Clinicopathological importance of Bcl-2 and p53 in postmenopausal triple-negative breast carcinoma and association with age.

Appropriate biomarkers are required to predict the clinical outcome of triple-negative breast cancer (TNBC). In this study, we focused on the clinical importance of two representative tumor-associated proteins, Bcl-2 and p53. Bcl-2 expression is usually related to estrogen receptor expression and a favorable outcome in breast cancer. TNBC has been reported to show a high frequency of p53 positivity suggesting TP53 mutations. The expressions of Bcl-2 and p53 were immunohistochemically examined in TNBC involving two age groups of postmenopausal women (≥75 y/o, n = 75; 55-64 y/o, n = 47), who underwent surgery without neoadjuvant therapy. We examined their associations with each other, or with clinicopathological factors including the outcome. Bcl-2 expression was inversely correlated with androgen receptor, apocrine morphology, and p53 expressions, and was an independent predictor of a poor outcome in total or in younger women. p53 positivity was associated with a more favorable outcome than p53 negativity in the younger group. In combined analyzes, none of the twenty Bcl-2-negative/p53-positive cases in the younger group exhibited recurrence, resulting in the independent favorable predictive value of Bcl-2-negative/p53-positive. The anti-apoptotic nature of Bcl-2 may be apparent in TNBC. The excellent outcome of Bcl-2-negative/p53-positive cases in the younger group warrants further combined investigation of Bcl-2/p53 in TNBC.

Morinda Officinalis-derived extracellular vesicle-like particles: Anti-osteoporosis effect by regulating MAPK signaling pathway.

BACKGROUND: Postmenopausal osteoporosis (PMOP) is a systemic bone disease characterized by low bone mass and microstructural damage. Morinda Officinalis (MO) contains various components with anti-PMOP activities. Morinda Officinalis-derived extracellular vesicle-like particles (MOEVLPs) are new active components isolated from MO, and no relevant studies have investigated their anti-osteoporosis effect and mechanism. PURPOSE: To investigate the alleviating effect of MOEVLPs on PMOP and the underlying mechanism. METHODS: Differential centrifugation and ultracentrifugation were used to isolate MOEVLPs from MO. Transmission electron microscopy (TEM), flow nano analyzer, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), agarose gel electrophoresis, and thin-layer chromatography were employed to characterize MOEVLPs. PMOP mouse models were utilized to examine the anti-PMOP effect of MOEVLPs. H&E and immunohistochemical staining were used for drug safety and osteogenic effect assessment. Mouse embryo osteoblast precursor cells (MC3T3-E1) were used in vitro experiments. CCK-8 kit, alizarin red staining, proteomic, bioinformatic analyses, and western blot were used to explore the mechanism of MOEVLPs. RESULTS: In this study, MOEVLPs from MO were successfully isolated and characterized. Animal experiments demonstrated that MOEVLPs exhibited specific femur targeting, were non-toxic to the heart, liver, spleen, lung, kidney, and aorta, and possessed anti-PMOP properties. The ability of MOEVLPs to strengthen bone formation was better than that of alendronate. In vitro experiments, results revealed that MOEVLPs did not significantly enhance osteogenic differentiation in MC3T3-E1 cells. Instead, MOEVLPs promoted the proliferation of MC3T3-E1 cells. Proteomic and bioinformatic analyses suggested that the proliferative effect of MOEVLPs was closely associated with the mitogen-activated protein kinase (MAPK) signaling pathway, particularly the altered expression of cAMP response element-binding protein (CREB) and ribosomal S6 kinase 1 (RSK1). Western blot results further confirmed these findings. CONCLUSION: Our studies successfully isolated high-quality MOEVLPs and demonstrated that MOEVLPs can alleviate PMOP by promoting osteoblast proliferation through the MAPK pathway. MOEVLPs have the potential to become a novel and natural anti-PMOP drug.

Exploring the anti-osteoporosis potential of Petroselinum crispum (Mill.) fuss extract employing experimentally ovariectomized rat model and network pharmacology approach.

