Treatment Of Postmenopausal Women Research Articles

Threshold based on bone mineral density for therapeutic decision-making in postmenopausal women and men over 50 years old under glucocorticoid therapy

Introduction and aimT-score bone mineral density (BMD) thresholds may influence guidance for treatment in patients under glucocorticoid (GC) therapy. Different BMD thresholds have been described but there is no international consensus. The aim of this study was to find a threshold to help in treatment decision-making in the population under GC therapy. MethodsA working group representing three scientific societies from Argentina was convened. The first team was formed by specialists with expertise in glucocorticoid-induced osteoporosis (GIO) who voted according to summary of evidence. The second team was constituted by a methodology group who coordinated and supervised each stage. We conducted two systematic reviews to synthesize the evidence. The first included trials of drugs used in GIO to analyze the BMD cut-off used as inclusion criteria. In the second, we analyzed the evidence regarding the densitometric thresholds to discriminate between fractured and non-fractured patients under GC treatment. ResultsIn the first review, 31 articles were included for qualitative synthesis and more than 90% of the trials included patients regardless of their densitometric T-score or range of osteopenia. In the second review, 4 articles were included and more than 80% of the T-scores were in the range −1.6 to −2.0. The summary of findings was analyzed and put to a vote. ConclusionsWith more than 80% agreement of the voting expert panel, a T-score≤−1.7 was considered the most appropriate for treatment in postmenopausal women and men over 50 years of age under GC therapy. This study could help in treatment decision-making in patients under GC therapy without fractures but other fracture risk factors should certainly be considered.

Endometrial safety of low-dose vaginal estrogens.

It is estimated that up to 50% to 90% of postmenopausal women may experience genitourinary syndrome of menopause (GSM), which may have a detrimental impact on quality of life. One of the most effective modes of treatment of GSM is low-dose vaginal estrogens. Numerous studies have addressed the safety of these estrogens using endometrial biopsy and/or endometrial thickness on ultrasound. Based on these studies, the consensus is that low-dose vaginal estrogens do not substantially increase the risk of endometrial hyperplasia or cancer; however, the data are severely limited by short duration of follow-up. Although long-term trials are warranted, they are difficult to carry out, costly, and will not yield data for years. More immediate information regarding endometrial safety may be obtained from studies measuring endometrial tissue and serum concentrations of estradiol, estrone, and relevant equine estrogens after administration of different estrogen formulations and doses. This would allow us to understand better the metabolism of estrogens by the vagina and endometrium, and how much estrogen is reaching the endometrium. Here, we discuss metabolism, receptor binding, and signaling of estrogens in vaginal and endometrial tissue, and summarize the existing studies on the endometrial impact of low-dose vaginal estrogen treatment in postmenopausal women.

Influence of the Osteogenomic Profile in Response to Alendronate Therapy in Postmenopausal Women with Osteoporosis: A Retrospective Cohort Study.

Postmenopausal osteoporosis is a multifactorial disease. Genetic factors play an essential role in contributing to bone mineral density (BMD) variability, which ranges from 60 to 85%. Alendronate is used as the first line of pharmacological treatment for osteoporosis; however, some patients do not respond adequately to therapy with alendronate. The aim of this work was to investigate the influence of combinations of potential risk alleles (genetic profiles) associated with response to anti-osteoporotic treatment in postmenopausal women with primary osteoporosis. A total of 82 postmenopausal women with primary osteoporosis receiving alendronate (70 mg administered orally per week) for one year were observed. The bone mineral density (BMD; g/cm2) of the femoral neck and lumbar spine was measured. According to BMD change, patients were divided into two groups: responders and non-responders to alendronate therapy. Polymorphic variants in CYP19, ESR1, IL-6, PTHR1, TGFβ, OPG and RANKL genes were determined and profiles were generated from the combination of risk alleles. A total of 56 subjects were responders to alendronate and 26 subjects were non-responders. Carriers of the G-C-G-C profile (constructed from rs700518, rs1800795, rs2073618 and rs3102735) were predisposed to response to alendronate treatment (p = 0.001). Our findings highlight the importance of the identified profiles for the pharmacogenetics of alendronate therapy in osteoporosis.

