Biology of Sex Differences最新文献

{"title":"Association of placental mitochondrial DNA mutations on infant negative affectivity: modifying effects of maternal lifetime stress and infant sex.","authors":"Agathe M de Pins, Hsiao-Hsien Leon Hsu, Rosalind J Wright, Kelly J Brunst","doi":"10.1186/s13293-025-00717-4","DOIUrl":"10.1186/s13293-025-00717-4","url":null,"abstract":"<p><p>Neuropsychiatric and behavioral disorders impact over 15% of U.S. children, with sex differences in manifestation. Prenatal exposure to psychosocial stress predicts adverse neurodevelopmental outcomes, particularly during gestation. Mechanisms remain poorly understood. Research links prenatal stress exposures with placental mitochondrial DNA (mtDNA) mutational load, suggesting that disrupted mitochondrial placental function may play a role. We conceptualize that placental mitochondrial biomarkers reflect environmentally-induced oxidation that may contribute to mechanisms influencing neurodevelopment. Furthermore, as maternal stress can impact female and male children differently, this may in part explain sex differences in early childhood neurobehavioral outcomes. This study explores the association between placental mtDNA mutational load and negative affectivity in infants, and whether these associations are modified by maternal lifetime stress and fetal sex. Placenta samples (N = 394) were collected at delivery and whole mtDNA sequencing was performed to identify gene-specific mutational loads. Mothers completed the Infant Behavior Questionnaire-Revised (IBQ-R) when children were 6.69 ± 1.61 months of age and the Negative Affectivity factor was derived. Multivariable regression analyses were performed to model Negative Affectivity in relation to placental mtDNA mutational load, first adjusting for child sex and maternal age, self-reported race, and education. Lastly, we examined effect modification by maternal stress and fetal sex using cross-product terms and contrast statements. Results showed that higher mutational load in the MT_CYB region was positively associated with increased negative affectivity. Notably, interactions between mtDNA regions (MT_DLOOP and MT_ND), child sex, and maternal stress revealed that girls with higher mutational loads in these regions were at greater risk for increased negative affectivity, particularly under high maternal stress. These findings suggest that placental mtDNA mutational load could serve as a biomarker for neurodevelopmental risk, with sex-specific vulnerabilities influenced by maternal stress. This study underscores the importance of considering both environmental factors and sex differences in understanding early neurodevelopmental trajectories, and the potential of the placenta as a tool for early detection and intervention. Further research is needed to validate these findings and explore their implications for long-term child development. Highlights Increased mutational load in the cytochrome B region of placental mtDNA is associated with higher infant negative affectivity. Girls exhibited greater sensitivity to mutations in the mitochondrial D-loop and NADH dehydrogenase regions, showing stronger links to negative affectivity compared to boys. Higher maternal lifetime stress amplified the impact of mitochondrial NADH dehydrogenase mutational load on negative affectivity in girls, highligh","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"40"},"PeriodicalIF":4.9,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-specific differences in preclinical models of advanced chronic liver disease and portal hypertension.","authors":"Peio Aristu-Zabalza, María Andrés-Rozas, Zoe Boyer-Díaz, David P Al-Adra, Douglas Maya-Miles, Sergi Guixé-Muntet, Anabel Fernández-Iglesias, Jordi Gracia-Sancho","doi":"10.1186/s13293-025-00721-8","DOIUrl":"10.1186/s13293-025-00721-8","url":null,"abstract":"<p><strong>Background: </strong>Chronic liver disease is a major health concern, but sex-specific differences in its pathophysiology remain unclear. Preclinical studies have predominantly used male animals, limiting findings' relevance to both sexes. This project aimed to explore sex differences in cirrhosis and portal hypertension (PH) in rats, and to find similarities in human samples for translational relevance.