA damage response, which provides an additional role of its inhibitor in cancer therapy. [ABSTRACT FROM AUTHOR]

Keratoconus (KC) is a corneal thinning dystrophy that leads to visual impairment. While the cause of KC remains poorly understood, changes in sex hormone levels have been correlated with KC development. This study investigated circulating gonadotropin-releasing hormone (GnRH) in control and KC subjects to determine if this master hormone regulator is linked to the KC pathology. Plasma and saliva were collected from KC subjects (n = 227 and n = 274, respectively) and non-KC controls (n = 58 and n = 101, respectively), in concert with patient demographics and clinical features. GnRH levels in both plasma and saliva were significantly lower in KC subjects compared to controls. This finding was retained in plasma when subjects were stratified based on age, sex, and KC severity. Control and KC corneal fibroblasts (HKCs) stimulated with recombinant GnRH protein in vitro revealed significantly increased luteinizing hormone receptor by HKCs and reduced expression of α-smooth muscle actin with treatment suggesting that GnRH may modulate hormonal and fibrotic responses in the KC corneal stroma. Further studies are needed to reveal the role of the hypothalamic–pituitary–gonadal axis in the onset and progression of KC and to explore this pathway as a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Distant recurrence in women with oestrogen receptor-positive early breast cancer persists at a constant rate for more than 20 years after diagnosis, with little equivalent data for oestrogen receptor-negative breast cancer. Using the database of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) we investigated rates of distant breast-cancer recurrence in oestrogen receptor-positive and oestrogen receptor-negative tumours and trends in outcomes over time. In this pooled analysis of randomised controlled trial data, patients in the EBCTCG database of more than 650 000 women in trials of treatment for early-stage breast cancer were screened for eligibility. Women were eligible if they were enrolled between 1990 and 2009 and newly diagnosed with oestrogen receptor-positive breast cancer and scheduled for at least 5 years of endocrine therapy, or oestrogen receptor-negative disease, and if they were younger than 75 years at diagnosis, had a tumour diameter of 50 mm or less, and fewer than ten positive axillary lymph nodes, and no evidence of distant metastases at entry. Trial of neoadjuvant therapy, or those in which adjuvant therapy was unclear, and women with oestrogen receptor-negative, progesterone receptor-positive disease, or those for whom outcome or baseline data were missing were excluded. The primary outcome was time to first distant recurrence as defined by each trial, ignoring any locoregional recurrence or contralateral breast cancer. 10-year risks of distant recurrence by period of diagnosis were compared using Cox regression adjusted for patient and tumour characteristics, trial, and assigned treatment. Of the 652 258 women with early breast cancer in the EBCTCG database on Jan 17, 2023, patient-level data were available from 151 randomised trials that included 155 746 women. Rates of distant tumour recurrence improved similarly in women with oestrogen receptor-positive and oestrogen receptor-negative tumours. 80·5% of the improvement for oestrogen receptor-positive disease and 89·8% of the improvement for eostrogen receptor-negative disease was explained by changes in patient and tumour characteristics and improved treatments, but remained significant (p<0·0001). More recently diagnosed patients were more likely to have node-negative disease. 10-year distant recurrence risks during 1990–99 versus 2000–09 were as follows: for node-negative disease, 10·1% versus 7·3% for oestrogen receptor-positive disease and 18·3% versus 11·9% for oestrogen receptor-negative disease; for disease with one to three positive nodes, 19·9% versus 14·7% for oestrogen receptor-positive disease and 31·9% versus 22·1% for oestrogen receptor-negative disease; and for disease with four to nine positive nodes, 39·6% versus 28·5% for oestrogen receptor-positive disease and 47·8% versus 36·5% for oestrogen receptor-negative disease. After adjustment for therapy, rates were reduced by 25% (oestrogen receptor-positive disease) and 19% (oestrogen receptor-negative disease) after 2000 versus the 1990s, with similar improvements observed in oestrogen receptor-positive disease beyond 5 years. Most of the improvement in trial outcomes is explained by a greater proportion of women with lower-risk disease entering trials and improved adjuvant treatment. After adjustment, women diagnosed since 2000 have about a fifth lower rate of distant recurrence than the 1990s. Long-term risks of distant recurrence for oestrogen receptor-positive disease remain, but are about a tenth lower now than in our previous report. Cancer Research UK, UK Medical Research Council. [ABSTRACT FROM AUTHOR]

A commentary published in Frontiers in Immunology explores the potential connection between gut dysbiosis and chronic pain. The study reviewed in the commentary found that individuals with chronic pain had imbalances in their gut microbiota, specifically a decrease in diversity and an increase in the genus Eggerthella. The commentary discusses the impact of Eggerthella on chronic pain, focusing on its involvement in dopamine metabolism and the regulation of female hormones. The findings suggest that combination therapies targeting both dopamine and estrogen pathways may be helpful in treating chronic pain. The article emphasizes the potential role of the gut microbiota in chronic pain and calls for further research to determine if it can be targeted for therapeutic interventions. [Extracted from the article]