One of the most prevalent secondary osteoporosis is ovariectomy-induced osteoporosis. Parsley (Petroselinum crispum) has potent estrogenic and antioxidant properties and was used traditionally in the treatment of amenorrhea and dysmenorrhea. The present study aimed to characterize parsley leaf extract (PLE) employing RP-HPLC-MS-MS/MS-based method and possible protective effect in ovariectomized (OVX)-induced osteoporosis in rats was assessed. Rats were randomly assigned into SHAM group, OVX group, PLE + OVX group (150 mg/kg/day, p.o), and estradiol benzoate (E2) + OVX group (30 µg/kg/day, s.c). After eight weeks following ovariectomy, biomarkers of bone strength, bone resorption, oxidative stress and histopathology were carried out. A network pharmacology approach investigated the key targets and potential mechanisms by of PLE metabolites against osteoporosis using databases: PubChem, BindingDB server, DisGeNET, ShinyGO, and KEGG Pathway. Moreover, FunRich 3.1.3, Cytoscape 3.10.0, and MOE 2019.0102 softwares were used for network pharmacology analysis and molecular docking studies. Flavones and hydroxycinnamic acid derivatives were predominant among 38 metabolites in PLE. It significantly restored bone strength and bone resorption biomarkers, osteocalcin (OST), oxidative stress biomarkers and histopathological alterations. The employed network pharmacology approach revealed that 14 primary target genes were associated with decreasing the severity of osteoporosis. Molecular docking revealed that cGMP-PKG signaling pathway has the highest fold enrichment and its downstream PDE5A. Luteolin, diosmetin, and isorhamnetin derivatives affected mostly osteoporosis targets. PLE exhibited protective action against ovariectomy-induced osteoporosis in rats and may be a promising therapy for premenopausal bone loss. cGMP-PKG signaling pathway could be a promising target for PLE in treating osteoporosis.

The association of FRAX with predictors of falls in the assessment of postmenopausal osteoporosis in Turkey: the fracture study of Turkey (FRACT study).

Although FRAX is used for fracture risk evaluation, this tool does not include balance and fall risk. The association between the predictors of falls and high FRAX scores we found in this study suggests that risk indicators for falls may add substantial value to FRAX by improving fracture risk prediction. PURPOSE: This observational, descriptive, and cross-sectional study aimed to assess the fall risk predictors and explore their association with FRAX in Turkish patients with postmenopausal osteoporosis. METHODS: Two hundred and nine (209) women with postmenopausal osteoporosis referred to the Fracture Liaison Service (FLS) at Istanbul University-Cerrahpasa were enrolled in the FRACT study (The Fracture Study of Turkey). Clinical risk factors were assessed using the FRAX tool. Tandem stance, Tandem walking, Timed up and go (TUG), and Chair stand tests were performed to assess balance and fall risk. RESULTS: Among patients with a mean age of 67.6 (± 9.7) years, 66 patients (31.6%) had osteoporosis without fractures and 143 patients (68.4%) had fragility fractures. The proportion of patients with poor performance of fall prediction tests was significantly higher in patients with a fragility fracture than those with osteoporosis alone. There was an inverse relationship between dynamic balance tests and the reported number of prior falls in the past year. FRAX score was higher in patients with impaired Tandem stance, Tandem walking, and TUG tests (p = 0.008, p = 0.035, p = 0.001, respectively). CONCLUSION: Assessment of fall risk predictors should be one of the major pillars in the physical evaluation of osteoporotic patients in the FLS setting. FRAX is a useful tool to determine the fracture risk of patients with both static and dynamic balance impairments. Combining balance assessment with FRAX may be an important step to optimize osteoporosis risk assessment.

Vaginal Hysterectomy at the Time of Total Colpocleisis: A Single-Center Experience.