</p><p><strong>Methods: </strong>Advanced chronic liver disease (ACLD) was induced in male and female Sprague-Dawley rats using thioacetamide (TAA, 250 mg/kg; 12 weeks) or bile duct ligation (BDL; 28 days). Healthy rats served as controls (n = 11-18/group). We assessed in vivo hepatic and systemic hemodynamic parameters, hepatic microvascular function, and hepatic transcriptomic analyses, including sex-specific differences in cellular composition using gene deconvolution (n = 5/group). Two human sample cohorts were compared to preclinical data for translational insights.</p><p><strong>Results: </strong>Both animal models showed PH. TAA males had similar portal pressure (PP) to females (14.2 vs 14.1 mmHg), but BDL males had significantly higher PP than females (14.5 vs 12.5 mmHg; p = 0.003). No differences were observed in hepatic microvascular function. In the BDL model, females had more fenestrae and porosity, and less fibrosis. Transcriptomic analysis revealed that TAA males had dysregulated metabolic pathways, while females had deregulated genes in hormone signaling. In the BDL model, males showed higher deregulation in platelet activation, protein degradation, vesicular transport, and disease-related pathways. Gene deconvolution showed males had a more specialized endothelial phenotype basally, with more changes in endothelial and macrophage phenotypes after injury. In MASLD patients, men had dysregulated metabolic pathways, while women showed deregulation in fibrosis, extracellular matrix, and endocrine regulation. In HBV patients, men had more dysregulation in fibrosis, inflammation, and immune response. Female MASLD patients had more activated hepatic stellate cells, and greater loss of endothelial phenotype compared to men.</p><p><strong>Conclusions: </strong>This study highlights sex-dependent molecular differences in the pathophysiology of cirrhosis in two preclinical models. Further research in preclinical and human liver disease is essential to develop safe and effective treatments for ACLD in both sexes.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"39"},"PeriodicalIF":4.9,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12131374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of social determinants of health on likelihood of systemic hormone therapy use in midlife women.","authors":"Juliana M Kling, Anna E Abraham, Ekta Kapoor, Kristin Cole, Mariam Saadedine, Chrisandra Shufelt, Stacey J Winham, Stephanie S Faubion","doi":"10.1186/s13293-025-00720-9","DOIUrl":"10.1186/s13293-025-00720-9","url":null,"abstract":"<p><strong>Objective: </strong>Social determinants of health (SDOH) can have a significant impact on women's health and quality of life. Little is known about the impact of SDOH during menopause, and whether certain SDOH impact the likelihood of using systemic hormone therapy (HT). Our objective was to evaluate the impact of SDOH on the likelihood of HT utilization among midlife women.</p><p><strong>Design: </strong>Midlife women between the ages of 45-60 years were surveyed about their menopause experience between March and June of 2021. The questionnaire included information on medications used to treat menopause symptoms. From the electronic medical record demographic information and self-reported SDOH data were obtained, including the amount of exercise/physical activity, whether the participants felt stressed, social interactions, abuse in the last year, ability to pay for basics, diet, alcohol intake, smoking status, and whether participants had regular dentist visits. SDOH were compared between using/not using HT currently.</p><p><strong>Results: </strong>One thousand nine hundred and eighty-eight women aged 45-60 years who received primary care at one of four geographic Mayo Clinic sites completed the survey and filled out SDOH questions within 2 years. Women were 54.4 years of age on average (SD 4.2), with a mean BMI of 30.2 (SD 7.5), and a majority White (97%). 258 (13.0%) women were currently using HT. In univariate analysis, women were less likely to be using HT if they had higher BMI (per 1 kg/m² increase, OR = 0.97, 95% 0.95-0.99, p = 0.002) were unpartnered (OR = 0.66, 95% CI 0.45-0.99, p = 0.04) had lower education (compared to post graduate studies, high school graduate/GED or less: OR = 0.45, 95% CI 0.24-0.85, p = 0.01; some college/2 year degree: OR = 0.69, 95% CI 0.49-0.96,p = 0.03), or were a smoker (compared to those who never smoked, current smoker: OR = 0.38, 95% CI 0.18-0.83, p = 0.02; former smoker: OR = 0.71, 95% CI 0.52-0.96, p = 0.03). Women who used extra virgin olive oil as main fat in diet were more likely to be using HT (OR = 1.46, 95% CI 1.10-1.94, p = 0.009). No other SDOH were associated with HT.