The major female ovarian hormone, 17ß-estradiol (E2), can alter neuronal excitability within milliseconds to regulate a variety of physiological processes. Estrogen receptor-a (ERa), classically known as a nuclear receptor, exists as a membrane-bound receptor to mediate this rapid action of E2, but the ionic mechanisms remain unclear. Here, we show that a membrane channel protein, chloride intracellular channel protein-1 (Clic1), can physically interact with ERa with a preference to the membrane-bound ERa. Clic1-mediated currents can be enhanced by E2 and reduced by its depletion. In addition, Clic1 currents are required to mediate the E2-induced rapid excitations in multiple brain ERa populations. Further, genetic disruption of Clic1 in hypothalamic ERa neurons blunts the regulations of E2 on female body weight balance. In conclusion, we identified the Clic1 chloride channel as a key mediator for E2-induced rapid neuronal excitation, which may have a broad impact on multiple neurobiological processes regulated by E2. [ABSTRACT FROM AUTHOR]

Estrogens are a growing problem in wastewater discharges because they are continuously entering the environment and are biologically active at extremely low concentrations. Their effects on wildlife were first identified several decades before, but the environmental limits and the remedial measures are still not completely elucidated. Most conventional treatment processes were not designed with sufficiently long retention times to effectively remove estrogens. Nature-based wastewater treatment technologies such as treatment wetlands (TW) and high-rate algal ponds (HRAP) are economically feasible alternatives for decentralized wastewater treatment and have promise for removing steroid hormones including estrogens. For small communities with populations below 50,000, the overall cost of TWs and HRAPs is considerably lower than that of advanced decentralized treatment technologies such as activated sludge systems (AS) and sequencing batch reactors (SBR). This results from the simplicity of design, use of less materials in construction, lower energy use, operation and maintenance costs, and operation by non-skilled personnel. The nature-based technologies show high removal (>80%) for both natural and synthetic estrogens. Estrogen removal in TWs can be enhanced using alternative media such as palm mulch, biochar, and construction wastes such as bricks, instead of traditional substrates such as sand and gravel. While TWs are effective in estrogen removal, they have the disadvantage of requiring a relatively large footprint, but this can be reduced by using intensified multilayer wetland filters (IMWF). Using filamentous algae in HRAP (high-rate filamentous algal pond; HRFAP) is an emerging technology for wastewater treatment. The algae supply oxygen via photosynthesis and assimilate nutrients into readily harvestable filamentous algal biomass. Diurnal fluctuations in oxygen supply and pH in these systems provide conditions conducive to the breakdown of estrogens and a wide range of other emerging contaminants. The performance of these nature-based systems varies with seasonal changes in environmental conditions (particularly temperature and solar irradiation), however a greater understanding of operating conditions such as loading rate, hydraulic retention time (HRT), pond/bed depth, dissolved oxygen (DO) concentration and pH, which influence the removal mechanisms (biodegradation, sorption and photodegradation) enable TWs and HRAPs to be successfully used for removing estrogens. [ABSTRACT FROM AUTHOR]

Acute pancreatitis is one of the severe complications of hypertriglyceridemia, which needs to be recognized early to provide appropriate treatment. Hypertriglyceridemia-induced pancreatitis has several causes, in which in vitro fertilization (IVF) is a rare etiology that is becoming increasingly popular. We report a 33-year-old female patient with a history of hypertension who has failed an IVF cycle and started a new IVF procedure 1 month before admission. She was diagnosed with severe triglyceridemia-induced acute pancreatitis with extremely high serum triglycerides (TGs) levels (18,547 mg/dL). We combined plasmapheresis and intravenous (IV) insulin and significantly reduced blood TG over a short time. She was discharged with a TG level of 366.7 mg/dL on the 10th day. It is essential to monitor serum TG levels in plasma before, during, and after this therapy, especially in the 1st month after initiating IVF. Although plasmapheresis combined with IV insulin is not officially recommended for acute triglyceridemia-induced pancreatitis, the therapy can be considered in cases with extremely high serum TG levels. [ABSTRACT FROM AUTHOR]

Currently, there are no specific antiviral therapeutic approaches targeting Human papillomaviruses (HPVs), which cause around 5% of all human cancers. Specific antiviral reagents are particularly needed for HPV-related oropharyngeal cancers (HPV+OPCs) whose incidence is increasing and for which there are no early diagnostic tools available. We and others have demonstrated that the estrogen receptor alpha (ERα) is overexpressed in HPV+OPCs, compared to HPV-negative cancers in this region, and that these elevated levels are associated with an improved disease outcome. Utilizing this HPV+-specific overexpression profile, we previously demonstrated that estrogen attenuates the growth and cell viability of HPV+ keratinocytes and HPV+ cancer cells in vitro. Expansion of this work in vivo failed to replicate this sensitization. The role of stromal support from the tumor microenvironment (TME) has previously been tied to both the HPV lifecycle and in vivo therapeutic responses. Our investigations revealed that in vitro co-culture with fibroblasts attenuated HPV+-specific estrogen growth responses. Continuing to monopolize on the HPV+-specific overexpression of ERα, our co-culture models then assessed the suitability of the selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen, and showed growth attenuation in a variety of our models to one or both of these drugs in vitro. Utilization of these SERMs in vivo closely resembled the sensitization predicted by our co-culture models. Therefore, the in vitro fibroblast co-culture model better predicts in vivo responses. We propose that utilization of our co-culture in vitro model can accelerate cancer therapeutic drug discovery. [ABSTRACT FROM AUTHOR]