OBJECTIVE: This study aims to evaluate the five-year experience of a single center regarding the total colpocleisis procedure. METHODS: This is a retrospective review of 24 women who underwent total colpocleisis at the study center between January 2017 and January 2023. Every participant was informed about this study, and written consent was obtained from each participant who then took Pelvic Floor Distress Inventory-20 (PFDI-20), Body Appreciation Scale-2 (BAS-2) and Decision Regret Scale (DRS) questionnaires consecutively. RESULTS: Eight patients (33.3%) underwent total colpocleisis, whereas 16 patients (66.7%) had concomitant colpocleisis and vaginal hysterectomy. The number of total colpocleisis cases did not change significantly with respect to the past years (p=0.117). The patients who underwent total colpocleisis and the patients who had concurrent colpocleisis and hysterectomy were statistically similar with respect to age, gravidity, chronic disease, blood group, American Society of Anesthesiologists classification, anesthesia type, surgery timing and preoperative and postoperative hemoglobin values (p>0.05 for all). Operative time was significantly shorter in patients who had colpocleisis alone (p=0.001). Both patient groups were also statistically similar in aspects of blood loss, transfusion need, hospital stay, postoperative complications and follow-up time as well as PFDI-20, BAS-2 and DRS scores (p>0.05 for all). Endometrial atrophy (56.3%), endometrial hyperplasia (18.8%) and adenomyosis (12.5%) were the most common histopathological findings detected in vaginal hysterectomy specimens. CONCLUSION: The combination of vaginal hysterectomy and total colpocleisis appears as a safe and efficient approach which does not contribute to the surgery-related morbidity despite the significantly longer operative time.

Atraumatic Spontaneous Transvaginal Small Bowel Evisceration: A Rare Surgical Emergency.

Abdominal pain ranks as the predominant cause for emergency department consultations. Although rare, transvaginal evisceration of the small intestine necessitates immediate surgical intervention due to its potential to induce intestinal ischemia and peritonitis. Key risk factors include postmenopausal status, a history of gynecologic surgery, and heightened abdominal pressure. Clinical presentation typically involves pain and protrusion of intestinal contents or even abdominal viscera. Diagnosis relies on thorough clinical assessment, and treatment strategies should be tailored to each patient. Here, we describe the case of a 65-year-old female patient with a non-traumatic evisceration of the ileum, who had undergone total abdominal hysterectomy following anterior colpocele a year ago, subsequently necessitating exploratory laparotomy and repair of the vaginal ampulla.

Age at natural menopause and development of chronic diseases in the female population of Kharameh, Iran: A historical cohort study.

Background and Aims: Declines in estradiol levels after menopause have been reported to be associated with several health outcomes. This study aimed to determine the effect of age at natural menopause (ANM) on some of the most common chronic diseases. Methods: This historical cohort study was performed on 2636 postmenopausal women aged 40-70 years participating in phase one of the PERSIAN cohort study in Kharameh, Iran, during 2015-2017. The effect of early (<45 years), intermediate (45-53 years), and late menopause (>53 years) on chronic diseases such as hypertension, diabetes, ischemic heart diseases, stroke, thyroid diseases, and depression was assessed using classic logistic regression for diseases with an incidence rate of more than 10% and Firth's logistic regression for diseases with an incidence of less than this amount. Results: The mean age of women was 53.48 ± 8.59. Respectively, early and intermediate menopause was associated with ischemic heart disease (odds ratio [OR = 1.61, 95% confidence interval [CI]: 1.08-2.42; p = 0.020), (OR = 1.57, 95% CI: 1.13-2.21; p = 0.008) and thyroid diseases (OR = 3.10, 95% CI: 1.64-6.24; p < 0.001), (OR = 1.83, 95% CI: 1.02-3.57; p = 0.042). furthermore, early menopause was a risk factor for diabetes (OR = 1.46, 95% CI: 1.07-2.00; p = 0.018), depression (OR = 4.79, 95% CI: 2.20-11.79; p = <0.001) and stroke (OR = 3.00, 95% CI: 1.08-9.32; p = 0.034). Conclusions: In this study, women with diabetes, ischemic heart diseases, stroke, thyroid disorders, and depression had a younger ANM compared to their healthy counterparts. Therefore, applying appropriate strategies to postpone the age of menopause, can reduce the incidence of these types of chronic diseases.

Nutrition-Based Support for Osteoporosis in Postmenopausal Women: A Review of Recent Evidence.

