Search Results (71)

Ovarian aging is characterized by a gradual decline in both reproductive and endocrine functions, ultimately culminating in the cessation of ovarian activity around the age of 50, when most women experience natural menopause. The decline begins early, as follicular attrition is initiated in utero and continues throughout childhood and reproductive life. Most follicles undergo atresia without progressing through substantial stages of growth. With increasing age, a pronounced reduction occurs in the population of resting follicles within the ovarian reserve, accompanied by a decline in the size of growing follicular cohorts. Around the age of 38, the rate of follicular depletion accelerates, sometimes resulting in diminished ovarian reserve (DOR). The subsequent menopausal transition involves complex, irregular hormonal dynamics, manifesting as increasingly erratic menstrual patterns, primarily driven by fluctuations in circulating estrogens and a rising incidence of anovulatory cycles. In parallel with the progressive depletion of the follicular pool, the serum concentrations of anti-Müllerian hormone (AMH) decline gradually, while reductions in inhibin B levels become more apparent during the late reproductive years. The concomitant decline in both inhibin B and estrogen levels leads to a compensatory rise in circulating follicle-stimulating hormone (FSH) concentrations. Together, these endocrine changes, alongside the eventual exhaustion of the follicular reserve, converge in the onset of menopause, which is defined by the absence of menstruation for twelve consecutive months. The mechanisms contributing to ovarian aging are complex and multifactorial, involving both the oocyte and the somatic cells within the follicular microenvironment. Oxidative stress is thought to play a central role in the age-related decline in oocyte quality, primarily through its harmful effects on mitochondrial DNA integrity and broader aspects of cellular function. Although granulosa cells appear to be relatively more resilient, they are not exempt from age-associated damage, which may impair their hormonal activity and, given their close functional relationship with the oocyte, negatively influence oocyte competence. In addition, histological changes in the ovarian stroma, such as fibrosis and heightened inflammatory responses, are believed to further contribute to the progressive deterioration of ovarian function. A deeper understanding of the biological processes driving ovarian aging has facilitated the development of experimental interventions aimed at extending ovarian functionality. Among these are the autologous transfer of mitochondria and stem cell-based therapies, including the use of exosome-producing cells. Additional approaches involve targeting longevity pathways, such as those modulated by caloric restriction, or employing pharmacological agents with geroprotective properties. While these strategies are supported by compelling experimental data, robust clinical evidence in humans remains limited. Full article

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide, with increasing evidence suggesting that their origins may lie in prenatal life. Endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), have been implicated in the alteration of fetal programming mechanisms that cause a predisposition to long-term cardiovascular vulnerability. However, the impact of prenatal endocrine disruption on fetal heart development and its sex-specific nature remains incompletely understood. This study investigates the molecular and structural effects of low-dose prenatal BPA exposure on fetal rat hearts. Our results reveal that BPA disrupts estrogen receptor (ER) signaling in a sex-dependent manner, with distinct alterations in ERα, ERβ, and GPER expression. BPA exposure also triggers significant inflammation, oxidative stress, and ferroptosis; this is evidenced by elevated NF-κB, IL-1β, TNF-α, and NLRP3 inflammasome activation, as well as impaired antioxidant defenses (SOD1, SOD2, CAT, and SELENOT), increased lipid peroxidation (MDA) and protein oxidation, decreased GPX4, and increased ACSL4 levels. These alterations are accompanied by increased markers of cardiac distension (ANP, BNP), extracellular matrix remodeling mediators, and pro-fibrotic regulators (Col1A1, Col3A1, TGF-β, and CTGF), with a more pronounced response in males. Histological analyses corroborated these molecular findings, revealing structural alterations as well as glycogen depletion in male fetal hearts, consistent with altered cardiac morphogenesis and metabolic stress. These effects were milder in females, reinforcing the notion of sex-specific vulnerability. Moreover, prenatal BPA exposure affected myocardial fiber architecture and vascular remodeling in a sex-dependent manner, as evidenced by reduced expression of desmin alongside increased levels of CD34 and Ki67. Overall, our findings provide novel insights into the crucial role of prenatal endocrine disruption during fetal heart development and its contribution to the early origins of CVD, underscoring the urgent need for targeted preventive strategies and further research into the functional impact of BPA-induced alterations on postnatal cardiac function and long-term disease susceptibility. Full article

