Influence Of Estrogen Research Articles

Hormone Replacement Therapy and Alzheimer's Disease: Current State of Knowledge and Implications for Clinical Use.

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.

The estrogen response in fibroblasts promotes ovarian metastases of gastric cancer

Younger premenopausal women are more prone to developing ovarian metastases (OM) of gastric cancer (GC) than metastases of other organs; however, the molecular mechanisms remain unclear. Here we perform single-cell RNA sequencing on 45 tumor samples from 18 GC patients with OM. Interestingly, fibroblasts in OM of GC express high levels of estrogen receptor (ER) and midkine (MDK), interacting with tumor cells through activating ER-MDK-LRP1 (low-density lipoprotein receptor-related protein 1) signaling axis. Functional experiments demonstrate that estrogen stimulation induces MDK secretion by ovarian fibroblasts, and binding of MDK to LRP1 increases GC cell migration and invasion. Furthermore, in vivo, estrogen stimulation remarkably augments ovarian engraftment and metastasis of LRP1+ GC cells. Collectively, our findings reveal that ER+ ovarian fibroblasts secrete MDK under estrogen influence, driving OM of GC via the MDK-LRP1 axis. Our study holds the potential to catalyze innovative therapeutic strategies aimed at intercepting and managing OM in GC.

Association between Estrogen Levels and Temporomandibular Disorders: An Updated Systematic Review.

The aim of this systematic review is to evaluate the impact of estrogen levels on the occurrence of temporomandibular disorders (TMDs) in humans. Searches were conducted in the same databases as follows: PubMed, the Cochrane Collaboration database, and the Scopus database. In accordance with the MeSH database and previous work, the following keywords were used: 'estrogens' and 'temporomandibular joint disorders'. Twelve studies were included in the review and were assessed for the quality of evidence. Estrogen levels are associated with pain modulation in the temporomandibular joint and the entire orofacial region. There is insufficient evidence to either confirm or refute the influence of estrogen on the occurrence of TMDs. The study was registered under the identifier: 10.17605/OSF.IO/BC7QF.

Identify Characteristics Patient Chronic Kidney Failure at Dr. R. Soetijono Hospital Blora

Background research based on the Global Burden of Disease (GBD) study shows that chronic kidney failure has been shown to be the main cause of death in the world. Kidney failure is one of the four diseases that can cause a high financial burden. Purposes is to know description of a case of chronic renal failureat Dr. R. Soetijono Hospital Blora for the period January 2021 to December 2022. Research methods used is the Retrospective Descriptive method using secondary data in the form of medical records / patient status stored in the Medical Records section of Dr. R. Soetijono Hospital Blora, period January 2021 to December 2022. Research result in the period January 2021 to December 2022, there were 221 cases of Chronic Kidney Failure, most of whom were adults and seniors, the gender was predominantly female, which is suspected to be the influence of kidney estrogen, as for the factors causing Chronic Kidney Failure, most of the patients had a history of Diabetes Mellitus with Hemodialysis therapy, and There was an increase in the number of cases by 27% from 2021 to 2022. Implications: The increase in the number of cases of Chronic Kidney Failure will have an impact on the readiness of health services in preparing facilities, resources, costs and technology to overcome problems that occur in CKF patients. Conclusion research that promotive and preventive efforts are very necessary in dealing with cases of Chronic Kidney Failure in adults with a history of Diabetes Mellitus.

Estrogenic regulation of hippocampal inhibitory system across lifespan.

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.

A circadian behavioral analysis suite for real-time classification of daily rhythms in complex behaviors.