Elevated adipose differentiation-related protein level in ovariectomized mice correlates with tissue-specific regulation of estrogen.

Redistribution of adipose tissue in the abdomen during the menopausal transition is attributable mostly to estrogen drop with aging. Adipose differentiation-related protein (ADRP), a major component of lipid droplets, is closely related to the onset of lipid accumulation. We hypothesized that estrogen exerted its tissue-specific effect in reducing abdominal fat accumulation by regulation of ADRP. Twenty-four female C57/BL6 mice aged 8 weeks were randomly divided into 3 groups: sham operation (Sham), bilateral ovariectomy (OVX), and OVX plus 17β-estradiol (OVX + E2). After being fed 8 weeks of a high-fat diet, plasma lipid profiles including total cholesterol (TC), total triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels, body weight gain, visceral, and subcutaneous adipose tissue, adipocyte size, and ADRP expression were measured. In comparison to sham-operated mice, OVX mice presented a weight gain with higher plasma TC, TG, LDL-C levels, and lower HDL-C levels. E2 supplement ameliorated the increase in weight and lipid profiles. Elevated ADRP expression was observed in visceral adipose tissue of OVX mice, whereas treatment of estrogen suppressed the ADPR expression and reversed the fat accumulation in the abdomen. However, no significant difference of ADRP expression in subcutaneous adipose tissue was detected between sham, OVX, and OVX + E2 mice. Our findings suggested that enhanced ADRP expression in ovariectomized mice correlates with the tissue-specific regulation of estrogen, which may provide useful clues for further exploring the regulatory mechanism and corresponding anti-abdominal obesity treatment in postmenopausal women.

Prevention of aromatase inhibitor-induced bone loss with anti-resorptive therapy in post-menopausal women with early-stage breast cancer.

This study aimed to describe changes in femoral and lumbar bone mineral density (BMD) after 24months of aromatase inhibitors (AIs) and antiresorptive treatment in postmenopausal women with estrogen receptor-positive breast cancer. Prospective, longitudinal study in a real-life setting with a 2-year follow-up. Patients underwent a complete baseline bone assessment including clinical assessment, biological evaluation, BMD measurement, and spine X-ray. Antiresorptive treatment was prescribed to patients with a T-score < - 2 or a T-score < - 1.5 SD with additional osteoporosis risk factors. A follow-up bone assessment was carried out after 24months. Among 328 patients referred to our center, 168 patients (67.7 ± 10.6years) were included in our study, and 144 were eligible for antiresorptive treatment. After 24months, patients receiving antiresorptive treatment experienced a significant increase of + 6.28% in femoral-BMD (F-BMD) and + 7.79% in lumbar-BMD (L-BMD). This increase was not significantly different between osteoporotic and osteopenic patients. Conversely, patients not receiving antiresorptive treatment presented significant F-BMD and L-BMD loss regardless of the baseline BMD. In the multivariate logistic model, the lack of antiresorptive treatment was the only predictive factor for major femoral bone loss with a 20.83 odds ratio (CI95%:4.2-100, p < 0.001). This real-life study confirmed that antiresorptive treatment significantly increases femoral and lumbar BMD regardless of the baseline BMD in postmenopausal patients receiving AIs for early breast cancer. Patients who did not receive antiresorptive treatment had a 20.8-fold increased risk of major bone loss. Nevertheless, the best threshold to adopt for starting antiresorptive agents remains undetermined.

Inferring Bacterial Community Interactions and Functionalities Associated with Osteopenia and Osteoporosis in Taiwanese Postmenopausal Women.