The goal of gender-affirming hormone therapy (GAHT) is to align an individual’s physical characteristics with their gender identity by suppressing endogenous sex hormones and replacing them with those consistent with their gender. Transgender women undergoing GAHT are at higher risk of cardiovascular complications, and since clinical evidence suggests that hypertension is associated with increased bone loss, we investigated the effects of estrogen treatment on bone health in a hypertensive transgender animal model. Male spontaneously hypertensive rats were orchiectomized (Orch), and half of them received estrogen treatment (Orch + Es), while a third group remained intact as controls. Bone marrow progenitor cells (BMPCs) were isolated to assess osteogenic potential, and femurs were collected for histological and mechanical analysis. BMPCs from Orch + Es rats exhibited enhanced osteogenic potential compared to those from Orch rats. Histological analysis revealed a higher number of osteocytes and fewer adipocytes in the Orch + Es group. Mechanical testing showed reduced bone strength in Orch rats, which was partially preserved in Orch + Es animals. In conclusion, estrogen administration mitigated the deleterious effects of testosterone depletion on BMPCs and provided protective effects on bone structure and strength in this preclinical model of GAHT in hypertensive rats. Full article

Fertility is a dynamic, multifactorial process governed by hormonal, immune, metabolic, and environmental factors. Recent evidence highlights the gut microbiota as a key systemic regulator of reproductive health, with notable impacts on endometrial function, implantation, pregnancy maintenance, and the timing of birth. This review examines the gut–endometrial axis, focusing on how gut microbial communities influence reproductive biology through molecular signaling pathways. We discuss the modulatory roles of microbial-derived metabolites—including short-chain fatty acids, bile acids, and tryptophan catabolites—in shaping immune tolerance, estrogen metabolism, and epithelial integrity at the uterine interface. Emphasis is placed on shared mechanisms such as β-glucuronidase-mediated estrogen recycling, Toll-like receptor (TLR)-driven inflammation, Th17/Treg cell imbalance, and microbial translocation, which collectively implicate dysbiosis in the etiology of gynecological disorders including endometriosis, polycystic ovary syndrome (PCOS), recurrent implantation failure (RIF), preeclampsia (PE), and preterm birth (PTB). Although most current evidence remains correlational, emerging insights from metagenomic and metabolomic profiling, along with microbiota-depletion models and Mendelian randomization studies, underscore the biological significance of gut-reproductive crosstalk. By integrating concepts from microbiology, immunology, and reproductive molecular biology, this review offers a systems-level perspective on host–microbiota interactions in female fertility. Full article

The COVID-19 pandemic has significantly increased the incidence of post-infection cardiovascular events, particularly myocardial infarction, in individuals over 40. While the underlying mechanisms remain elusive, this study employs a hybrid machine learning approach to analyze epidemiological data in assessing 13 key heart attack risk factors and their susceptibility. Based on a unique dataset that combines demographic, biochemical, ECG, and thallium stress tests, this study aims to design, develop, and deploy a clinical decision support system. Assimilating outcomes from five clustering techniques applied to the ‘Kaggle heart attack risk’ dataset, the study categorizes distinct subpopulations against varying risk profiles and then divides the population into ‘at-risk’ (AR) and ‘not-at-risk’ (NAR) groups using clustering algorithms. The GMM algorithm outperforms its competitors (with clustering accuracy and Silhouette coefficient scores of 84.24% and 0.2623, respectively). Subsequent analyses, employing Pearson correlation and linear regression as descriptors, reveal a strong association between the likelihood of experiencing a heart attack and the 13 risk factors studied, and these are statistically significant (p < 0.05). Our findings provide valuable insights into the development of targeted risk stratification and preventive strategies for high-risk individuals based on heart attack risk scores. The aggravated risk for postmenopausal patients indicates compromised individual risk factors due to estrogen depletion that may be further compromised by extraneous stress impacts, like anxiety and fear, aspects that have traditionally eluded data modeling predictions. The model can be repurposed to analyze the impact of COVID-19 on vulnerable populations. Full article