Measuring animal behavior over long timescales has been traditionally limited to behaviors that are easily measurable with real-time sensors. More complex behaviors have been measured over time, but these approaches are considerably more challenging due to the intensive manual effort required for scoring behaviors. Recent advances in machine learning have introduced automated behavior analysis methods, but these often overlook long-term behavioral patterns and struggle with classification in varying environmental conditions. To address this, we developed a pipeline that enables continuous, parallel recording and acquisition of animal behavior for an indefinite duration. As part of this pipeline, we applied a recent breakthrough self-supervised computer vision model to reduce training bias and overfitting and to ensure classification robustness. Our system automatically classifies animal behaviors with a performance approaching that of expert-level human labelers. Critically, classification occurs continuously, across multiple animals, and in real time. As a proof-of-concept, we used our system to record behavior from 97 mice over two weeks to test the hypothesis that sex and estrogen influence circadian rhythms in nine distinct home cage behaviors. We discovered novel sex- and estrogen-dependent differences in circadian properties of several behaviors including digging and nesting rhythms. We present a generalized version of our pipeline and novel classification model, the "circadian behavioral analysis suite," (CBAS) as a user-friendly, open-source software package that allows researchers to automatically acquire and analyze behavioral rhythms with a throughput that rivals sensor-based methods, allowing for the temporal and circadian analysis of behaviors that were previously difficult or impossible to observe.

The role of estrogen in Alzheimer's disease pathogenesis and therapeutic potential in women.

Estrogens are pivotal regulators of brain function throughout the lifespan, exerting profound effects from early embryonic development to aging. Extensive experimental evidence underscores the multifaceted protective roles of estrogens on neurons and neurotransmitter systems, particularly in the context of Alzheimer's disease (AD) pathogenesis. Studies have consistently revealed a greater risk of AD development in women compared to men, with postmenopausal women exhibiting heightened susceptibility. This connection between sex factors and long-term estrogen deprivation highlights the significance of estrogen signaling in AD progression. Estrogen's influence extends to key processes implicated in AD, including amyloid precursor protein (APP) processing and neuronal health maintenance mediated by brain-derived neurotrophic factor (BDNF). Reduced BDNF expression, often observed in AD, underscores estrogen's role in preserving neuronal integrity. Notably, hormone replacement therapy (HRT) has emerged as a sex-specific and time-dependent strategy for primary cardiovascular disease (CVD) prevention, offering an excellent risk profile against aging-related disorders like AD. Evidence suggests that HRT may mitigate AD onset and progression in postmenopausal women, further emphasizing the importance of estrogen signaling in AD pathophysiology. This review comprehensively examines the physiological and pathological changes associated with estrogen in AD, elucidating the therapeutic potential of estrogen-based interventions such as HRT. By synthesizing current knowledge, it aims to provide insights into the intricate interplay between estrogen signaling and AD pathogenesis, thereby informing future research directions and therapeutic strategies for this debilitating neurodegenerative disorder.

#1905 Sex differences in primary distal renal tubular acidosis: a single-centre retrospective study