</p><p><strong>Conclusion: </strong>Certain SDOH were associated with HT use for menopause treatment. Favorable SDOH likely correlate with better access to menopause care. To assure equitable menopause treatment for all women, clinicians should evaluate and address SDOH with their midlife women patients.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"37"},"PeriodicalIF":4.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High ovarian hormones present during fear extinction reduce fear relapse through a nigrostriatal dopamine pathway.","authors":"Alyssa A Hohorst, Margaret K Tanner, Rebecca Han, Kamryn M Korth, Jessica D Westerman, Carolina Sanchez Mendoza, Miles Q Dryden, Lareina A Alvarez, Remla A Abdul, Esteban C Loetz, Erik B Oleson, Benjamin N Greenwood","doi":"10.1186/s13293-025-00722-7","DOIUrl":"10.1186/s13293-025-00722-7","url":null,"abstract":"<p><strong>Background: </strong>Elevated ovarian hormones during fear extinction can enhance fear extinction memory retention and reduce fear renewal, but the mechanisms remain unknown. High levels of ovarian hormones are associated with heightened dopamine (DA) transmission, a key player in fear extinction. In males, stimulation of substantia nigra (SN) DA neurons during fear extinction reduces renewal; an effect mimicked by DA D1 receptor agonist administration into the dorsolateral striatum (DLS), a primary target of the SN. The current studies tested the role of the SN-DLS pathway in estrous cycle-modulation of fear extinction and relapse.</p><p><strong>Methods: </strong>Male and female Long-Evans rats were used to investigate the effects of sex and ovarian hormone levels during fear extinction on later fear relapse and underlying mechanisms. Fear extinction-induced cFos in SN DA neurons was quantified with double-label immunohistochemistry. An intersectional chemogenetic approach was used to determine whether SN-DLS pathway activity during fear extinction is necessary and sufficient for observed effects of ovarian hormones on fear relapse. Finally, fast scan cyclic voltammetry revealed the effects of sex and ovarian hormones on electrically-evoked DA release in the DLS and verified the effectiveness of chemogenetic approaches.</p><p><strong>Results: </strong>Female rats exposed to fear extinction during proestrus or estrus (Pro/Est; high hormones) had less relapse (renewal and spontaneous recovery) compared to males or females exposed to fear extinction during metestrus or diestrus (Met/Di; low hormones). Fear extinction-induced cFos within SN DA neurons and electrically-evoked DA release in the DLS was highest in female rats during Pro/Est. The behavioral and neurochemical effects of Pro/Est were mimicked by estradiol administration to ovariectomized female rats. Inhibition of the SN-DLS pathway suppressed electrically-evoked DA release in the DLS and restored fear renewal in females exposed to simultaneous fear extinction and SN-DLS inhibition during Pro/Est. Conversely, stimulation of the SN-DLS pathway during extinction reduced fear renewal in males.</p><p><strong>Conclusions: </strong>Results indicate that ovarian hormones present during fear extinction reduce later fear relapse through a SN-DLS dopamine pathway. Data suggest the SN-DLS DA pathway is a novel target for the reduction of fear relapse in both sexes.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"38"},"PeriodicalIF":4.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping the hippocampal spatial proteomic signature in male and female mice of an early Alzheimer's disease model.","authors":"Ana Contreras, Raquel Jiménez-Herrera, Souhail Djebari, Juan D Navarro-López, Lydia Jiménez-Díaz","doi":"10.1186/s13293-025-00697-5","DOIUrl":"10.1186/s13293-025-00697-5","url":null,"abstract":"<p><strong>Background: </strong>Hippocampal dysfunction induced by soluble amyloid-β oligomers (oAβ) is an early neuropathological hallmark of Alzheimer's disease (AD). oAβ shifts hippocampal synaptic-plasticity induction threshold facilitating long-term depression (LTD) instead of long-term potentiation (LTP, the functional basis of memory), thereby leading to memory deficits in early AD-like amyloidosis mouse models. In this regard, the spatial distribution of the underlying synaptic-plasticity/memory proteome changes in the hippocampus, and potential sex differences, remain unknown. Here we postulated that some protein changes related to synaptic-plasticity and memory may be unique to sex and/or specific to the dorsal or ventral hippocampus -as both regions have distinct functionality and connectivity-, potentially providing sex- and spatial-specific proteomic phenotypes for early AD-amyloidosis interventions.