Background: Estrogen depletion alters bone mineralization and oxidative stress. Antioxidants like humic acids (HA) may help mitigate bone demineralization and redox imbalances. Thus, this study evaluated the effects of HA on bone mineral composition and oxidative stress markers in an experimental menopause model. Methods: Twenty-four female C57BL/6 mice were divided into four groups (n = 6/group): Sham; Sham + HA; Ovariectomized (OVX); and OVX + HA. The menopause model was induced by bilateral ovariectomy at the beginning of the experiment. HA derived from biomass vermicompost was administered daily by gavage for 28 days. After euthanasia, femurs and fragments of the gastrocnemius muscle, liver, and kidney were collected. Bone elemental composition was analyzed using scanning electron microscopy (SEM) coupled with energy dispersive spectroscopy (EDS). Superoxide dismutase (SOD), catalase (CAT), and hydrogen peroxide (H₂O₂) activities were assessed in muscle, renal, and hepatic tissues. Data were analyzed using two-way ANOVA and Bonferroni’s post hoc test. Results: Untreated OVX mice exhibited a significant reduction in femoral calcium content (p < 0.05). However, HA treatment increased calcium levels and improved the Ca/P ratio (p < 0.05). H₂O₂ activity was reduced in the liver and kidney of OVX + HA mice compared to untreated animals (p < 0.05). CAT activity in muscle increased in the OVX + HA group compared to the OVX (p < 0.05). Conclusions: HA treatment improved femoral elemental composition and modulated oxidative stress markers in an experimental menopause model. Full article

This study investigates the cardioprotective effects of intense caloric restriction (ICR) from birth in ovariectomized rats, a model of estrogen deficiency mimicking menopause. Our findings demonstrate that ICR significantly improved both basal and post-ischemic cardiac function, even in the absence of estrogens. The restricted animals exhibited enhanced cardiac contractility and relaxation, particularly after ischemia/reperfusion (I/R) injury, with superior functional recovery compared to control groups. Notably, ICR reduced key cardiometabolic risk factors, including blood pressure, heart rate, and adiposity, while improving glucose tolerance and insulin sensitivity. Additionally, while mitochondrial biogenesis remained unaffected, ICR preserved mitochondrial integrity by reducing the number of damaged mitochondria. This was linked to a reduction in oxidative stress, as evidenced by lower reactive oxygen species (ROS) production in the hearts of restricted animals. These results suggest that ICR offers a protective effect against cardiovascular dysfunction induced by estrogen depletion, potentially through enhanced antioxidant defenses and mitochondrial protection. Full article