Abstract Background and Aims The kidney has been described as one of the most estrogen-responsive organs after reproductive ones. Many non-X-linked renal diseases present with sex differences. Although not completely elucidated, an influence of estrogens has been described in several transporters along the renal tubule such as the Na+/phosphate cotransporter (NaPi-IIa) in the proximal tubule, the Na+/K+/2Cl⁻ cotransporter (NKCC) in the thick ascending limb of the loop of Henle, the thiazide-sensitive Na+/Cl⁻ cotransporter (NCC) in the distal convoluted tubule and the epithelial sodium channel (ENaC) expressed by the principal cells of the collecting duct. Our study aimed to investigate possible phenotypic sex differences over the natural history of primary distal renal tubular acidosis (dRTA), a rare genetic condition characterized by impaired urinary acidification in the collecting duct that results in non-anion gap metabolic acidosis, hypokalemia, hypercalciuria, nephrolithiasis and nephrocalcinosis, which can lead to chronic kidney disease (CKD). Method We included a cohort of 31 genetically confirmed dRTA patients (19 women and 12 men) followed at the London Tubular Centre. We retrospectively collected data from 2012 to 2023. Estimated glomerular filtration rate (eGFR) was calculated with the CKD-EPIcr formula. Hypokalemia was defined as serum potassium < 3.5 mmol/L, hypercalciuria was defined as urinary calcium/creatinine (uCa/Cr) > 0.7 mmol/mmol and acidosis was defined as HCO3− ≤ 22 mmol/L. Data were analyzed using non-parametric Mann-Whitney as appropriate (Prism GraphPad 8.0.2). A p value < 0.05 was considered as statistically significant. Results Baseline characteristics and prevalence of different mutations are shown in Table 1. At baseline, both cohorts were young, with preserved kidney function. 60% of women were acidotic compared to 50% of men, and 30% of men were hypokalemic compared to 8% of women. The majority of patients in both cohorts presented with overt hypercalciuria (60% of women vs 90% of men). Prevalence of nephrolithiasis and nephrocalcinosis was similar among women and men. At baseline, no statistically significant difference between sexes was found for serum or urinary parameters. Interestingly, men exhibited a tendency towards higher annual mean slope of eGFR (−3.3 ± 2.5 mL/min/1.73 m2) compared to women (−0.5 ± 1.5 mL/min/1.73 m2) in a statistically significant fashion (Fig. 1a). Although not statically significant, we noticed a tendency towards higher fractional excretion of phosphate (FEPO4) (Fig. 1b) and dyslipidemia in men (Fig. 1c). There was no difference in PTH between the two groups (Fig. 1c). Conclusion Men affected by primary dRTA are at increased risk of CKD progression, tend to have a more severe phenotype at baseline and appear to be more dyslipidemic than women. This is consistent with findings in the literature that report accelerated CKD progression and higher cardiovascular morbidity and mortality in men. To our knowledge, this is the first study reporting sex differences in primary dRTA.

Genetic and epigenetic alterations in precursor lesions of endometrial endometrioid carcinoma.

The hyperplasia-carcinoma sequence is a stepwise tumourigenic programme towards endometrial cancer in which normal endometrial epithelium becomes neoplastic through non-atypical endometrial hyperplasia (NAEH) and atypical endometrial hyperplasia (AEH), under the influence of unopposed oestrogen. NAEH and AEH are known to exhibit polyclonal and monoclonal cell growth, respectively; yet, aside from focal PTEN protein loss, the genetic and epigenetic alterations that occur during the cellular transition remain largely unknown. We sought to explore the potential molecular mechanisms that promote the NAEH-AEH transition and identify molecular markers that could help to differentiate between these two states. We conducted target-panel sequencing on the coding exons of 596 genes, including 96 endometrial cancer driver genes, and DNA methylome microarrays for 48 NAEH and 44 AEH lesions that were separately collected via macro- or micro-dissection from the endometrial tissues of 30 cases. Sequencing analyses revealed acquisition of the PTEN mutation and the clonal expansion of tumour cells in AEH samples. Further, across the transition, alterations to the DNA methylome were characterised by hypermethylation of promoter/enhancer regions and CpG islands, as well as hypo- and hyper-methylation of DNA-binding regions for transcription factors relevant to endometrial cell differentiation and/or tumourigenesis, including FOXA2, SOX17, and HAND2. The identified DNA methylation signature distinguishing NAEH and AEH lesions was reproducible in a validation cohort with modest discriminative capability. These findings not only support the concept that the transition from NAEH to AEH is an essential step within neoplastic cell transformation of endometrial epithelium but also provide deep insight into the molecular mechanism of the tumourigenic programme. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Role of estrogen signaling in fibroblastic reticular cellsfor innate and adaptive immune responses in antigen-induced arthritis.

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.

Preimplantation Genetic Diagnosis of Androgen Resistance Syndrome Caused by Mutation on the AR Gene in Vietnam.