Background: Transgender individuals frequently undergo gender-affirming hormone therapy (GAHT) during their gender transition which plays a vital role in gender identity affirmation. Cholelithiasis, a common condition affecting 10-15% of the US population, has been linked to estrogen therapy in cisgender women. Despite the fact that hormonal profiles achieved after GAHT are not always identical to cisgender individuals, the effects of GAHT on gallbladder disease (GBD) risk have not been evaluated in transgender populations. This research aims to address this gap utilizing a large nationwide database. Methods: The study analyzed medical records data from the TrinetX database from 52,847 trans men and 38,114 trans women. Four cohorts were created: trans women and men either receiving either hormone therapy or no intervention. Descriptive statistics were calculated before matching to estimate disease burden. The groups were then propensity score matched on known risk factors (age, race, BMI, etc.) and rates of GBD were compared. Results: Before matching, trans women on hormone therapy (TWHT) had a significantly higher 10-year GBD probability than those naïve to therapy (TWNI) (4.69% vs 1.88%). For trans men, there was no significant difference in 10-year rates between those on therapy (TMHT) and those not (TMNI) (3.15% vs 3.87%). Cholecystectomy rates were significantly higher for TWHT than TWNI (1.10% vs. 0.57%), but similar between TMHT and TMNI (0.95% vs. 1.10%). After accounting for risk factors, TWHT had increased GBD risk (HR 1.832), while TMHT showed no significant change. Discussion: This study suggests a link between estrogen GAHT and increased GBD risk in transgender women. Notably, testosterone GAHT did not offer protection against GBD in transgender men, contrary to expectations. This study is, to our knowledge, the first to describe the burden of GBD in the transgender population and to investigate the effects of GAHT on GBD risk. [ABSTRACT FROM AUTHOR]

Objective: We sought to review the biology and clinical benefits of genistein, a plant-derived isoflavone with emphasis on perimenopausal and postmenopausal women. The focus is on assessing its impact on skin health and aesthetics as well as bone density and cardiovascular and metabolic functions. Methods: This narrative review used PubMed to collect studies relating to the biology and clinical effects of genistein on postmenopausal signs and symptoms, including bone density loss, metabolic issues and symptoms, and skin aging. Articles were selected based on relevance to the scope of genistein's influence on estrogen receptors and their downstream effects. This review included in vitro, in vivo, animal, and human studies. Results: According to the current literature, genistein demonstrates efficacy in mitigating menopausal signs and symptoms such as hot flashes, bone density loss and rate of osteoporosis, and skin aging. It shows a protective effect against cardiovascular diseases by improving lipid profiles, weight changes, and reducing low-density lipoprotein cholesterol. It also displays benefits in increasing bone mineral density but has not displayed the side effects commonly associated with estrogen replacement. Regarding skin health, genistein appears to enhance photoprotection, wound healing, elasticity, and hydration, inhibits skin cancer, and reduces wrinkles. Conclusion: Genistein acts as a selective estrogen receptor modulator (SERM) with benefits across a spectrum of menopausal signs and symptoms, presenting a viable alternative to estrogen replacement in perimenopausal and postmenopausal women. Its utility extends to improving cardiovascular health, bone density, and skin quality, making it a comprehensive treatment option for peri and postmenopausal women. [ABSTRACT FROM AUTHOR]

Key content: Urethral caruncle is a common post‐menopausal finding.This common benign lesion can be mistaken as a malignancy.Management should be based on the patient's symptoms.Vaginal estrogen should be considered as first‐line management before surgical excision. Learning objectives: To evaluate the symptomatic presentation of urethral caruncle.To establish the differential diagnosis of a mass in the urethra.To review the management options of urethral caruncle including medical and surgical excision.To highlight primary care management of urethral caruncle. Ethical issues: Owing to poor recognition of urethral caruncle, many patients are put through the emotional distress of referral to cancer pathways.Surgery should be considered first line for large urethral caruncle or in symptomatic patients. [ABSTRACT FROM AUTHOR]

Gender is one of the most essentialized social categories, with putative differences between cisgender men and cisgender women often framed in biological terms. We propose that the consequences of inaccurate and widely held essentialist beliefs about gonadal hormones (EBAGHs) in particular—that is, that androgens signify "men" and estrogens signify "not-men"—have yet to be fully appreciated. For example, placebo effects such as increased strength, sexual desire, and irritability have been documented for the androgen testosterone. Accumulating research also suggests that lay understandings exaggerate the causal importance of testosterone in men's aggression. Consequently, testosterone is often either eschewed (i.e., men are "poisoned" by it) or enshrined ("more is good, less is bad"). Moreover, the efficacy-bolstering role of estrogens such as estradiol across the physical, cognitive, and sexual health domains for men has been downplayed or ignored by those who assert pejorative links between estrogen and weakness or effeminacy. Critically, EBAGHs may fuel "hypermasculine" behaviors such as excessive red meat consumption, problematic alcohol intake, and anabolic steroid misuse as well as treatment seeking for "low T" in the absence of proper medical diagnosis—which can all, ironically, result in disrupting men's optimal hormonal balance. Implications of our analysis for research (e.g., EBAGHs as predictors men's health behaviors, use of bogus "hormonal profiles" to induce or assuage threats to masculinity in experimental studies) and interventions (e.g., "hormone education" to offset the adverse effects of EBAGHs) are discussed. Public Significance Statement: Inaccurate beliefs about gonadal hormones may cause testosterone to be either valued or devalued—and estrogen to be portrayed as the enemy—in men. Such beliefs may contribute to hypermasculine behaviors, poor diet, misguided health care, and other negative outcomes for men. Biologically accurate hormone education may therefore have beneficial consequences for men's self-perception, perception by others, and overall well-being. [ABSTRACT FROM AUTHOR]