</p><p><strong>Methods: </strong>An innovative spatial-resolution proteomics study was performed to map whole hippocampal proteome distribution using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry. For this purpose, sixteen adult male and female mouse brains intracerebroventricularly injected with oAβ_1-42/vehicle were analyzed. MALDI-imaging RapifleXTM-MALDI-TissuetyperTM TOF/TOF mass spectrometer was used, followed by traditional tandem mass spectrometry (MS/MS) for precise protein identification on tissue.</p><p><strong>Results: </strong>34 proteins showed significant differences in expression levels due to treatment, sex, or hippocampal location among 234 peptides initially detected; and displayed significant protein-protein interaction (PPI), indicating main functional relationship to LTP/LTD pathways and memory. Thus, 14 proteins related to synaptic-plasticity and/or AD were further studied, showing that most modulated glycogen synthase kinase-3β (GSK-3β), a protein widely involved in synaptic-plasticity induction threshold regulation towards LTD. Accordingly, hippocampal GSK-3β was found to be overactivated in AD-like amyloidosis mice.</p><p><strong>Conclusions: </strong>We show for the first-time specific sex-dependent synaptic-plasticity proteome changes in dorsal/ventral hippocampi that modulate GSK-3β activity. These findings provide new insight into the early amyloidosis pathogenesis in AD and offer valuable, unique proteomic phenotypes as potential biomarkers and targets for early diagnosis and therapy in both sexes.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"36"},"PeriodicalIF":4.9,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-related differences and associated transcriptional signatures in the brain ventricular system and cerebrospinal fluid development in full-term neonates.","authors":"Yuxin Sun, Chenxin Fu, Lifan Gu, Huifang Zhao, Yuying Feng, Chao Jin","doi":"10.1186/s13293-025-00719-2","DOIUrl":"10.1186/s13293-025-00719-2","url":null,"abstract":"<p><strong>Background: </strong>The cerebrospinal fluid (CSF) is known to serve as a unique environment for neurodevelopment, with specific proteins secreted by epithelial cells of the choroid plexus (CP) playing crucial roles in cortical development and cell differentiation. Sex-related differences in the brain in early life have been widely identified, but few studies have investigated the neonatal CSF system and associated transcriptional signatures.</p><p><strong>Methods: </strong>This study included 75 full-term neonates [44 males and 31 females; gestational age (GA) = 37-42 weeks] without significant MRI abnormalities from the dHCP (developing Human Connectome Project) database. Deep-learning automated segmentation was used to measure various metrics of the brain ventricular system and CSF. Sex-related differences and relationships with postnatal age were analyzed by linear regression. Correlations between the CP and CSF space metrics were also examined. LASSO regression was further applied to identify the key genes contributing to the sex-related CSF system differences by using regional gene expression data from the Allen Human Brain Atlas.</p><p><strong>Results: </strong>Right lateral ventricles [2.42 ± 0.98 vs. 2.04 ± 0.45 cm3 (mean ± standard deviation), p = 0.036] and right CP (0.16 ± 0.07 vs. 0.13 ± 0.04 cm3, p = 0.024) were larger in males, with a stronger volume correlation (male/female correlation coefficients r: 0.798 vs. 0.649, p < 1 × 10^- 4). No difference was found in total CSF volume, while peripheral CSF (male/female β: 1.218 vs. 1.064) and CP (male/female β: 0.008 vs. 0.005) exhibited relatively faster growth in males. Additionally, the volumes of the lateral ventricular system, third ventricle, peripheral CSF, and total CSF were significantly correlated with their corresponding CP volume (r: 0.362 to 0.799, p < 0.05). DERL2 (Degradation in Endoplasmic Reticulum Protein 2) (r = 0.1319) and MRPL48 (Mitochondrial Large Ribosomal Subunit Protein) (r=-0.0370) were identified as potential key genes associated with sex-related differences in CSF system.