Growing evidence suggests that the gut microbiota and their metabolites are associated with bone homeostasis and fragility. However, this association is limited to microbial taxonomic differences. This study aimed to explore whether gut bacterial community associations, composition, and functions are associated with osteopenia and osteoporosis. We compared the gut bacterial community composition and interactions of healthy postmenopausal women with normal bone density (n = 8) with those of postmenopausal women with osteopenia (n = 18) and osteoporosis (n = 21) through 16S rRNA sequencing coupled with network biology and statistical analyses. The results of this study showed reduced alpha diversity in patients with osteoporosis, followed by that in patients with osteopenia, then in healthy controls. Taxonomic analysis revealed that significantly enriched bacterial genera with higher abundance was observed in patients with osteoporosis and osteopenia than in healthy subjects. Additionally, a co-occurrence network revealed that, compared to healthy controls, bacterial interactions were higher in patients with osteoporosis, followed by those with osteopenia. Further, NetShift analysis showed that a higher number of bacteria drove changes in the microbial community structure of patients with osteoporosis than osteopenia. Correlation analysis revealed that most of these driver bacteria had a significant positive relationship with several significant metabolic pathways. Further, ordination analysis revealed that height and T-score were the primary variables influencing the gut microbial community structure. Taken together, this study evaluated that microbial community interaction is more important than the taxonomic differences in knowing the critical role of gut microbiota in postmenopausal women associated with osteopenia and osteoporosis. Additionally, the significantly enriched bacteria and functional pathways might be potential biomarkers for the prognosis and treatment of postmenopausal women with osteopenia and osteoporosis.

Effect of Core Muscle Stabilisation Exercises on Disability Associated with Non Specific Low Back Pain in Postmenopausal Women: A Prospective Longitudinal Study

Introduction: Non Specific Low Back Pain (NSLBP) is a frequent problem faced by the majority of postmenopausal women at some stage of their lives, resulting in a significant level of disability. Aim: To evaluate the effectiveness of core stabilisation exercises compared to traditional physical treatment in postmenopausal women with NSLBP. Materials and Methods: A prospective longitudinal study was conducted from January 2022 to August 2022, including 50 postmenopausal women aged 45-60 years with NSLBP. They were placed into two groups. Conventional LBP physical therapy methods were administered to group 2. The identical traditional and Core muscle Stabilisation Exercises (CSE) were implemented in the group 1. The Modified Oswestry Disability Index (MODI) was used for the assessment of disability. The Mann-Whitney U test and Friedman Analysis of Variance (ANOVA) were conducted to analyse changes in disability scores across and among groups at the ends of the second, fourth, and sixth weeks of treatment. Results: Of 50 patients initially enrolled in the study, 33 patients were available for the final follow-up. Group 1 consisted of 16 patients, while group 2 had 17 patients. Significant reduction in disability was found across the two groups at the second, fourth, and sixth weeks of treatment (p-value&lt;0.05). In the sixth week of treatment, group 1 had a statistically greater decrease in ODI score (41.16±13.53) than group 2 (30.74±13.28) (p-value =0.003). Conclusion: CSE were found to be more effective than conventional physical therapy in reducing disability associated with NSLBP in postmenopausal women.

EE361 Cost-Effectiveness Analysis of Ribociclib Versus Abemaciclib in the First-Line (1L) Treatment of Postmenopausal Women With HR+/HER2- Advanced Breast Cancer (ABC)

EE361 Cost-Effectiveness Analysis of Ribociclib Versus Abemaciclib in the First-Line (1L) Treatment of Postmenopausal Women With HR+/HER2- Advanced Breast Cancer (ABC)

Adjuvant aromatase inhibitor treatment worsens depressive symptoms and sleep quality in postmenopausal women with localized breast cancer: A one-year follow-up study

First-line treatment in postmenopausal women with estrogen- and/or progesterone-positive breast cancer consists of aromatase inhibitors (AROi). The ability of AROi to promote or worsen cognitive function, depressive symptoms, sleep quality and performance in basic activities of daily life as primary and concomitant outcomes in long longitudinal studies in post-menopausal women has been seldom investigated. This study is a cohort trial which aimed to determine if there were differences in cognitive function assessment, depressive symptoms, and sleep quality after 1 year under AROi treatment and to determine the interrelations between these symptoms. Methods: A prospective 1-year longitudinal study was performed in a representative sample of tertiary hospital. Women with localized breast cancer newly treated with AROi therapy were evaluated for cognitive functions, depressive symptoms, sleep problems and ability to perform basic activities of the daily life at baseline and after 6 months and 12 months under adjuvant AROi treatment. Results: Analysis of cognitive functions by the Mini-Mental State Examination (MMSE) scores did not show significantly worsening under AROi treatment after 6 months and 12 months of treatment compared to the baseline. Analysis of depressive symptoms with the Geriatric Depression Scale and sleep quality with the Athens Insomnia Scale (AIS) scores showed significant (p < 0.05) changes after 6 and 12 months of treatment with AROi, with women describing more depressive symptoms and more sleep disturbances. Conclusions: Our study found impairments in sleep quality and an increase in depressive symptoms, which has important implications for clinicians as they impair quality of life and adherence to treatment.