Activation of G protein-coupled estrogen receptor 1 (GPER1) elicits antihypertensive actions in different animal models. The endothelin-1 signaling system plays a fundamental role in blood pressure regulation. Lack of functional endothelin receptor B (ETB) evokes hypertension and salt sensitivity. GPER1 and ETB interact to promote urinary sodium excretion in female rats. We hypothesized that activation of GPER1 protects against hypertension and salt sensitivity induced by ETB antagonism in female rats. Female Sprague-Dawley rats were implanted with radiotelemetry. Animals were then subjected to ovariectomy and simultaneously implanted with minipumps to deliver either the GPER1 agonist G1 or its corresponding vehicle. Two weeks post surgery, we initiated treatment of rats with the ETB antagonist A-192621. Animals were maintained on a normal-salt diet and then challenged with a high-salt diet for an additional 5 days. Assessment of mean arterial blood pressure revealed an increase in vehicle-treated, but not G1-treated, rats in response to ovariectomy. A-192621 increased blood pressure in normal-salt diet-fed vehicle- and G1-treated rats. G1 improved the circadian blood pressure rhythms that were disrupted in A-192621-treated ovariectomized rats. Thus, although systemic GPER1 activation did not protect ovariectomized rats from hypertension and salt sensitivity induced by ETB antagonism, it maintained circadian blood pressure rhythms. Functional ETB is required to elicit the antihypertensive actions of GPER1. Additional studies are needed to improve our understanding of the interaction between G protein-coupled receptors in regulating circadian blood pressure rhythm. NEW & NOTEWORTHY: Systemic G protein-coupled estrogen receptor 1 (GPER1) activation in rats prevents the increase in blood pressure evoked by ovariectomy. Blockade of endothelin receptor B negates the blood pressure-lowering impact of GPER1 in ovariectomized rats. Endothelin receptor B plays an important role in mediating the blood pressure-lowering action of GPER1 activation in female rats. [ABSTRACT FROM AUTHOR]

The association between current use of oral contraceptives (OCs) among women younger than 50 years (n  = 306 541), and hormone therapy (HT) among women aged 50 years or older (n  = 323 203), and coronavirus 2019 (COVID-19) infection and hospitalization was evaluated in this population-based cohort. Current OC/HT use was recorded monthly using prescription dispensing data. COVID-19 infections were identified from March 2020 through February 2021. COVID-19 infections and hospitalizations were identified through diagnosis codes and laboratory tests. We used weighted generalized estimating equations models to estimate multivariable adjusted odds ratios (aORs) for COVID-19 infection associated with time-varying OC/HT use. Among women with COVID-19, logistic regression models were used to evaluate OC/HT use and COVID-19 hospitalization. Over 12 months, 11 727 (3.8%) women younger than 50 years and 8661 (2.7%) women aged 50 years or older experienced COVID-19 infections. There was no evidence of an association between OC use and infection (aOR = 1.05; 95% CI, 0.97-1.12). There was a modest association between HT use and infection (aOR = 1.19; 95% CI, 1.03-1.38). Women using OCs had a 39% lower risk of hospitalization (aOR = 0.61; 95% CI, 0.38-1.00), but there was no association of HT use with hospitalization (aOR = 0.89; 95% CI, 0.51-1.53). These findings do not suggest a meaningfully greater risk of COVID-19 infection associated with OC or HT use. OC use may be associated with lower COVID-19 hospitalization risk. [ABSTRACT FROM AUTHOR]

Background Breast cancer brain metastasis is a rising occurrence, necessitating a better understanding of the mechanisms involved for effective management. Breast cancer brain metastases diverge notably from the primary tumor, with gains in kinase and concomitant losses of steroid signaling observed. In this study, we explored the role of the kinase receptor RET in promoting breast cancer brain metastases and provide a rationale for targeting this receptor. Methods RET expression was characterized in a cohort of patients with primary and brain metastatic tumors. RET functionality was assessed using pharmacological inhibition and gene silencing in patient-derived brain metastatic tumor explants and in vivo models, organoid models, and brain organotypic cultures. RNA sequencing was used to uncover novel brain metastatic relevant RET mechanisms of action. Results A statistically significant enrichment of RET in brain metastases was observed in estrogen receptor–positive breast cancer, where it played a role in promoting cancer cell adhesion, survival, and outgrowth in the brain. In vivo , RET overexpression enhanced brain metastatic competency in patient-derived models. At a mechanistic level, RET overexpression was found to enhance the activation of gene programs involved in cell adhesion, requiring EGFR cooperation to deliver a pro–brain metastatic phenotype. Conclusion Our results illustrate, for the first time, the role of RET in regulating colonization and outgrowth of breast cancer brain metastasis and provide data to support the use of RET inhibitors in the management strategy for patients with breast cancer brain metastases. [ABSTRACT FROM AUTHOR]