Androgen resistance syndrome or androgen insensitivity syndrome (AIS - Androgen Insensitivity Syndrome, OMIM 300068) is an X-linked recessive genetic syndrome causing disorders of sexual development in males. This disease is caused by mutations in the AR gene located on the X chromosome, which encodes the protein that structures the androgen receptor, with the role of receiving androgens. Mutation of the AR gene causes complete or partial loss of androgen receptor function, thereby androgen not being obtained and exerting its effect on target organs, resulting in abnormalities of the male reproductive system due to this organ system, differentiating towards feminization under the influence of estrogen. Disease prevention can be achieved by using pre-implantation genetic diagnosis, which enables couples carrying the mutation to have healthy offspring. To carry out preimplantation genetic diagnosis of androgen resistance syndrome. Sanger sequencing was used to detect the mutation in the blood samples of the couple, their son, and 01 embryo that were biopsied on the fifth day based on the findings of next-generation sequencing (NGS) of the affected son. We combined Sanger sequencing and linkage analysis using short tandem repeats (STR) to provide diagnostic results. We performed preimplantation genetic diagnosis for AIS on an embryo from a couple who had previously had an affected son. Consequently, one healthy embryo was diagnosed without the variant NM_000044: c.796del (p.Asp266IlefsTer30). We report on a novel variant (NM_000044: c.796del (p.Asp266IlefsTer30)) in the AR gene discovered in Vietnam. The developed protocol was helpful for the preimplantation genetic diagnosis process to help families with the monogenic disease of AIS but wish to have healthy children.

The Influence of IGF-1, Progesterone, Androstenedione, Aromatase, and Estrogen in Successful and Unsuccessful IVF Treatments

Follicular steroidogenesis, involving proteins including insulin-like growth factor 1 (IGF-1), progesterone (P4), androstenedione, aromatase, and estrogen (E2), may influence the success of in vitro fertilization (IVF) treatments. This research aimed to 1) compare levels of these proteins in follicular fluid (FF) between subjects with successful (n=10) and unsuccessful (n=20) outcomes; 2) compare these proteins between FF and serum within each group; and 3) investigate correlations of these proteins with reproductive hormones. Classification into successful and unsuccessful groups was based on the detection of fetal heartbeat. Blood samples were collected to measure anti-Müllerian hormone (AMH) and follicle-stimulating hormone (FSH) at baseline as well as IGF-1, FSH, P4, androstenedione, aromatase, and E2 in FF and serum on the day of ovum pick-up (OPU). In unsuccessful pregnancies, FF and serum IGF-1 levels and FF aromatase levels were significantly higher, whereas FF and serum androstenedione levels were significantly lower when compared to successful pregnancies ( P<0.05 all). There were no significant differences in FF E2 and P4 levels between groups; however, there was a non-significant trend towards decreased FF E2 levels in unsuccessful pregnancies. Levels of IGF-1, P4, androstenedione, and E2 were significantly higher in FF than in serum in both successful and unsuccessful groups ( P<0.01 all). The FF/serum ratios for successful and unsuccessful subjects were 2.28 and 2.06 for IGF-1, 7,920.61 and 1,919.26 for P4, 5.49 and 4.00 for androstenedione, and 193.45 and 225.60 for E2, respectively. For correlation analyses, basal AMH showed significant positive correlations with serum androstenedione in all subjects and a significant negative correlation with FF E2 in unsuccessful subjects ( P<0.05 all). Basal FSH levels were significantly negatively correlated with serum androstenedione levels in all subjects ( P<0.05). On OPU day, FF androstenedione levels showed significant positive correlations with FF and serum E2 levels in unsuccessful subjects ( P<0.05 all). Serum androstenedione levels were significantly positively correlated with FF E2 levels in successful subjects and with serum E2 levels in all and unsuccessful subjects ( P<0.01 all). FF aromatase levels had significant positive correlations with serum FSH levels in all and unsuccessful subjects ( P<0.01 all). FF E2 levels were significantly positively correlated with FF androstenedione levels in unsuccessful subjects and with serum androstenedione levels in successful subjects ( P<0.01 all). In unsuccessful pregnancies, elevated aromatase levels, despite similar or insignificantly lower FF E2 levels, could likely result from high FSH levels, potentially indicating defective FF E2 production processes that may be due to inadequate substrate availability or decreased aromatase activity. Lower androstenedione levels in unsuccessful pregnancies suggest that there may be a defect in substrate production; however, we could not determine whether there is a defect in aromatase function in these subjects. Lower FF and serum androstenedione levels in unsuccessful pregnancies might be due to poor ovarian response, as indicated by lower basal AMH and higher FSH levels observed in these subjects in our previous study, findings further supported by a positive correlation between androstenedione and basal AMH, and a negative correlation with basal FSH. The elevated IGF-1 levels in the unsuccessful group might be attributable to high FSH levels. Higher levels of IGF-1, P4, androstenedione, and E2 in FF than in serum indicate that these hormones might be primarily secreted into FF before being released into circulation. In conclusion, unsuccessful pregnancies exhibited lower FF and serum androstenedione levels, but higher FF aromatase and IGF-1 levels in both FF and serum, indicating a decreased substrate availability for E2 production in subjects with poor ovarian response. IGF-1, P4, androstenedione, and E2 were likely synthesized primarily in FF rather than serum. This research was funded by the Faculty of Medicine Siriraj Hospital Research Fund ((IO) R016433005 and Grant to support Strategic Driving Project for pushing the World University Rankings by Subject, Fiscal Year 2021 ((IO) R016421007). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effect of estrogens on apoptosis in the pituitary of viscachas (Lagostomus maximus maximus)