206 (PB-030) Poster - Cost-effectiveness of first-line ribociclib use vs palbociclib in the treatment of postmenopausal women with HR+/HER2− advanced breast cancer: analysis based on final OS results of MONALEESA-2 and PALOMA-2

Background: The combination of a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) plus aromatase inhibitor is the standard of care in first-line (1L) treatment of hormone receptor–positive/human epidermal growth factor receptor–negative (HR+/HER2−) advanced breast cancer (ABC). Among the 3 CDK4/6is, only ribociclib has shown a statistically significant benefit in overall survival (OS) (MONALEESA [ML]-2 and -7) in 1L use: palbociclib did not demonstrate a significant OS benefit (PALOMA-2 [PAL-2]) and the final OS results for abemaciclib (MONARCH-3) are pending.

Anti-osteoporosis treatments changed body composition in postmenopausal women: A systematic review and meta-analysis.

Whether the widespread anti-osteoporosis treatments in postmenopausal women also benefit the change of body composition (lean body mass [LBM] and body fat mass [FM]) remains controversial. In order to solve this issue and find out the most effective treatment, we conducted this meta-analysis. We searched the literature, via PubMed, Embase, Scopus, Web of Science, and Cochrane to screen citations from inception to March 26, 2022, for inclusion in this study. Only clinical trials that used anti-osteoporosis treatments in postmenopausal women and displayed the alteration of body composition were included. Stata 14.0 was used for the meta-analysis. Our meta-analysis results presented that: compared with placebo, hormone replacement therapy (HRT) was associated with increased LBM (standardized mean differences [SMD] = 0.32, 95% confidence interval [CI] = 0.02-0.61) and reduced FM (SMD = -0.30, 95% CI = -0.51 to -0.09) in postmenopausal women. Compared with placebo, physical exercise training showed an effect of decreasing FM (SMD = -0.66, 95% CI = -0.94 to -0.38) but not significant influence LBM (SMD = 1.31, 95% CI = -0.29 to 2.91). The network meta-analysis of our study showed that oral estrogen and progestogen plus exercise (OEPE) treatment might be the most effective anti-osteoporosis treatment (surface under the cumulative ranking curve 99.9) to reduce FM in postmenopausal women. anti-osteoporosis treatments, especially HRT, affect body composition. Furthermore, the combination of HRT and exercise training are the most effective treatment to reduce FM while maintaining LBM.

Trabecular bone score as an additional therapeutic decision tool in osteoporosis and osteopenia

ObjectivesTo evaluate the role of trabecular bone score (TBS), in addition to bone mineral density (BMD), and to aid decision making to initiate anti-osteoporotic treatment in postmenopausal women with osteopenia. MethodsTBS was assessed in a cohort of Thai postmenopausal women with BMD of femoral neck (FN), total hip (TH), and lumbar spine (LS) performed at the Police General Hospital, Bangkok, Thailand from July 2019 to October 2020. We retrospectively reviewed hospital database for underlying diseases, medication, and fractures, including relevant imaging and vertebral fracture assessment (VFA). Patients with previous osteoporosis treatment, skeletal malignancy, high-energy trauma, and uninterpretable BMD were excluded. ResultsIn total there were 407 postmenopausal women, including 115 with osteoporotic fractures. The mean TBS of the cohort was 1.264 ± 0.005. The proportion of osteoporotic subjects ranged from 9.1% by TH BMD to 27.0% by lowest BMD. In fractured patients, 21.7%–54.8% were found to have osteoporosis while osteopenia was found in 37.4%–43.5%. Among subjects with osteopenia and degraded TBS, fractures ranged from 21.7 to 50.9%. Addition of osteopenic subjects with degraded microarchitecture yielded a significantly higher number of subjects eligible for treatment with 3.25-fold increase in non-fractured participants, and 7 to 11 additional osteopenic patients should be treated to detect 1 fracture. ConclusionsAddition of TBS helped capturing osteopenic women with high risk of fracture. Decision to treat osteopenic women with degraded TBS increased the number of patients receiving treatment. We recommend evaluating TBS in osteopenic women without fractures to aid therapeutic decision on treatment initiation.