Menopause occurs due to the depletion of the ovarian reserve, leading to a progressive decline in estrogen (E2) levels. This decrease in E2 levels increases the risk of developing several diseases and can coexist with chronic kidney disease (CKD). Arterial hypertension (AH) is another condition associated with menopause and may either contribute to or result from CKD. Ovariectomy (OVX) induces hypoestrogenism, which can lead to mitochondrial bioenergetic dysfunction in the kidneys. Previous studies have suggested that exercise training has beneficial effects on adults with CKD and AH. To investigate the effects of OVX and resistance training (RT) on hemodynamic parameters and mitochondrial bioenergetic function of the kidney, female Wistar rats were divided into ovariectomized (OVX) and intact (INT) groups. These rats were either kept sedentary (SED) or subjected to RT for thirteen weeks. The RT involved climbing a vertical ladder with a workload apparatus. Hemodynamic parameters were assessed via tail plethysmography. Mitochondrial respiratory function was evaluated with high-resolution respirometry. Gene expression related to the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS) was evaluated by real-time qPCR. At week 13, key hemodynamic parameters (systolic blood pressure and mean arterial pressure) were significantly elevated in the OVX-SED group. Compared with those in the other groups, mitochondrial bioenergetics were impaired in the OVX-SED group. In contrast, the trained groups presented improved mitochondrial bioenergetic function compared with the sedentary groups. OVX led to reduced gene expression related to the mitochondrial ETC and OXPHOS, whereas RT both prevented this reduction and increased gene expression in the trained groups. Our results indicate that hypoestrogenism significantly decreases OXPHOS and ETC capacity in the kidneys of sedentary animals. However, RT effectively increased the expression of genes related to mitochondrial ETC and OXPHOS, thereby counteracting the effects of OVX. Full article

Background/Objectives: Estrogen receptor-α coactivator MED1 is overexpressed in 40–60% of human breast cancers, and its high expression correlates with poor disease-free survival of patients undergoing anti-estrogen therapy. However, the molecular mechanism underlying MED1 upregulation and activation in breast cancer treatment resistance remains elusive. Methods: miRNA and mRNA expression analysis was performed using the NCBI GEO database. MED1 targeting and its impact on therapy resistance was evaluated in control and tamoxifen-resistant breast cancer cell lines by miR-205 overexpression and inhibition. Immunoblotting, chromatin immunoprecipitation, and luciferase reporter assays were used to understand the molecular mechanism of MED1-mediated tamoxifen resistance. Mice xenograft models were used to validate treatment efficacy and molecular mechanisms in vivo. Results: miR-205 was found to directly target and suppress the expression of MED1 through bioinformatic analyses and experimental validations. An inverse correlation of miR-205 and MED1 was observed in breast cancer patients with high MED1/low miR-205, indicative of poor prognosis in long-term anti-estrogen treatment. Furthermore, the depletion of miR-205 was observed in tamoxifen-resistant breast cancer cells overexpressing MED1. The restoration of miR-205 expression attenuated MED1 expression and re-sensitized cells to tamoxifen both in vitro and in vivo. Interestingly, miR205 was also found to target another key regulatory gene, HER3, which drives PI3K/Akt signaling and MED1 activation by phosphorylation. Importantly, we found ER target gene transcription and promoter cofactor recruitment by tamoxifen can be reversed by induced miR205 expression. Conclusions: Altogether, miR-205 functions as a negative regulator of MED1 and HER3, affecting the regulation of the HER3-PI3K/Akt-MED1 axis in anti-estrogen resistance, and could serve as a potential therapeutic regime to overcome treatment resistance. Full article

Background/Objectives: Hormonal alterations during menopause result in substantial physiological changes. Although hormone replacement therapy (HRT) is widely used as a treatment strategy for these changes, its use remains controversial due to its associated risks. Plant isoflavones are phytoestrogens that are considered a potential alternative therapy for postmenopausal syndrome. We aimed to investigate the efficacy of ethanolic extracts from Styphnolobium japonicum fruit (SJF) and germinated soybean embryo (GSE) in alleviating prominent menopausal symptoms. Methods: A cell model (MCF7 human breast cancer cells) was used to investigate estrogen-like activity. A rat ovariectomy model was used to simulate estrogen depletion after menopause and to evaluate the efficacy of the SJF–GSE complex extract at ratios of 1:1, 1:2, and 2:1. Results: Treatment with the SJF–GSE extract elicited estrogen-like effects, raising pS2 and estrogen receptor α expression in MCF7 cells. The extract was found to contain 48–72 mg/g sophoricoside and 8–12 mg/g soyasaponin 1, identified as active compounds. In ovariectomized rats, the extract effectively reduced body weight and fat content, alleviated vasomotor symptoms, improved vaginal mucosal health, and exerted osteoprotective effects by enhancing bone density and structure, reducing bone-resorption markers and positively altering estradiol levels and lipid profiles. Conclusions: The SJF–GSE extract, working synergistically, provides a safe and effective alternative to HRT for managing postmenopausal symptoms and enhancing bone health, without adverse effects. These findings support the inclusion of SJF and GSE in health-functional foods and underscore the importance of further research into plant-based therapies for menopause. Full article