In aging women, cognitive decline and increased risk of dementia have been associated with the cessation of ovarian hormones production at menopause. In the brain, presence of the key enzyme aromatase required for the synthesis of 17‐β‐estradiol (E2) allows for local production of E2 in absence of functional ovaries. Understanding how aromatase activity is regulated could help alleviate the cognitive symptoms. In female rodents, genetic or pharmacological reduction of aromatase activity over extended periods of time impair memory formation, decreases spine density, and hinders long‐term potentiation (LTP) in the hippocampus. Conversely, increased excitatory neurotransmission resulting in rapid N‐methyl‐d‐aspartic acid (NMDA) receptor activation rapidly promotes neuroestrogen synthesis. This rapid modulation of aromatase activity led us to address the hypothesis that acute neuroestrogens synthesis is necessary for LTP at the Schaffer collateral‐cornu ammonis 1 (CA1) synapse in absence of circulating ovarian estrogens. To test this hypothesis, we did electrophysiological recordings of field excitatory postsynaptic potential (fEPSPs) in hippocampal slices obtained from ovariectomized mice. To assess the impact of neuroestrogens synthesis on LTP, we applied the specific aromatase inhibitor, letrozole, before the induction of LTP with a theta burst stimulation protocol. We found that blocking aromatase activity prevented LTP. Interestingly, exogenous E2 application, while blocking aromatase activity, was not sufficient to recover LTP in our model. Our results indicate the critical importance of rapid, activity‐dependent local neuroestrogens synthesis, independent of circulating hormones for hippocampal synaptic plasticity in female rodents. [ABSTRACT FROM AUTHOR]

Oral hormonal contraception (OHC) is a widely employed method in females for the prevention of unintended pregnancies, as well as for the treatment of menstrual disorders, endometriosis, and polycystic ovarian syndrome. However, it is believed that with OHCs use, some females may have higher risk of cardiovascular diseases, such as hypertension, diabetes, myocardial infarction, thrombosis, and heart failure. Although such risks are infrequently detected in healthy young females with the use of oral contraceptives, slightly elevated risks of cardiovascular diseases have been observed among reproductive-aged healthy females. However, prolonged use of OHC has also been claimed to have protective cardiac effects and may contribute to reduced risk of cardiovascular disease. In fact, the debate on whether OHC administration increases the risk of cardiovascular diseases has been ongoing with inconsistent and controversial viewpoints. Nevertheless, a great deal of work has been carried out to understand the relationship between OHC use and the occurrence of cardiovascular risk in females who use OHC for preventing the unwanted pregnancy or treatment of other disorders. Therefore, in this review we summarize the most recent available evidence regarding the association between the use of oral hormonal contraceptives and the risk for cardiovascular disease in females who are using OHC to prevent unintended pregnancy. [ABSTRACT FROM AUTHOR]

It has now been about a century since a flurry of discoveries identified first the pituitary, then more specifically the anterior pituitary and soon thereafter the central nervous system as components regulating gonadal and downstream reproductive functions. This was an era of ablation/replacement designs using at first rudimentary and then increasingly pure preparations of gonadal and pituitary "activities" or transplanting actual glands, whole or homogenized, among subjects. There was, of course, controversy as is typical of lively and productive scientific debates to this day. The goals of this commentary are to briefly review the history of this work and how the terms referring to interactions among the components of the hypothalamo (as the central neural component was soon associated with)–pituitary–gonadal (HPG) axis evolved, and then to question if the current terms used have kept up with our understanding of the system. The focus in this review will be the actions of estradiol primarily upon the hypothalamus. Important actions of progesterone on the hypothalamus as well as both steroids on the pituitary response to hypothalamic factors are both acknowledged and largely ignored in this document, as are any sex differences as we focus on females. [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]

Hormone receptor (HR)-positive breast cancer represents tumours that express estrogen and/or progesterone enzymes, which play a crucial role in the growth and proliferation of breast cancer cells. Aromatase inhibitors (AIs) are drugs that inhibit the enzyme aromatase, involved in the biosynthesis of estrogen and are used for the treatment of HR-positive breast cancer. The USFDA-approved nonsteroidal AIs contain 1,2,4-triazole heterocycle. So, in the present study, we screened seventy-eight 1,2,4-triazole analogues from different literature resources and generated a pharmacophore model. After several validation protocols, Hypo1 was selected as the best model and was used as a 3D query for screening 1,2,4-triazole analogues (15,583) obtained from the CHEMBL database. A dataset containing 320 ligands with estimated activity (IC50< 0.1 µM) was subjected to molecular docking against the aromatase enzyme (PDB ID: 3S79). Amongst the 320 ligands, 30 compounds exhibited better binding energy compared to the standard drug letrozole. These 30 hits were further considered for the design of two novel molecules which were initially assessed for their ADMET properties followed by pharmacophore mapping, docking and molecular dynamics simulation. The in silico findings suggest that both the designed molecules can be considered drug-like candidates for the treatment of breast cancer through aromatase inhibition. [ABSTRACT FROM AUTHOR]