Postmenopausal osteoporosis stands as the predominant bone disorder in the developed world, posing a significant public health challenge. Nutritional factors play a crucial role in bone health and may contribute to its prevention or treatment. Calcium and vitamin D, extensively studied with robust scientific evidence, are integral components of the non-pharmacological treatment for this disorder. Nevertheless, other less-explored nutritional elements appear to influence bone metabolism. This review provides a comprehensive summary of the latest evidence concerning the relationship between various nutrients, such as phosphorus, magnesium, vitamins, phytate, and phytoestrogens; specific foods like dairy or soy, and dietary patterns such as the Mediterranean diet with bone health and osteoporosis.

Enhanced oral bioavailability of levormeloxifene and raloxifene by nanoemulsion: simultaneous bioanalysis using liquid chromatography-tandem mass spectrometry.

Aim & objective: Levormeloxifene (L-ORM) and raloxifene (RAL) are selective estrogen receptor modulators used in the treatment of postmenopausal osteoporosis and breast cancer. Here, we developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous estimation of both drugs. Materials & methods: A quality-by-design (QbD) approach was used for the optimization of the nanoemulsion, and US FDA guidelines were followed for method validation. Results: Multiple reaction monitoring transitions were used for L-ORM (459.05→98.50), RAL (475.00→112.02) and internal standard (180.10→110.2). Analytes were resolved in a C18 column with 80:20 v/v% acetonitrile (ACN), 0.1% formic acid in triple-distilled water as a mobile phase. The developed method was linear over a concentration range of 1-600 ng/ml. Pharmacokinetic results of free L-ORM-RAL and the L-ORM-RAL nanoemulsion showed Cmax of free L-ORM - 70.65 ± 16.64, free RAL 13.53 ± 2.72, L-ORM nanoemulsion 65.07 ± 14.0 and RAL-nanoemulsion 59.27 ± 17.44 ng/ml. Conclusion: Future findings will contribute to the treatment of postmenopausal osteoporosis and breast cancer using L-ORM and RAL.

Health Problems and Disabilities Among the Postmenopausal Saudi Women in Bisha City Receiving Home Care: A Descriptive Cross-Sectional Study.

BACKGROUND: Postmenopausal women experience physical and psychological changes that may affect their health status. In Saudi Arabia, where the population of postmenopausal women is increasing, there is a need to examine the health problems and disabilities experienced by this group, particularly those who receive home care. This study aims to identify the common health problems and disabilities experienced by postmenopausal Saudi women in Bisha city who receive home care services. METHODS: A cross-sectional study in Bisha city, Saudi Arabia, involved 155 postmenopausal women (age 60 years and above) receiving home care services. Data were collected using structured interviews and medical records. RESULTS: The study found that the most common health problems among postmenopausal women receiving home care were cardiovascular diseases in 85 women (54.84%), diabetes in 85 women (54.84%), and musculoskeletal disorders in 56 women (36.13%). There was a significant association between the number of health problems and disabilities, indicating that women with more health problems were more likely to experience disabilities (p-value ≤ 0.05). The results showed that age (OR=1.56, 95% CI 1.23-1.99, p=0.001), chronic diseases (OR=2.34, 95% CI 1.43-3.84, p=0.001), and lower education level (OR=1.45, 95% CI 1.01-2.08, p=0.045) were significantly associated with the presence of health problems and disabilities among postmenopausal Saudi women receiving home care in Bisha city. However, marital status and employment status were not found to be significant predictors. CONCLUSION: Postmenopausal women in Bisha city who receive home care services experience a range of health problems and disabilities, particularly related to hypertension, diabetes, and musculoskeletal disorders. The findings of this study can help healthcare providers develop effective interventions and strategies to improve the health outcomes of this population.

Postmenopausal Hyperandrogenism Associated With Synchronous Ovarian Brenner Tumor, Bilateral Leydig Cell Tumor, and Adrenal Mass.