Declining estrogen (E2) leads to physical inactivity and adipose tissue (AT) dysfunction. Mechanisms are not fully understood, but E2’s effects on dopamine (DA) activity in the nucleus accumbens (NAc) brain region may mediate changes in mood and voluntary physical activity (PA). Our prior work revealed that loss of E2 robustly affected NAc DA-related gene expression, and the pattern correlated with sedentary behavior and visceral fat. The current study used a new transgenic mouse model (D1ERKO) to determine whether the abolishment of E2 receptor alpha (ERα) signaling within DA-rich brain regions affects PA and AT metabolism. Adult male and female wild-type (WT) and D1ERKO (KD) mice were assessed for body composition, energy intake (EE), spontaneous PA (SPA), and energy expenditure (EE); underwent glucose tolerance testing; and were assessed for blood biochemistry. Perigonadal white AT (PGAT), brown AT (BAT), and NAc brain regions were assessed for genes and proteins associated with DA, E2 signaling, and metabolism; AT sections were also assessed for uncoupling protein (UCP1). KD mice had greater lean mass and EE (genotype effects) and a visible change in BAT phenotype characterized by increased UCP1 staining and lipid depletion, an effect seen only among females. Female KD had higher NAc Oprm1 transcript levels and greater PGAT UCP1. This group tended to have improved glucose tolerance (p = 0.07). NAc suppression of Esr1 does not appear to affect PA, yet it may directly affect metabolism. This work may lead to novel targets to improve metabolic dysfunction following E2 loss, possibly by targeting the NAc. Full article

Lipedema is a chronic, idiopathic, and painful disease characterized by an excess of adipose tissue in the extremities. The goal of this study is to characterize the gene expression of estrogen receptors (ERα and ERβ), G protein-coupled estrogen receptor (GPER), and ER-metabolizing enzymes: hydroxysteroid 17-beta dehydrogenase (HSD17B1, 7, B12), cytochrome P450 (CYP19A1), hormone-sensitive lipase (LIPE), enzyme steroid sulfatase (STS), and estrogen sulfotransferase (SULT1E1), which are markers in Body Mass Index (BMI) and age-matched non-lipedema (healthy) and lipedema ASCs and spheroids. Flow cytometry and cellular proliferation assays, RT-PCR, and Western Blot techniques were used to determine the expression of ERs and estrogen-metabolizing enzymes. In 2D monolayer culture, estrogen increased the proliferation and the expression of the mesenchymal marker, CD73, in hormone-depleted (HD) healthy ASCs compared to lipedema ASCs. The expression of ERβ was significantly increased in HD lipedema ASCs and spheroids compared to corresponding healthy cells. In contrast, ERα and GPER gene expression was significantly decreased in estrogen-treated lipedema spheroids. CYP19A1 and LIPE gene expressions were significantly increased in estrogen-treated healthy ASCs and spheroids, respectively, while estrogen upregulated the expression of PPAR-ϒ2 and ERα in estrogen-treated lipedema-differentiated adipocytes and spheroids. These results indicate that estrogen may play a role in adipose tissue dysregulation in lipedema. Full article