Traitements médicamenteux préventifs des ostéoporoses

Osteoporosis and fragility fractures represent a public health issue, responsible for an increased morbidity and mortality. We should consider the prevention of this chronic disease. We can differentiate primary prevention, meaning bone loss prevention in patients with normal bone density, and secondary prevention, meaning fracture prevention in patients with low bone density. We will not discuss about tertiary prevention, which is prevention of fracture recurrence. We will discuss here drug prevention treatment in post-menopausal women, in cancer with hormonotherapy, and in cortico-induced osteoporosis.

Androstenedione and Follicle-Stimulating Hormone Concentration Predict the Progression of Frailty Syndrome at One Year Follow-Up in Patients with Localized Breast Cancer Treated with Aromatase Inhibitors.

Background: The standard treatment in postmenopausal women with estrogen- and progesterone-positive localized breast cancer consists of aromatase inhibitors (AROi). The ability of AROi to promote or worsen frailty syndrome over time and the relationship with changes in gonadal hormones concentration in blood have not been investigated. Methods: A prospective study to evaluate the relationship between frailty syndrome and gonadal hormones concentrations in blood at baseline (prior to AROi treatment) and after 6 and 12 months under AROi treatment in post-menopausal women with breast cancer. Frailty syndrome was evaluated by the Fried’ criteria. We evaluated whether hormone concentration at baseline could predict frailty syndrome at follow-up. Results: Multinomial regression analysis showed that of the different hormones, those significantly (p < 0.05) associated to the worsening of frailty syndrome were high androstenedione levels and low follicle-stimulating hormone (FSH) levels in blood. Receiver operating characteristic curve analysis showed both androstenedione and FSH significantly (p < 0.05) discriminate patients who developed or presented worsening of frailty syndrome over time, with acceptable sensitivity (approximately 80% in both cases) but low specificity (40%). Conclusion: Hormonal concentrations before AROi treatment constitute possible biomarkers to predict the progression of frailty syndrome.

HPR11 Multicriteria Decision Analysis (MCDA) to Identify Criteria for Guiding Decision Making for Post-Menopausal Osteoporosis Treatment in the Brazilian Public Healthcare System

To identify criteria for prioritizing osteoporosis treatments in postmenopausal women at very high fracture risk, based on the preferences of three groups of stakeholders: medical specialists, representatives of patient associations and healthcare managers (HM).

EE372 Cost-Utility of Ribociclib As the First-Line Treatment in Postmenopausal Women with Hormone Receptor Positive and Human Epidermal Growth Factor Receptor-2 Negative Advanced/Metastatic Breast Cancer in Colombia

To estimate the cost-utility of the currently approved Cyclin-Dependent Kinase 4 and 6 Inhibitors (CDK4/6i) as the first-line treatment in postmenopausal women with Hormone Receptor positive (HR+) and Human Epidermal Growth Factor Receptor-2 negative (HER2-) advanced/metastatic breast cancer, from the perspective of the Colombian health system.

Abstract 650: Reparixin, CXCR1/2 inhibitor in combination with CDK4/6 inhibitors attenuates endocrine resistant breast cancer growth and metastasis