Estrogens, acting through their receptors (ERα and ERβ), regulate cell turnover in the pituitary gland, influencing cell proliferation and apoptosis across various species. However, their role in pituitary processes in seasonally reproducing animals remains poorly understood. This study aims to investigate the influence of estrogens, through the expression of their specific receptors, on the apoptosis of PD cells in relation to sexual maturity, the reproductive cycle, and pregnancy in a seasonal reproductive rodent (Lagostomus maximus maximus). ERα and caspase-3-cleaved (CASP3c) immunoreactive (-ir) cells were identified through immunohistochemistry. Apoptotic cells were detected using the TUNEL technique, with quantitative analysis facilitated by image analysis software, alongside measurement of serum estradiol levels using radioimmunoassay The immunostaining pattern for ERα included nuclear (ERαn) and cytoplasmic (ERαc) staining. In male viscachas, ERα expression significantly increases from immature to adult animals, correlating with the rise in serum estradiol levels and a decrease in the percentage of apoptotic cells. During the gonadal regression period in adult males, a decrease in the number of ER-ir cells and serum levels of estradiol corresponds with an increase in the number of apoptotic cells. In females, serum levels of estradiol peaked during mid-pregnancy, coinciding with a significant decrease in the number of apoptotic cells in the PD. Simultaneously, the percentage of ERαn-ir cells reaches its maximum value during late pregnancy, indicating the need to maintain the protective action of this gonadal hormone throughout the extensive pregnancy in these rodents. Regional ERα receptor expression and apoptotic cells appear to be associated with distinct PD cell populations and their hormonal responses. Finally, elevated estradiol levels coincide with diminished apoptotic cells in the male reproductive cycle and during pregnancy, suggesting an antiapoptotic role of estradiol in this species.

Unveiling the Nexus: Cellular Metabolomics Unravels the Impact of Estrogen on Nicotinamide Metabolism in Mitigating Rheumatoid Arthritis Pathogenesis.