Hyperandrogenism in postmenopausal females may arise from either ovarian or adrenal sources and can pose a challenging diagnostic dilemma. We present the case of a 66-year-old female with postmenopausal hyperandrogenism with virilization, adrenal incidentaloma, and concurrent finding of two extremely rare ovarian tumors, including bilateral Leydig cell tumor and Brenner tumor. Laboratory tests showed elevated testosterone and androstenedione and normal dehydroepiandrosterone sulfate (DHEAS). Response to 1 mg overnight dexamethasone suppression test demonstrated persistently elevated testosterone and incomplete suppression of androstenedione. Computed tomography (CT) scan showed a left adrenal nodule and an unremarkable appearance of the ovaries. The pelvic ultrasound did not show an ovarian tumor on the right ovary, and the left ovary was not seen. Adrenal and ovarian vein sampling suggested the ovaries as the source of the testosterone. Given the ovarian vein sampling results, a multidisciplinary discussion between endocrinology and gynecologic oncology concluded that bilateral salpingo-oophorectomy (BSO) was the next best step for diagnosis and management. Laparoscopic BSO was performed. Histopathology showed bilateral Leydig cell tumors and a left ovarian Brenner tumor. At one-year postoperative follow-up, alopecia improved, and testosterone level normalized. This case highlights the importance of diagnostic pathways and interdisciplinary collaboration in managing rare clinical scenarios of hyperandrogenism in postmenopausal females. As in our case, surgeons may be hesitant to remove normal-appearing ovaries. While the three presented tumor types in this case arise from distinct tissues and exhibit different histological characteristics, the presence of such a unique triad prompts consideration of potential unifying pathogenic mechanisms.

Efficacy and safety of fezolinetant for vasomotor symptoms in postmenopausal women: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Vasomotor symptoms (VMS), such as hot flashes and night sweats, are highly prevalent and burdensome for women experiencing menopausal transition. Fezolinetant, a selective neurokinin 3 receptor (NK3R) antagonist, is a potential therapeutic option for mitigating VMS. OBJECTIVES: Our aim is to assess the efficacy and evaluate the safety profile of fezolinetant compared with placebo in post-menopausal women suffering from VMS, by pooling all the relevant data and reflecting the most current evidence. SEARCH STRATEGY/SELECTION CRITERIA: An extensive literature search was performed in the PubMed, Medline and Cochrane Library databases from inception until June 2023 to identify relevant trials. DATA COLLECTION AND ANALYSIS: Mean differences (MDs) and 95% confidence intervals (CIs) were calculated for continuous outcomes. Risk ratios (RRs) were calculated for dichotomous outcomes. All statistical analyses were performed using R Statistical Software. MAIN RESULTS: A total of six randomized controlled trials were added. For the frequency of daily VMS, the combined pooled result favored the fezolinetant group over placebo (MD -2.38, 95% CI -2.64 to -2.12; P < 0.001, I2 = 0%). For the severity of daily VMS, fezolinetant was again found to be superior to the placebo group (MD -0.40, 95% CI -0.51 to -0.29; P < 0.001, I2 = 70%). Fezolinetant (120 mg) consistently demonstrated a significant reduction in the severity of daily moderate/severe VMS compared with other doses at both 4 and 12 weeks. Patient-reported outcomes (PROs) of Greene Climacteric Scale (GCS), PROMIS the Sleep Disturbance Short Form 8b and Menopause-Specific Quality of Life (MENQoL) scores indicated significant improvement with fezolinetant. No significant difference in efficacy of fezolinetant at 4 and 12 weeks were observed in any outcome. As for safety, no significant differences in the treatment emergent adverse events at 12 weeks were found between fezolinetant and placebo. CONCLUSIONS: Our study significantly favors fezolinetant over placebo regarding the primary efficacy outcomes of daily moderate to severe VMS frequency and severity, including PROs, while both the groups are comparable in terms of treatment emergent adverse events. Further studies are needed to confirm these findings.

The association of vasomotor symptoms with fracture risk and bone mineral density in postmenopausal women: a systematic review and meta-analysis of observational studies.