</p><p><strong>Conclusion: </strong>Male neonates present larger volumes and faster growth of the right lateral ventricle, likely linked to corresponding CP volume and growth pattern. The downregulation of DERL2 and upregulation of MRPL48 may contribute to these sex-related variations in the CSF system, suggesting a molecular basis for sex-specific brain development.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"35"},"PeriodicalIF":4.9,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in the modulation of anxiety- and depression-like behaviors by matrix metalloproteinase-9 expression levels in mice.","authors":"Júlia Senserrich, Elena Castro, Eva Florensa-Zanuy, Álvaro Díaz, Ángel Pazos, Albert Adell, Athina Tzinia, Fuencisla Pilar-Cuéllar","doi":"10.1186/s13293-025-00716-5","DOIUrl":"10.1186/s13293-025-00716-5","url":null,"abstract":"<p><strong>Background: </strong>Major depressive disorder is one of the main causes of disability worldwide, but its etiopathology remains largely unknown, although several hypotheses have been proposed. Recent studies suggest a potential role for matrix metalloproteinase 9 (MMP-9) in depression, as it is overexpressed in the plasma of depressed patients and normalizes following chronic antidepressant treatment. This study aimed to characterize anxiety and depression-like behaviors in transgenic MMP-9 mice, as well as the expression of different neuroplasticity markers associated with depression, in both sexes.</p><p><strong>Methods: </strong>In this study, we characterized the behavioral phenotypes of both MMP-9 knockout and MMP-9-overexpressing male and female mice. Here, we used a battery of tests to assess anxiety (open field, light‒dark box, elevated plus maze, and novelty‒suppressed feeding tests), depressive-like (tail suspension and social interaction tests), and cognitive (T-maze) behaviors.</p><p><strong>Results: </strong>MMP-9 knockout female mice displayed increased innate anxiety (open field test), decreased behavioral despair (tail suspension test). Compared with control mice, female MMP-9 knockout mice presented increased levels of different neuroplasticity markers in the hippocampus. With respect to MMP-9-overexpressing mice, females presented decreased innate anxiety (elevated plus maze). Male MMP-9-overexpressing mice presented greater conflict-based anxiety (novelty-suppressed feeding test) than control mice did.</p><p><strong>Conclusions: </strong>MMP-9 activity modifies anxiety- and depression-like behaviors, as well as neuroplasticity markers, in female but not in male mice. These findings reinforce the sex differences in the etiopathology of depression.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"34"},"PeriodicalIF":4.9,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of sex differences in cardiovascular, metabolic, and immune functions in health and disease: a review for \"Sex Differences in Health Awareness Day\".","authors":"Lana McClements, Alexandra Kautzky-Willer, Georgios Kararigas, Sofia B Ahmed, John N Stallone","doi":"10.1186/s13293-025-00714-7","DOIUrl":"10.1186/s13293-025-00714-7","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Sexual dimorphism is a fundamental characteristic of the anatomy and physiology of animals and humans, yet biomedical research has largely ignored these phenomena in the study of health and disease, despite early studies in the eighteenth and nineteenth centuries that demonstrated the importance of sex differences. With the explosive growth of biomedical research following World War II, especially in the 1970s through the 1990s, preclinical and clinical studies led to a greater recognition of sex differences in physiological function, particularly the significant disparities in the incidence of and mortality from cardiovascular diseases, which generally occur more frequently in men than in premenopausal women. There is a growing awareness that metabolic and immune dysfunction are intimately tied to the development of cardiovascular diseases. Thus, this review article focuses on sexual dimorphism in cardiovascular, metabolic, and immune function in health and disease, and was prepared for the journal Biology of Sex Differences as part of its recognition of \"Sex Differences in Health Awareness Day.