Rheumatoid arthritis (RA) is a metabolic joint disorder influenced by hormonal regulation, notably estrogen, which plays a cytoprotective role against inflammation. While estrogen's impact on RA pathogenesis has been studied, the altered metabolite expression under estrogen's influence remains unexplored. This study investigated the changes in the metabolome of synovial fibroblasts isolated from RA patients under 17β-estradiol (E2) using the liquid chromatography with tandem mass spectrometry (LC-MS/MS) approach followed by multivariate and biological pathway analysis along with in vitro validation. Results identified 3624 m/z, among which eight metabolites were significant (p < 0.05). Nicotinate and nicotinamide metabolism was found to be highly correlated with the treatment of E2, with metabolites NAD+ and 1-methynicotinamide (1-MNA) upregulated by E2 induction in RA-FLS. PharmMapper analysis identified potential gene targets of 1-MNA, which were further matched with RA gene targets, and thus, STAT1, MAPK14, MMP3, and MMP9 were concluded to be the common targets. E2 treatment affected the expression of these gene targets and ameliorated the development of oxidative stress associated with RA inflammation, which can be attributed to increased concentration of 1-MNA. Thus, an LC-MS/MS-based metabolomics study revealed the prominent role of estrogen in preventing inflammatory progression in RA by altering metabolite concentration, which can support its therapeutic capacity in remitting RA.

Lightness Peaks during the Menstrual Phase: A Retrospective Challenge to a Visual Arousal Theory of Estrogen

(1) Background: The influence of estrogen on cognitive and perceptual functions is debated. Some research suggests that estrogen increases arousal, improving cognitive function, while others propose that increased arousal might reduce performance in certain tasks. This study investigates the effects of menstrual cycle phase and estrogen levels on lightness perception in cycling women and hormonal contraceptive (HC) users. (2) Methods: Sixteen women (nine with natural cycles and seven HC users) completed three sessions aligned with different menstrual cycle phases. During these sessions, participants adjusted the luminance of five test stimuli (representing blue, green, green-yellow, yellow, and red) until they matched a flickering reference white stimulus. Lightness was calculated as the ratio of the reference stimulus luminance (5 cd/m2) divided by the test luminance required to match. Estrogen levels were also determined for each participant from saliva samples collected on the morning of each session. The effects of wavelength and menstrual cycle phase on lightness perception were analyzed, followed by post hoc comparisons and correlations between lightness perception and estrogen levels for both cycling women and HC users. (3) Results: Lightness varied by menstrual phase (MCP) in cycling women and was slightly higher during the low estrogen menstrual phase compared to peri-ovulation or luteal phases. In HC users, lightness measures were equivalent across phases. For cycling women, lightness was negatively correlated with estrogen for the green and green-yellow stimuli. There were no such associations among HC users. (4) Conclusions: This report challenges the concept that high estrogen phases of the menstrual cycle always positively influence perception. Conversely, these results revealed that—at least in cycling, non-hormonal contraceptive users—lightness perception was both at a maximum during the low estrogen menstrual phase and negatively associated with estrogen levels across all tested wavelengths.

Abstract 1614: Macroscopic clonal expansion with driver mutations in normal human endometrium