BACKGROUND/AIMS: Vasomotor symptoms (VMS) adversely affect postmenopausal quality of life. However, their association with bone health has not been elucidated. This study aimed to systematically review and meta-analyze the evidence regarding the association of VMS with fracture risk and bone mineral density (BMD) in peri- and postmenopausal women. METHODS: A literature search was conducted in PubMed, Scopus and Cochrane databases until 31 August 2023. Fracture, low BMD (osteoporosis/osteopenia) and mean change in lumbar spine (LS) and femoral neck (FN) BMD were assessed. The results are presented as odds ratio (OR) and mean difference (MD), respectively, with a 95% confidence interval (95% CI). The I2 index quantified heterogeneity. RESULTS: Twenty studies were included in the qualitative and 12 in the quantitative analysis (n=49,659). No difference in fractures between women with and without VMS was found (n=5, OR 1.04, 95% CI 0.93-1.16, I2 16%). However, VMS were associated with low BMD (n=5, OR 1.54, 95% CI 1.42-1.67, I2 0%). This difference was evident for LS (MD -0.019 g/cm2, 95% CI -0.03 to -0.008, I2 85.2%), but not for FN BMD (MD -0.010 g/cm2, 95% CI -0.021 to 0.001, I2 78.2%). These results were independent of VMS severity, age and study design. When the analysis was confined to studies that excluded menopausal hormone therapy use, the association with BMD remained significant. CONCLUSIONS: The presence of VMS is associated with low BMD in postmenopausal women, although it does not seem to increase fracture risk.

Unraveling Key m6A Modification Regulators Signatures in Postmenopausal Osteoporosis through Bioinformatics and Experimental Verification.

OBJECTIVE: Bone marrow mesenchymal stem cells (BMSCs) show significant potential for osteogenic differentiation. However, the underlying mechanisms of osteogenic capability in osteoporosis-derived BMSCs (OP-BMSCs) remain unclear. This study aims to explore the impact of YTHDF3 (YTH N6-methyladenosine RNA binding protein 3) on the osteogenic traits of OP-BMSCs and identify potential therapeutic targets to boost their bone formation ability. METHODS: We examined microarray datasets (GSE35956 and GSE35958) from the Gene Expression Omnibus (GEO) to identify potential m6A regulators in osteoporosis (OP). Employing differential, protein interaction, and machine learning analyses, we pinpointed critical hub genes linked to OP. We further probed the relationship between these genes and OP using single-cell analysis, immune infiltration assessment, and Mendelian randomization. Our in vivo and in vitro experiments validated the expression and functionality of the key hub gene. RESULTS: Differential analysis revealed seven key hub genes related to OP, with YTHDF3 as a central player, supported by protein interaction analysis and machine learning methodologies. Subsequent single-cell, immune infiltration, and Mendelian randomization studies consistently validated YTHDF3's significant link to osteoporosis. YTHDF3 levels are significantly reduced in femoral head tissue from postmenopausal osteoporosis (PMOP) patients and femoral bone tissue from PMOP mice. Additionally, silencing YTHDF3 in OP-BMSCs substantially impedes their proliferation and differentiation. CONCLUSION: YTHDF3 may be implicated in the pathogenesis of OP by regulating the proliferation and osteogenic differentiation of OP-BMSCs.

Single-cell RNA sequencing reveals that an imbalance in monocyte subsets rather than changes in gene expression patterns is a feature of postmenopausal osteoporosis.

The role of monocytes in postmenopausal osteoporosis is widely recognized; however, the mechanisms underlying monocyte reprogramming remain unknown. In this study, single-cell RNA sequencing (scRNA-seq) was conducted on CD14+ bone marrow monocytes obtained from three postmenopausal women with normal bone mineral density (BMD) and three women with postmenopausal osteoporosis (PMOP). Monocle2 was used to classify the monocytes into 7 distinct clusters. The proportion of Cluster 1 significantly decreased in PMOP patients, while the proportion of Cluster 7 increased. Further analysis via GSEA, transcription factor activity analysis, and sc-metabolic analysis revealed significant differences between Clusters 1 and 7. Cluster 7 exhibited upregulated pathways associated with inflammation, immunity, and osteoclast differentiation, whereas Cluster 1 demonstrated the opposite results. Monocle2, TSCAN, VECTOR and scVelo data indicated that Cluster 1 represented the initial subset and that Cluster 7 represents one of the terminal subsets. BayesPrism and ssGSEA were employed to analyze the bulk transcriptome data obtained from the GEO database. The observed alterations in the proportions of Clusters 1 and 7 were validated and found to have diagnostic significance. CD16 serves as the marker gene for Cluster 7, thus leading to an increased proportion of CD16+ monocytes in women with PMOP. Flow cytometry was used to assess the consistency of outcomes with those of the bioinformatic analysis. Subsequently, an additional scRNA-seq analysis was conducted on bone marrow mononuclear cells obtained from three patients with PMOP and three postmenopausal women with normal BMD. The differential proportions of Cluster 1 and Cluster 7 were once again confirmed, with the pathological effect of Cluster 7 may attribute to cell-cell communication. The scRNA-seq findings suggest that an imbalance in monocyte subsets is a characteristic feature of PMOP. These findings elucidate the limitations of utilizing bulk transcriptome data for detecting alterations in monocytes, which may influence novel research inquiries.