Abstract Various endocrine therapies have been developed such as selective estrogen receptor modulation (SERM), selective estrogen receptor downregulator (SERD) and ligand deprivation using aromatase inhibitors (AI). Tamoxifen (TAM), a SERM and AIs are the most commonly used adjuvant treatment for postmenopausal women with early-stage estrogen receptor positive breast cancer. Despite the relative safety and significant anti-neoplastic and chemopreventive activities of tamoxifen and AIs, many initially responsive breast tumors develop resistance and ultimately recur. Many underlying molecular events that confer resistance are known, but a unifying theme is yet to be revealed. While the tumor microenvironment is being increasingly recognized as a key factor in multiple stages of disease progression, particularly local resistance, immune-escaping, and distant metastasis, our previous work shows that the critical molecular and cellular players secreted from a crosstalk between breast cancer cells and stromal cells can regulate the tumor growth and process of metastasis in breast cancer. In this report, using established endocrine resistant breast cancer (ERBC) cells and ESR1 mutant cells (Y537S and D538G), we screened the secreted factors in crosstalk between cancer cells and fibroblasts using cytokine antibody arrays and found that CXCL1 is highly upregulated in fibroblasts. To investigate a potential impact given the current clinical landscape of endocrine resistant breast cancer, we performed a high throughput cell-based screen to identify effective combinations of drugs that will be tested in vivo using reparixin, CXCR1/2 inhibitor, tamoxifen (SERM), fulvestrant (SERD), and CDK4/6 inhibitors (Palbociclib and Ribociclib) in co-culture with ERBC cells and fibroblast. Significantly, reparixin decreased ERBC cell viability compared to vehicle while reparixin in combination with tamoxifen and fulvestrant, enhanced the inhibitor effects in ERBC cell growth. We found that the combination treatment of reparixin and Palbociclib and ribociclib significantly inhibited ERBC cell growth and migration compared the single treatment. The inhibitory effect of reparixin was higher in combination with CDK4/6 inhibitors that the combination with tamoxifen and fulvestrant. Furthermore, reparixin in combination with CDK4/6 inhibitors decreased ERBC cell migration and promotes apoptosis.These findings implicate CXCL1 signaling as a critical event in ERBC tumor growth and metastasis via crosstalk between cancer cells and stromal components. Further, these studies suggest that CXCL1 act as key regulators orchestrating ERBC. Therefore, we have provided evidence that supports the hypothesis that functional inhibition of the CXCL1 and CDK4/6 signaling pathway has the potential to circumvent ERBC growth and metastasis. Citation Format: Sneha Pandithar, Olivia Reff, Kideok Jin. Reparixin, CXCR1/2 inhibitor in combination with CDK4/6 inhibitors attenuates endocrine resistant breast cancer growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 650.

Hormonal and Genetic Regulatory Events in Breast Cancer and Its Therapeutics: Importance of the Steroidogenic Acute Regulatory Protein.

Estrogen promotes the development and survival of the majority of breast cancers (BCs). Aromatase is the rate-limiting enzyme in estrogen biosynthesis, and it is immensely expressed in both cancerous and non-cancerous breast tissues. Endocrine therapy based on estrogen blockade, by aromatase inhibitors, has been the mainstay of BC treatment in post-menopausal women; however, resistance to hormone therapy is the leading cause of cancer death. An improved understanding of the molecular underpinnings is the key to develop therapeutic strategies for countering the most prevalent hormone receptor positive BCs. Of note, cholesterol is the precursor of all steroid hormones that are synthesized in a variety of tissues and play crucial roles in diverse processes, ranging from organogenesis to homeostasis to carcinogenesis. The rate-limiting step in steroid biosynthesis is the transport of cholesterol from the outer to the inner mitochondrial membrane, a process that is primarily mediated by the steroidogenic acute regulatory (StAR) protein. Advances in genomic and proteomic technologies have revealed a dynamic link between histone deacetylases (HDACs) and StAR, aromatase, and estrogen regulation. We were the first to report that StAR is abundantly expressed, along with large amounts of 17β-estradiol (E2), in hormone-dependent, but not hormone-independent, BCs, in which StAR was also identified as a novel acetylated protein. Our in-silico analyses of The Cancer Genome Atlas (TCGA) datasets, for StAR and steroidogenic enzyme genes, revealed an inverse correlation between the amplification of the StAR gene and the poor survival of BC patients. Additionally, we reported that a number of HDAC inhibitors, by altering StAR acetylation patterns, repress E2 synthesis in hormone-sensitive BC cells. This review highlights the current understanding of molecular pathogenesis of BCs, especially for luminal subtypes, and their therapeutics, underlining that StAR could serve not only as a prognostic marker, but also as a therapeutic candidate, in the prevention and treatment of this life-threatening disease.