Abstract Introduction: The epithelial cells of the endometrium undergo rapid proliferation and shedding each month under the influence of estrogen and progesterone. Recent studies have demonstrated pervasive driver mutations in the endometrium with ageing. However, previous observations have been limited to the microscopic scale, and it is still unclear how clonal expansion occurs over the entire endometrium and what driver mutations are responsible therein. To address these issues, we performed multisampling of the endometrium with extensive spatial mapping. Methods: We collected multiple endometrial glands from normal endometrium in a 5mm lattice in 19 patients aged 30 to 85 years who underwent hysterectomy (3-31 samples per case), followed by DNA extraction, detected somatic mutations by whole exome sequencing, to identify large clones that spread across samples based on shared mutations. Results: In total, 213 bulk endometrial glands were analyzed. The number of detected somatic mutations per sample ranged from 4 to 81 (mean±SD: 32.5±14.1), with at least one known driver gene mutation detected in 204 of 213 samples (mean±SD: 3.03±1.78). The mutational signature analysis revealed the predominance of the age-related SBS1 and SBS5 signatures. dN/dS analysis identified 20 genes that were positively selected in normal endometrium, including PIK3CA, PIK3R1, KRAS, PPP2R1A, ARHGAP35, and FBXW7, most of which are also known as driver genes for endometrial cancer. The number of mutations and their frequency for each driver gene did not differ by background diseases: endometriosis, endometriosis-associated ovarian cancer and other non-endometrial related diseases. In contrast to the high frequency of driver gene mutations, copy-number alterations were found in only 3 samples, such as +1q, +7, +10 and +12. We found clones showing a large expansion involving multiple samples in 8 cases, most of which harbored one or more driver mutations, such as PIK3CA and KRAS. The size of the largest clone carrying a KRAS mutation, which was found in a 32-year-old woman with cervical cancer, spanned as long as 10 mm in diameter. This suggests that clonal expansion in the endometrium could be very rapid even in healthy women, which contrasts to the observations that clonal expansion in other organs is usually seen in aged individuals. Conclusion: We confirmed the high frequency of driver mutations in the normal endometrium, most of which overlapped to those found in endometrial cancers, suggesting that these driver genes are involved in the early phase of the development in the endometrial cancer. Some of the driver-mutated clones expanded in macroscopic size. Our findings provide an interesting insight into the clonal structure and underlying genetic variation in the normal endometrium. Citation Format: Koichi Watanabe, Nobuyuki Kakiuchi, Kosuke Ieiri, Hirona Maeda, Tomonori Hirano, Sachiko Kitamura, Mana Taki, Koji Yamanoi, Ryusuke Murakami, Ken Yamaguchi, Junzo Hamanishi, Hiroko Tanaka, Satoru Miyano, Masaki Mandai, Seishi Ogawa. Macroscopic clonal expansion with driver mutations in normal human endometrium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1614.

Exploring the Link between Chronic Inflammation and Atherosclerosis-Endometriosis Association

Background: Atherosclerotic cardiovascular disease (ASCVD) and endometriosis are both inflammatory diseases with significant implications for clinical practice and public health. Evidence Acquisition: To examine the clinical question regarding the relationship between ASCVD and endometriosis, we gathered data from various sources, including research studies and subsequent reference searches of retrieved articles. Our research strategies focused on identifying high-quality evidence through comprehensive study time periods and rigorous methods for quality assessment and article inclusion. Results: Our review of the literature reveals significant findings regarding the interplay between ASCVD and endometriosis. Both conditions share inflammation as a key factor in their pathophysiology. Inflammation not only contributes to the initiation and progression of vascular damage in ASCVD but also plays a role in the development and persistence of endometriosis. Women with endometriosis demonstrate higher levels of inflammatory markers and endothelial activation. Conclusions: Based on the available evidence, we conclude that there is a likely genetic link between ASCVD and the development of endometriosis. Additionally, the influence of estrogen on ASCVD varies depending on the stage of atherosclerosis. While estrogen may be protective in women with early artery blockages, it can pose a potential risk to those with established atherosclerosis. Clinicians should consider these factors when managing patients with ASCVD and endometriosis to optimize care.

An Estrogen-NK Cells Regulatory Axis in Endometriosis, Related Infertility, and Miscarriage.

Endometriosis is a common estrogen-dependent condition that impacts 8-10% of women in their reproductive age, resulting in notable pain, morbidity, and infertility. Despite extensive research endeavors, the precise cause of endometriosis remains elusive, and the mechanisms contributing to its associated infertility are still not well comprehended. Natural killer (NK) cells, vital innate immune cells crucial for successful pregnancy, have been investigated for their potential involvement in the pathogenesis of endometriosis. Prior research has mainly concentrated on the diminished cytotoxicity of NK cells in endometrial fragments that evade the uterus. Interestingly, accumulating evidence suggests that NK cells play multifaceted roles in regulating the biology of endometrial stromal cells (ESCs), promoting local immune tolerance, influencing endometrial receptivity, oocyte development, and embryo implantation, thereby contributing to infertility and miscarriage in patients with endometriosis. In this comprehensive review, our goal is to summarize the current literature and provide an overview of the implications of NK cells in endometriosis, especially concerning infertility and pregnancy loss, under the influence of estrogen.