Estrogen plays an important role in osteoporosis prevention. We herein report the possible novel signaling pathway of 17β-estradiol (E2) in the matrix mineralization of MC3T3-E1, an osteoblast-like cell line. In the culture media-containing stripped serum, in which small lipophilic molecules such as steroid hormones including E2 were depleted, matrix mineralization was significantly reduced. However, the E2 treatment induced this. The E2 effects were suppressed by ICI182,780, the estrogen receptor (ER)α, and the ERβ antagonist, as well as their mRNA knockdown, whereas Raloxifene, an inhibitor of estrogen-induced transcription, and G15, a G-protein-coupled estrogen receptor (GPER) 1 inhibitor, had little or no effect. Furthermore, the E2-activated matrix mineralization was disrupted by PMA, a PKC activator, and SB202190, a p38 MAPK inhibitor, but not by wortmannin, a PI3K inhibitor. Matrix mineralization was also induced by the culture media from the E2-stimulated cell culture. This effect was hindered by PMA or heat treatment, but not by SB202190. These results indicate that E2 activates the p38 MAPK pathway via ERs independently from actions in the nucleus. Such activation may cause the secretion of certain signaling molecule(s), which inhibit the PKC pathway. Our study provides a novel pathway of E2 action that could be a therapeutic target to activate matrix mineralization under various diseases, including osteoporosis. Full article

Breast cancer is the most frequently diagnosed female cancer worldwide. Environmental contaminant exposure is suspected to be crucial, but the broad-spectrum communal properties that these suspected contaminants all share remain to be explored, especially in source and drinking water. In this work, we focused on the Pearl River Basin, which has the highest breast cancer incidence and mortality in China, and hypothesized that the breast cancer risk in this area is associated with its water source. Our objective was to resolve the possible communal properties that are associated with breast cancer from water mixture extracts of source and drinking water and to identify the key drivers by utilizing the latest epidemiology data, performing an exhaustive water toxicological and chemical characterization, and combining partial least-squares path statistics modeling (PLS-PM). We proposed a path for a drinking water-toxicity-induced breast cancer risk and confirmed its association with estrogen-receptor- and thiol-depletion-relevant mechanisms. The breast cancer incidence risk was associated with water-mixture-promoted mammalian cell proliferation (i.e., estrogenic effect), while the mortality risk was associated with a greater thiol depletion (i.e., oxidative stress). Endocrine-disrupting chemicals (EDCs) and dissolved organic matter (DOM) from anthropogenic sources in drinking water are key drivers for estrogenic effects and oxidative stress, respectively. The PLS-PM standardized effects of the DOM and EDCs in treated water on the breast cancer incidence and mortality were −0.07 and 0.31, and 0.35 and 0.31, respectively, further revealing that EDCs strongly influence the incidence risk, whereas the mortality risk resulted from the joint effects of EDCs and DOM. This study clearly shows an association between the breast cancer risk and drinking water toxicity in a high-prevalence area of China, broadening the future perspectives for water-contaminant-specific breast cancer prevention research. Full article

Isoflavones, belonging to polyphenolic compounds, show structural similarity to natural estrogens, and in this context, they have been extensively studied. Some of them are also applied as cosmetic additives; however, little is known regarding their effects on skin cells. In this investigation, common isoflavones, including genistein, daidzein, glycitein, formononetin, and biochanin A, as well as coumestrol, were evaluated for antioxidant activity and their impact on human skin fibroblasts and keratinocytes. Antioxidant effects were assessed using DPPH, ABTS, and FRAP tests, and the ability to scavenge reactive oxygen species (ROS) was tested in cells with H₂O₂-provoked oxidative stress. The impact on the activity of antioxidant enzymes (SOD, CAT, GSH) and lipid peroxidation (MDA) was also explored. As shown by Alamar Blue and neutral red uptake assays, the compounds were not toxic within the tested concentration range, and formononetin and coumestrol even demonstrated a stimulatory effect on cells. Coumestrol and biochanin A demonstrated significant antioxidative potential, leading to a significant decrease in ROS in the cells stimulated by H₂O₂. Furthermore, they influenced enzyme activity, preventing depletion during induced oxidative stress, and also reduced MDA levels, demonstrating protection against lipid peroxidation. In turn, genistein, daidzein, and glycitein exhibited low antioxidant capacity. Full article