Background: Abnormal uterine bleeding is a prevalent issue among women of reproductive age, primarily stemming from hormonal imbalances. It is characterized by flow volume, duration, and frequency variations outside of pregnancy. Occurring frequently during perimenopause and menstruation, abnormal uterine bleeding is associated with several benign tumors within the female reproductive system, including leiomyomas and endometriomas. Leiomyomas, composed of smooth muscle cells originating from the uterine wall, are influenced by genetic and environmental factors. Objective: This review explored the complications linked with abnormal uterine bleeding and identified crucial genes involved in developing leiomyomas. Methods: The International Federation of Gynecology and Obstetrics (FIGO) has established a classification and terminology system for the causes of abnormal uterine bleeding (AUB). This standardization aims to enhance research efficiency, facilitate diagnosis, and improve the management of clinical cases. Articles in English were searched in the PubMed, Embase, Scopus, ScienceDirect, and MEDLINE databases using the terms abnormal uterine bleeding, leiomyomas, and genes. The selection included systematic reviews, meta-analyses, randomized controlled trials, and reviews. Data were searched from 2016 to May 2023. Results: The research reveals that uterine leiomyomas affect a substantial percentage of females by age 50, underlining the need for a comprehensive understanding of their genetic underpinnings. The knowledge gained from this study contributes to the potential development of more targeted and efficient treatments for leiomyomas, offering hope for improved outcomes in managing these common gynecological disorders. Conclusion The findings underscore the complexity of abnormal uterine bleeding, emphasizing its connection with leiomyomas and the genetic factors influencing their development. By employing the FIGO classification system, researchers and clinicians can standardize their approach to diagnosis and management, paving the way for more efficient future research and diagnostics. Identifying critical genes associated with leiomyomas provides insights into the underlying mechanisms, particularly the involvement of hormones and genetic pathways. [ABSTRACT FROM AUTHOR]

Hypospadias is a common malformation of the genitourinary system and is thought with a complex interplay between genetics and environmental factors likely contributing to its pathogenesis. This study aimed to investigate the receptor gene expressions of sex hormones, FGFR2, FGF8 and BMP7 and DNA methylations in these genes as an epigenetic mark, which may play a role in the etiology of hypospadias. The samples from the foreskin of 20 patients with hypospadias and 20 healthy children who underwent circumcision operations were collected. AR, ESR1, FGF8, FGFR2 and BMP7 gene expressions and DNA methylation rates of these genes were investigated in tissues. While ESR1, FGFR2 and BMP7 gene expressions were found to be significantly higher in the hypospadias group, AR gene expression was found to be lower. In the hypospadias group, DNA methylation rates were found to be significantly higher in the ESR1, FGF8 and FGFR2 genes, but lower in the AR gene (Table). Recent clinical studies suggest that epigenetic modifications may play a significant role in genital development, potentially contributing to the etiology of hypospadias. Our recent study demonstrated significant differences in foreskin AR, ESR1, and FGFR2 gene expression between patients with hypospadias and controls. To address this, the present study investigated DNA methylation levels of these same genes in hypospadias patients, hypothesizing that epigenetic modifications might be responsible for the observed gene expression changes. We again observed abnormalities in AR, ESR1, and FGFR2 gene expression in hypospadias patients. Furthermore, we found that DNA methylation patterns associated with these genes differed significantly between hypospadias and control groups. Our study demonstrates significant alterations in DNA methylation of sex hormone receptor genes (ESR1 and AR), FGFR2, and FGF8, which correlate with abnormal expression of these genes in hypospadias cases. These findings suggest a potential role for epigenetic modifications in hypospadias etiology. Summary table Comparison of gene expressions and DNA methylation rates of groups. Summary table Gene Expression (Mean ± SD) p value DNA Methylation (Mean ± SD) p value ESR-1 Hypospadias 1.79 ± 1.11 0.001 11.1 ± 5.78 0.001 Control 1.07 ± 0.74 6.26 ± 4.91 AR Hypospadias 2.36 ± 0.98 0.001 3.33 ± 0.87 0.001 Control 4.19 ± 12.18 5.31 ± 3.64 FGFR-2 Hypospadias 0.77 ± 0.56 0.001 3.79 ± 0.96 0.001 Control 0.62 ± 0.47 2.89 ± 0.52 FGF-8 Hypospadias 2.81 ± 5.85 >0.05 18.93 ± 5.53 0.001 Control 1.86 ± 2.69 26.19 ± 4.7 BMP-7 Hypospadias 2.45 ± 6.32 0.001 4.92 ± 1.22 0.676 [ABSTRACT FROM AUTHOR]