Estrogen supplementation deteriorates visceral adipose function in aged postmenopausal subjects via Gas5 targeting IGF2BP1.

Increased visceral fat is strongly associated with a series of metabolic complications. Postmenopausal women have an increased risk of visceral fat accumulation, metabolic disorders, and a high incidence of cardiovascular events. However, the effect of estrogen replacement therapy on visceral adipose tissue among postmenopausal women of different ages remains controversial, and the underlying mechanism remains unclear. Hence, it is important to understand when estrogen replacement therapy affects the function of visceral adipose tissue (VAT). Therefore, we collected VAT from pre- and post-menopausal females and we observed increased pro-inflammatory cytokines and insulin resistance-inducing factors, decreased insulin-sensitizing factors, and thermogenic factors in VAT of postmenopausal women. The analysis of adipocytes isolated from the VAT of females of different ages indicated that adiponectin and browning signature genes were significantly decreased with estrogen treatment in postmenopausal women, but were not altered in the young group. Estrogen supplementation in aged female mice (22m) significantly prevented visceral fat accumulation. However, it deteriorated VAT function by inducing pro-inflammatory cytokines and insulin resistance-inducing factors and decreasing insulin-sensitizing and thermogenic factors. Mechanistically, estrogen induced the expression of long non-coding RNA Gas5 via binding ERα in premenopausal women, which therefore suppressed IGF2BP1 to maintain VAT function. After menopause, with the reversal of ERα/ERβ ratio in VAT, estrogen supplementation mainly worked through ERβ, which led to low expression levels of Gas5 and eventually caused VAT dysfunction. Our study demonstrated the adverse effects of estrogen supplementation on VAT function in aged postmenopausal population and further elucidated the involved mechanism.

Aromatase inhibitors for breast cancer therapy: Analysis of real-world FAERS data.

1051 Background: Aromatase inhibitors (AIs) are extremely effective adjuvant treatment in postmenopausal women with hormone receptor-positive breast cancer (HRPBC). We utilized the Food and Drug Administration Adverse Event Reporting System (FAERS) database to evaluate the musculoskeletal (MSK), fractures, and ischemic heart disease (IHD) adverse events (AEs) caused by AIs. Methods: We conducted a retrospective FAERS public database review to assess the MSK, fracture, and IHD AEs for the three AIs (anastrozole, letrozole, and exemestane) from 2001 through 2021. Chi-square was used to compare categorical variables. Results: A total of 31,683 AEs reports were identified, out of which, 15,140 (47.8%) were MSK, 13,311 (42.0%) were fracture, and 3,232 (10.2%) were IHD. The differences in AEs distributions among the three drug classes were statistically significant for MSK and fracture AEs (P &lt; 0.001) but not reached statistical significance for IHD AEs (P = 0.140). MSK AEs were mostly reported with anastrozole, followed by exemestane, and letrozole in 35.23%, 33.97%, and 32.06%, respectively (P &lt; 0.001). Compared to older individuals, younger adults (≤65 years) had higher rates of MSK AEs—mostly with anastrozole (38.43%, P &lt; 0.001), followed by exemestane (36.37%, P = 0.006) and letrozole (34.28%, P &lt; 0.001). Fracture AEs were mostly reported, in descending order, with letrozole, exemestane, and anastrozole in 12.07%, 11.41%, and 9.34% respectively (P &lt; 0.001). Older adults (&gt; 65 years) had higher rates of fracture AEs with letrozole (16.77%, P &lt; 0.001) and anastrozole (10.37%, P &lt; 0.001), while unable to demonstrate statistical significance with exemestane (13.48%, P = 0.108). Among older adults (&gt; 65 years), IHD AEs were significantly reported with anastrozole (21.56%, P &lt; 0.001) and exemestane (14.18%, P = 0.016) but no statistical significance reached for letrozole (14.12%, P = 0.528). Conclusions: The findings in this study highlight trends for selected AEs with various AI regimens, provide further insights, and help guide therapeutic decisions for patients with HRPBC.