\" This article clearly reveals the striking importance of sex differences in cardiovascular, metabolic, and immune system functions in health and in the pathogenesis of disease processes, which likely involve a combination of effects of the sex chromosomes as well as the gonadal steroid hormones. In the developing fetus, fetal sex clearly influences the pathogenesis of the hypertensive diseases of pregnancy, and sex differences in the effects of the fetus continue beyond pregnancy and appear to influence the future risk of maternal cardiometabolic diseases. Similarly, there is strong evidence of many clinically-relevant sexually dimorphic characteristics of obesity and type 2 diabetes mellitus which appear to involve both chromosomal and humoral effects, although the underlying pathophysiological mechanisms are poorly understood. The gonadal steroid hormones (both androgens and estrogens) are known to exert important effects on the regulation of intermediary metabolism; however, recent studies reveal the emerging importance of these hormones in the regulation of inflammation. For example, menopausal declines in estrogen are associated with increases in inflammatory markers and the development of heart failure in women. Similar effects on inflammatory function may also occur in men with progressive age-dependent declines in testosterone. Declines in androgen levels in men are also associated with detrimental effects on cardiovascular and metabolic function, especially the development of metabolic syndrome and type 2 diabetes, important risk factors for cardiovascular disease. Interestingly, pathophysiological increases in the normally lower testosterone levels in women are associated with the same detrimental effects on cardiovascular and metabolic function, revealing striking bi-directional sex differences in the effects of the androgens. Finally, i","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"33"},"PeriodicalIF":4.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12076860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in bladder cancer: understanding biological and clinical implications.","authors":"Prakash Chaudhary, Biplab Singha, Hany A Abdel-Hafiz, Maria Velegraki, Debasish Sundi, Swati Satturwar, Anil V Parwani, Sergei I Grivennikov, Sungyong You, Helen S Goodridge, Qin Ma, Yuzhou Chang, Anjun Ma, Bin Zheng, Dan Theodorescu, Zihai Li, Xue Li","doi":"10.1186/s13293-025-00715-6","DOIUrl":"10.1186/s13293-025-00715-6","url":null,"abstract":"<p><p>Bladder cancer (BC) remains a significant global health concern, with substantial sex and racial disparities in incidence, progression, and outcomes. BC is the sixth most common cancer among males and the seventeenth most common among females worldwide. Over 90% of BC cases are urothelial carcinoma (UC) with high degrees of pathological heterogeneity. Molecular subtyping of BC has also revealed distinct luminal, basal, and neuroendocrine subtypes, each with unique genetic and immune signatures. Emerging research uncovers the biasing effects of the sex hormones with androgens increasing BC risk through both tumor cell intrinsic and extrinsic mechanisms. The sex chromosomes, including both the X and Y chromosomes, also contribute to the sex differences in BC. The effect of sex chromosome is both independent from and synergistic with the effects of sex hormones. Loss of the Y chromosome is frequently observed in BC patients, while an extra copy of the X chromosome confers better protection against BC in females than in males. Advent of advanced technologies such as multiomics and artificial intelligence will likely further improve the understanding of sex differences in BC, which may ultimately lead to personalized preventative and treatment strategies depending on the biological sex of patients. This review delves into the impacts of biology of sex on BC, emphasizing the importance of further research into sex-specific biology to improve cancer prevention and care.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"31"},"PeriodicalIF":4.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex still matters for the brain and mental health across the lifespan.","authors":"Adriene M Beltz, Natalie C Tronson, Meharvan Singh, Samar Rezq","doi":"10.1186/s13293-025-00710-x","DOIUrl":"10.1186/s13293-025-00710-x","url":null,"abstract":"","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"16 1","pages":"32"},"PeriodicalIF":4.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}