Background: Thermogenesis is influenced by fluctuations in sex hormones during the menstrual cycle in premenopausal women. The thermogenic activity and mass of brown adipose tissue (BAT) are regulated by endocrine factors, including sex hormones and fibroblast growth factor 21 (FGF21). However, the relationship between human BAT and these endocrine fluctuations within individuals remains to be elucidated. This study aimed to assess variations in BAT activity between the luteal and follicular phases and identify correlations with circulating levels of sex hormones and FGF21. Methods: Healthy young women were enrolled in an observational study. Measurement of BAT activity and blood analyses were performed in both the follicular and luteal phases. BAT activity was analyzed using thermography with 2-h cold exposure. Plasma 17β-estradiol, progesterone, and FGF21 levels were determined by enzyme-linked immunosorbent assay. A comparative analysis within individuals was conducted in 13 women to compare the follicular and luteal phases. Furthermore, sensitivity analysis was carried out in 21 women during the follicular phase only. Results: Plasma 17β-estradiol and progesterone levels were significantly higher in the luteal phase, whereas plasma FGF21 level was significantly higher in the follicular phase. Comparison analysis found no significant differences in cold-induced BAT activity between the follicular and luteal phases in young women. Correlation analysis in both comparison and sensitivity analyses found that plasma 17β-estradiol and progesterone levels were not associated with BAT activity, whereas plasma FGF21 levels were significantly and positively correlated with BAT activity only in the follicular phase. In addition, plasma 17β-estradiol levels in the follicular phase were significantly and positively associated with plasma FGF21 levels in both the comparison and sensitivity analyses. Conclusions: The thermogenic activity of BAT during cold exposure was comparable between the follicular and luteal phases in young women. Higher BAT activity was associated with elevated levels of plasma FGF21 only in the follicular phase, which is related to increased plasma 17β-estradiol levels. [ABSTRACT FROM AUTHOR]

Background: In the rural regions of Telangana State, many women are actively involved in the occupation of beedi rolling. Cigarette smoke either active or passive exerts deleterious effects on reproductive organs and function by means of both direct toxic influences, termed ovotoxicity, and the reduction of hormone secretion. Methods: The study involved a cohort of 320 women employed as beedi rollers and 280 women with no occupational exposure to chemicals for comparison. Serum samples were used to estimate the levels of Estrogen, Progesterone, Testosterone, Follicle Stimulating Hormone, luteinizing hormone, T3, T4 and TSH using Sandwich and competitive ELISA methods. Conclusion: The findings of the current study unveiled compelling statistical significance in the levels of estrogen, progesterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), T3 and T4.In conclusion, our study reveals a noteworthy correlation between beedi rolling and alterations in hormonal profiles of rural women in Telangana. [ABSTRACT FROM AUTHOR]

A telomere is a repetitive DNA sequence located at the end of human chromosomes, and its length shortens with age. Research has demonstrated that estrogen is associated with the aging of various types of cells, including brain, muscle, and bone cells. This study explored the cross-sectional association between estrogen usage and telomere length, utilizing data from the US National Health and Nutrition Examination Survey (NHANES) 1999-2002. The final number of participants included in this study was 491. This study's bivariate Rao-Scott χ2 test revealed a significant association between telomere length and gender (p < 0.01). Females have longer telomeres than males, indicated by a rate ratio of 1.72. A positive relationship between estrogen usage and telomere length was observed among female participants, yielding a rate ratio of 1.44. The mosaic diagram and Pearson residuals confirmed the statistical significance of this difference (p < 0.001). This suggests that estrogen administration may preserve telomeres and contribute to healthy aging. In conjunction with the findings from the literature, this study supports the need for further investigations into the effects of estrogen administration on telomere length. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia, characterized by muscle mass decline due to aging or other causes, is exacerbated by decreased estrogen levels after menopause in women. Isoflavones, a class of flavonoids acting on estrogen receptors, may have beneficial effects on metabolic disorders. We examined these effects in ovariectomized mice fed a high-fat, high-sucrose diet (HFHSD). Methods: At 7 weeks old, female C57BL6/J mice (18–20 g, n = 12) underwent bilateral ovariectomy (OVX), and were then fed a high-fat, high-sucrose diet starting at 8 weeks of age. Half of the mice received isoflavone water (0.1%). Metabolic analyses, including glucose and insulin tolerance tests, were conducted. Muscle analysis involved grip strength assays, next-generation sequencing, quantitative RT–PCR, and western blotting of skeletal muscle after euthanizing the mice at 14 weeks old. Additionally, 16S rRNA gene sequence analysis of the gut microbiota was performed. Results: The results demonstrated that isoflavone administration did not affect body weight, glucose tolerance, or lipid metabolism. In contrast, isoflavone-treated mice had higher grip strength. Gene expression analysis of the soleus muscle revealed decreased Trim63 expression, and western blotting showed inactivation of muscle-specific RING finger protein 1 in isoflavone-treated mice. Gut microbiota analysis indicated higher Bacteroidetes and lower Firmicutes abundance in the isoflavone group, along with increased microbiota diversity. Gene sets related to TNF-α signaling via NF-κB and unfolded protein response were negatively associated with isoflavones. Conclusions: Isoflavone intake alters gut microbiota and increases muscle strength, suggesting a potential role in improving sarcopenia in menopausal women. [ABSTRACT FROM AUTHOR]