Monocytes are a type of white blood cell that plays a role in postmenopausal osteoporosis (PMOP), a condition where bones become weak and brittle after menopause. However, how monocytes change in this condition is not fully understood. In this study, single-cell RNA sequencing was used to analyze bone marrow monocytes from postmenopausal women with normal bone density and those with osteoporosis. Two distinct types of monocytes were identified, which were called Clusters 1 and 7. In women with PMOP, there was a decrease in Cluster 1 monocytes and an increase in Cluster 7 monocytes. This change was validated in external data sets and in peripheral blood. Further analysis showed that Cluster 7 monocytes positively correlated with inflammation, immunity, and osteoclast differentiation (a process that leads to bone resorption). Cluster 1 monocytes were found to be the initial subset, while Cluster 7 monocytes were one of the terminal subsets. Overall, this study suggests that an imbalance in monocyte subsets is a characteristic feature of postmenopausal osteoporosis. These findings have important implications for understanding the role of monocytes in bone health.

The Heterogeneity of Post-Menopausal Disease Risk: Could the Basis for Why Only Subsets of Females Are Affected Be Due to a Reversible Epigenetic Modification System Associated with Puberty, Menstrual Cycles, Pregnancy and Lactation, and, Ultimately, Menopause?

For much of human evolution, the average lifespan was <40 years, due in part to disease, infant mortality, predators, food insecurity, and, for females, complications of childbirth. Thus, for much of evolution, many females did not reach the age of menopause (45-50 years of age) and it is mainly in the past several hundred years that the lifespan has been extended to >75 years, primarily due to public health advances, medical interventions, antibiotics, and nutrition. Therefore, the underlying biological mechanisms responsible for disease risk following menopause must have evolved during the complex processes leading to Homo sapiens to serve functions in the pre-menopausal state. Furthermore, as a primary function for the survival of the species is effective reproduction, it is likely that most of the advantages of having such post-menopausal risks relate to reproduction and the ability to address environmental stresses. This opinion/perspective will be discussed in the context of how such post-menopausal risks could enhance reproduction, with improved survival of offspring, and perhaps why such risks are preserved. Not all post-menopausal females exhibit risk for this set of diseases, and those who do develop such diseases do not have all of the conditions. The diseases of the post-menopausal state do not operate as a unified complex, but as independent variables, with the potential for some overlap. The how and why there would be such heterogeneity if the risk factors serve essential functions during the reproductive years is also discussed and the concept of sets of reversible epigenetic changes associated with puberty, pregnancy, and lactation is offered to explain the observations regarding the distribution of post-menopausal conditions and their potential roles in reproduction. While the involvement of an epigenetic system with a dynamic "modification-demodification-remodification" paradigm contributing to disease risk is a hypothesis at this point, validation of it could lead to a better understanding of post-menopausal disease risk in the context of reproduction with commonalities may also lead to future improved interventions to control such risk after menopause.

Association between Daily Dietary Calcium Intake and the Risk of Cardiovascular Disease (CVD) in Postmenopausal Korean Women.