Mineralocorticoid receptor and aldosterone: Interaction between NR3C2 genetic variants, sex and age in a mixed cohort.

Hypertension, a prevalent cardiovascular risk, often involves dysregulated aldosterone and its interaction with the mineralocorticoid receptor (MR). Experimental designs in animal models and human cohorts have demonstrated a sex and age dependency of aldosterone secretion that expands our pathophysiologic understanding. This study explores the genetic variation of NR3C2, which encodes MR, in relation to aldosterone, considering age, sex, and race. Incorporating 720 Caucasians and 145 Africans from the HyperPATH cohort, we investigated the impact of rs4835490, a single nucleotide risk allele variant, on aldosterone levels and vasculature. Notably, a significant association between rs4835490 and plasma aldosterone under liberal salt conditions emerged in individuals of European ancestry (P=0.0002). Homozygous carriers of the risk A allele exhibited elevated plasma aldosterone levels (AA=8.1±0.9 vs GG=4.9±0.5 ng/dl). Additionally, aldosterone activation through posture (P=0.025) and urinary excretion (P=0.0122) showed notable associations. Moreover, genetic interactions with race, sex, and age were observed. Caucasian females under 50 years displayed higher plasma aldosterone, urine aldosterone, and posture aldosterone with the AA genotype compared to females over 50 years, suggesting a potential connection with menopausal or estrogen influences. Interestingly, such age-dependent interactions were absent in the African cohort. our study highlights the significance of NR3C2 genetic variation and its interplay with age, sex, and race in aldosterone activation. The findings point towards an estrogen-modulating effect on MR activation, particularly in women underlining the role of aldosterone dysregulation in hypertension development. This insight advances our comprehension of hypertension's complexities and opens avenues for personalized interventions.

Association between C10X polymorphism in the CARD8 gene and inflammatory markers in young healthy individuals in the LBA study

BackgroundThe Caspase activation and recruitment domain 8 (CARD8) protein is a component of innate immunity as a negative regulator of NF- ĸB, and has been associated with regulation of proteins involved in inflammation. Expression of CARD8 mRNA and protein has been identified in human atherosclerotic lesions, and the truncated T30A variant (rs2043211) of CARD8 has been associated with lower C-reactive (CRP) and MCP-1 levels in myocardial infarction patients. The present study examines the role of a genetic variation in the CARD8 gene in relation to a selection of markers of inflammation.MethodsIn a cross-sectional study of young healthy individuals (18.0–25.9 yrs, n = 744) the association between the rs2043211 variant in the CARD8 gene and protein markers of inflammation was assessed. Genotyping of the CARD8 C10X (rs2043211) polymorphism was performed with TaqMan real time PCR on DNA from blood samples. Protein levels were studied via Olink inflammation panel (https://olink.com/). Using linear models, we analyzed men and two groups of women with and without estrogen containing contraceptives separately, due to previous findings indicating differences between estrogen users and non-estrogen using women. Genotypes were analyzed by additive, recessive and dominant models.ResultsThe minor (A) allele of the rs2043211 polymorphism in the CARD8 gene was associated with lower levels of CCL20 and IL-6 in men (CCL20, Additive model: p = 0.023; Dominant model: p = 0.016. IL-6, Additive model: p = 0.042; Dominant model: p = 0.039). The associations remained significant also after adjustment for age and potential intermediate variables.ConclusionsOur data indicate that CARD8 may be involved in the regulation of CCL20 and IL-6 in men. No such association was observed in women.These findings strengthen and support previous in vitro data on IL-6 and CCL20 and highlight the importance of CARD8 as a factor in the regulation of inflammatory proteins. The reason to the difference between sexes is however not clear, and the influence of estrogen as a possible factor important for the inflammatory response needs to be further explored.