COVID-19 outcomes are less severe in women than men suggesting that female sex is protective. The steroids estradiol (E2) and progesterone (P4) promote anti-inflammatory immune responses and their therapeutic use for COVID-19 has been under investigation. The aim of the study was to evaluate the efficacy of a short systemic E2 and P4 combination in mitigating COVID-19 severity in hospitalized men and women. In a phase 2, single center, double blind, randomized placebo-controlled trial, ten male and female participants hospitalized for COVID-19 with scores 3–5 on the 9-point WHO ordinal scale were randomized to receive either (1) E2 cypionate (5 mg, IM) and micronized P4 (200 mg, PO), or (2) placebo-equivalent, in addition to standard of care (SOC). The primary outcome was the proportion of patients whose WHO scores improved to 1–2 on the day of discharge. Secondary outcomes included length of hospital stay (LOS), days on oxygen therapy (DOT), readmission rates (RR), adverse events (AEs), and change in circulating biomarkers using untargeted proteomics and cytokine profiling. There were no significant changes between the groups in primary outcome, LOS, DOT, RR or AEs. The E2P4 group exhibited a decrease in biomarker pathways of respiratory and gastrointestinal disease inflammation, infection by coronavirus, and immune cell trafficking and inflammatory response. A short-term E2P4 treatment in patients hospitalized for COVID-19 decreases biomarkers of inflammation. Considering the availability, low cost, and safety of E2 and P4, our results warrant additional studies to explore their effects in mitigating other viral pandemics. Clinical Trial Registration NCT04865029, ClinicalTrials.gov; (First trial registration 29/04/2021). [ABSTRACT FROM AUTHOR]

Background: Gallstones are a common health concern, particularly in women. Estrogen is suspected to play a role, potentially altering bile composition and promoting gallstone development. This review explores the link between estrogen exposure and gallstone formation in various contexts, including pregnancy, postmenopausal hormone replacement therapy (HRT), and gender-affirming hormone therapy (GAHT). Methods: Two independent authors systematically searched PubMed, Cochrane, and Embase for literature relevant to estrogen-induced gallstones. Studies were included if they discussed the role of estrogen in the induction of gallstones by different conditions such as HRT, GAHT, prostatic carcinoma, and pregnancy. A scoping review identified 18 studies (1979–2021) encompassing over 211,000 patients and healthy controls. We investigated the risk of gallstones in postmenopausal HT users, pregnant women, oral contraceptive users, men receiving estrogen therapy for prostate cancer, and individuals on GAHT. Results: Our findings suggest an increased risk of gallstones with prolonged HT use (> 45 years). Estrogen therapy elevated biliary cholesterol saturation in both men and women taking oral contraceptives. A low incidence (2%) of gallstones was observed in the third trimester of pregnancy. Interestingly, a case of GAHT-associated gallstone development in a transgender woman emerged. Conclusions: Estrogen exposure, both natural and through various therapies, appears to be associated with an increased risk of gallstones. Further research is needed to elucidate the specific mechanisms in different contexts. Notably, estrogen therapy for specific conditions like hypogonadism or surgical menopause seems unrelated to gallstone formation. [ABSTRACT FROM AUTHOR]

The main genetic risk factor for Alzheimer's disease (AD) is the apolipoprotein E ε4 allele (APOE4). AD risk associated with APOE4 disproportionately affects women. Furthermore, human and rodent studies indicate that the cognitive deficits associated with APOE4 are greater in females. One modifiable AD risk factor is obesity during middle age. Given that approximately two-thirds of US adults are overweight, it is important to understand how obesity affects AD risk, how it interacts with APOE4, and the extent to which its detrimental effects can be mitigated with therapeutics. One intervention study for women is estrogenbased hormone therapy, which can exert numerous health benefits when administered in early middle age. No experimental studies have examined the interactions among APOE4, obesity, and hormone therapy in aging females. To begin to explore these issues, we considered how obesity outcomes are affected by treatment with estradiol at the onset of middle age in female mice with human APOE3 and APOE4. Furthermore, to explore how gene dosage affects outcomes, we compared mice homozygous for APOE3 (3/3) and homozygous (4/4) or hemizygous (3/4) for APOE4. Mice were examined over a 4-month period that spans the transition into reproductive senescence, a normal age-related change that models many aspects of human perimenopause. Beginning at 5 months of age, mice were maintained on a control diet (10% fat) or high-fat diet (HFD; 60% fat). After 8 weeks, by which time obesity was present in all HFD groups, mice were implanted with an estradiol or vehicle capsule that was maintained for the final 8 weeks. Animals were assessed on a range of metabolic and neural measures. Overall, APOE4 was associated with poorer metabolic function and cognitive performance. However, an obesogenic diet induced relatively greater impairments in metabolic function and cognitive performance in APOE3/3 mice. Estradiol treatment improved metabolic and cognitive outcomes across all HFD groups, with APOE4/4 generally exhibiting the greatest benefit. APOE3/4 mice were intermediate to the homozygous genotypes on many measures but also exhibited unique profiles. Together, these findings highlight the importance of the APOE genotype as a modulator of the risks associated with obesity and the beneficial outcomes of estradiol. [ABSTRACT FROM AUTHOR]