We aimed to evaluate the association between daily dietary calcium intake and the risk of cardiovascular disease (CVD) in postmenopausal women using data from the Korean National Health and Nutrition Examination Survey (KNHANES). This cross-sectional study included 12,348 women aged 45-70 years who had reached natural menopause. They were classified into three groups according to daily dietary calcium intake: <400 mg, 400-800 mg, and >800 mg. The risks of CVD, stroke, angina, and myocardial infarction were assessed in each group. Further, we performed subgroup analysis according to the post-menopause duration (≤10 vs. >10 postmenopausal years). We performed logistic regression analysis with adjustment for age, menopausal age, income, urban area, education, insulin use, body mass index, hypertension, diabetes mellitus, dyslipidemia, high alcohol intake, smoking, exercise, oral contraceptive use, and hormonal therapy use. Calcium intake level was not significantly associated with the risk of CVD in the total population and the ≤10 postmenopausal years subgroup. However, in the >10 postmenopausal years subgroup, daily calcium intake >800 mg was associated with significantly decreased risks of all CVD (odds ratio [OR], 0.27; 95% confidence interval [CI], 0.11-0.64), stroke (OR, 0.06; 95% CI, 0.01-0.42), and myocardial infarction (OR, 0.27; 95% CI, 0.11-0.64). Our findings suggest that a dietary calcium intake of >800 mg/day decreases the risk of CVD events in women who have been menopausal for >10 years.

Catgut embedding in acupoints combined with repetitive transcranial magnetic stimulation for the treatment of postmenopausal osteoporosis: study protocol for a randomized clinical trial.

Background: To date, the clinical modulation for bone metabolism based on the neuro-bone mass regulation theory is still not popular. The stimulation of nerve systems to explore novel treatments for Postmenopausal osteoporosis (PMOP) is urgent and significant. Preliminary research results suggested that changes brain function and structure may play a crucial role in bone metabolism with PMOP. Thus, we set up a clinical trial to investigate the effect of the combination of repetitive transcranial magnetic stimulation (rTMS) and catgut embedding in acupoints (CEA) for PMOP and to elucidate the central mechanism of this neural stimulation in regulating bone metabolism. Method: This trial is a prospective and randomized controlled trial. 96 PMOP participants will be randomized in a 1:1:1 ratio into a CEA group, an rTMS group, or a combined one. Participants will receive CEA, rTMS, or combined therapy for 3 months with 8 weeks of follow-up. The primary outcomes will be the changes in Bone Mineral Density scores, total efficiency of Chinese Medicine Symptoms before and after treatment. Secondary outcomes include the McGill Pain Questionnaire Short-Form, Osteoporosis Symptom Score, Mini-Mental State Examination, and Beck Depression Inventory-II. The leptin, leptin receptor, and norepinephrine levels of peripheral blood must be measured before and after treatment. Adverse events that occur during the trial will be recorded. Discussion: CEA achieves brain-bone mass regulation through the bottom-up way of peripheral-central while rTMS achieves it through the top-down stimulation of central-peripheral. CEA combined with rTMS can stimulate the peripheral-central at the same time and promote peripheral bone mass formation. The combination of CEA and rTMS may play a coordinating, synergistic, and side-effect-reducing role, which is of great clinical significance in exploring better treatment options for PMOP.Clinical trial registration: https://www.chictr.org.cn/, identifier ChiCTR2300073863.

The effect of polycystic ovarian syndrome on fibrocystic breast changes in postmenopausal women.

Background: Fibrocystic breast changes (FCCs) are benign lesions thought to be caused by an increased estrogen-to-progesterone ratio. One of the most common endocrinopathies that increases this ratio is polycystic ovarian syndrome (PCOS). Although nonproliferative FCCs do not increase the risk of breast cancer, they can make mammographic detection of malignancy in postmenopausal women more difficult. The aim of this study was to investigate the effects of PCOS on the development of postmenopausal FCCs. Methods: This retrospective cohort study used the TriNetX research network to identify two cohorts of postmenopausal women (Z78.0) older than 45, without a prior diagnosis of FCCs (N60.1) or hormone replacement therapy (Z79.890). One cohort included a diagnosis of PCOS (E28.2). The cohorts were balanced for age, race, ethnicity, and hormonally relevant comorbidities. The cohorts were then evaluated for the development of FCCs after menopause. Results: Postmenopausal patients with PCOS were 52% more likely to develop FCCs than those without PCOS (2.2% vs. 1.4%, relative risk 1.52, 95% confidence interval 1.05, 2.22, P = 0.03). Conclusion: Postmenopausal women with PCOS have a higher risk of developing FCCs. Further studies are needed to improve the differentiation of benign FCCs from malignant lesions on imaging for postmenopausal women with PCOS who develop FCCs.