Biology of Sex Differences最新文献

{"title":"Challenges and knowledge gaps in sex differences in cardio-kidney-metabolic syndrome across the lifespan.","authors":"Aline M A de Souza, Alexandra Kautzky-Willer, Damian G Romero, Licy L Yanes Cardozo, Sofia B Ahmed, Samar Rezq","doi":"10.1186/s13293-026-00878-w","DOIUrl":"10.1186/s13293-026-00878-w","url":null,"abstract":"<p><p>Cardiovascular-kidney-metabolic (CKM) syndrome represents a continuum of interrelated adiposity, insulin resistance, cardiovascular disease, kidney dysfunction, and metabolic disturbances that evolve across the lifespan. Emerging evidence demonstrates that both biological sex and sociocultural gender significantly shape CKM risk, progression, and clinical expression. CKM syndrome pathogenesis reflects complex multisystem interactions involving adipose tissue dysfunction, neurohormonal activation, inflammatory signaling, and vascular impairment, all of which exhibit important sex-specific patterns. This review examines CKM syndrome from a sex- and gender-informed perspective, highlighting how endogenous and exogenous sex hormones, reproductive transitions, pregnancy-related complications, and dietary exposures shape the long-term CKM syndrome risk. Particular attention is given to the roles of estrogen and testosterone in modulating adipose biology, vascular function, and metabolic regulation. Polycystic ovary syndrome is discussed as a model of androgen excess and multisystem metabolic vulnerability that accelerates CKM features. Finally, we address brain vulnerability within CKM syndrome, emphasizing shared inflammatory, vascular, and neuroendocrine mechanisms linking metabolic dysfunction to cognitive decline and neuropsychiatric disorders. Recognizing these interconnected and sex-specific influences is critical for advancing precision prevention and treatment strategies across the CKM syndrome spectrum.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"17 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13162479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873085","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":"How biological sex shapes differences in immune responses to infection.","authors":"Megan J Wilson, Amedeo Amedei, Pora Kim, DeLisa Fairweather","doi":"10.1186/s13293-026-00881-1","DOIUrl":"10.1186/s13293-026-00881-1","url":null,"abstract":"","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"17 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13162391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873127","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":"Twenty years of sex and gender science in health research: a policy statement from the Organization for the Study of Sex Differences.","authors":"Sofia B Ahmed, Jill B Becker, Katelyn A Bruno, Sandra M Dumanski, Liisa A M Galea, Marija Kundakovic, Armin Raznahan, Natalie C Tronson, Rebecca L Cunningham","doi":"10.1186/s13293-026-00894-w","DOIUrl":"10.1186/s13293-026-00894-w","url":null,"abstract":"<p><p>Sex and gender are fundamental determinants of health, disease risk, and treatment responses, yet they remain inconsistently and inadequately integrated into biomedical research. Despite major funding and regulatory policies over the past two decades, sex and gender continue to be treated primarily as descriptive variables rather than drivers of discovery. As the Organization for the Study of Sex Differences (OSSD) marks twenty years of leadership in this field, this policy statement articulates OSSD's position on best practices for the integration of sex and gender in health research. Drawing on empirical evidence, landmark policies, and persistent gaps in implementation, this statement provides clear guidance for researchers, funders, and journals. OSSD explicitly recommends prespecified sex- and gender-responsive questions, appropriate study design and statistical power, transparent analysis and reporting, and accountability mechanisms to translate into practice. Adoption of these standards is essential to improving scientific rigor, reproducibility, and clinical relevance.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"17 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13162465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873083","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":"Life-course immunology: reframing sex differences in the immune system to better understand women's health.","authors":"Syreen Goulmamine, Sarah Chew","doi":"10.1186/s13293-026-00889-7","DOIUrl":"10.1186/s13293-026-00889-7","url":null,"abstract":"<p><p>Sex differences are observed in the immune system in innate and adaptive immune responses. These sex differences can be pronounced during periods of significant hormonal change for women, such as puberty, pregnancy, and menopause. Despite evidence of these immunological sex differences shifting and changing during the life course, some research imprecisely conceptualizes sex differences as simply comparative. The dynamic nature of sex differences in the immune system requires moving beyond static male-female comparisons that ignore life-stage transitions and instead adopting a life-course lens that recognizes how immune function-particularly in women-is continuously reshaped across biological transitions. Evidence demonstrates meaningful sex differences across immune-mediated conditions, infection outcomes, and reactogenicity, yet critical gaps remain in the understanding of mechanism and life-course variation in these immune responses. To meaningfully advance research on sex differences in immunity, studies must explicitly and intentionally account for life-stage transitions, moving beyond static male-female comparisons that do not account for life-stage transitions. This shift requires the use of research designs that appropriately consider sex differences and life stage and that studies are powered for life-stage immune questions. Sex differences in immunity are continuously reshaped by and across the lifespan due to aging, hormonal changes, and social and environmental exposures. The field of immunology and immunology research must reconsider life stage as a core principle of sex differences. Failure to intentionally study sex differences across the life course in immunology leaves major gaps in our understanding of immune function in women across the life course and drive disparities, inefficiencies, and inaccuracies in research, treatment, and clinical care.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"17 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13162383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873099","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":"Breastfeeding in infancy confers sex-specific, long-term protection against metabolic dysfunction-associated steatohepatitis and adverse liver outcomes.","authors":"Huiyi Chen, Haobin Chen, Sheng Shen, Xinfeng Ji, Huiling Deng, Qian Wang, Qingying Zhang, Maolong Dong, Jun Ren, Guifang Hu, Jian Sun, Kaifeng Wang","doi":"10.1186/s13293-026-00919-4","DOIUrl":"10.1186/s13293-026-00919-4","url":null,"abstract":"<p><strong>Background: </strong>It remains unclear whether breastfeeding in infancy is associated with risk of metabolic dysfunction-associated steatohepatitis (MASH) and adverse liver outcomes in adulthood.</p><p><strong>Methods: </strong>We analyzed data from the prospective UK Biobank. Breastfeeding in infancy was ascertained via self-report. In a cross‑sectional analysis involving 26,850 participants with liver MRI data, metabolic dysfunction-associated steatotic liver disease (MASLD) was defined as PDFF > 5.5%, and MASH as PDFF > 5.5% combined with cT1 > 800 ms. Additionally, a longitudinal analysis of 378,702 participants assessed associations with incident cirrhosis, hepatocellular carcinoma (HCC), and liver‑related mortality.</p><p><strong>Results: </strong>In MRI-based analysis, breastfeeding in infancy was associated with lower odds of MASLD (OR 0.89, 95% CI 0.80-0.99) and MASH (OR 0.79, 95% CI 0.65-0.97) in females but not males, with a significant sex interaction for MASH (P for interaction = 0.023) but not for MASLD (P for interaction = 0.301). Over a median follow‑up of 14.9 years, breastfeeding was associated with reduced risks of cirrhosis (HR 0.71, 95% CI 0.60-0.83), HCC (HR 0.52, 95% CI 0.33-0.82), and liver‑related mortality (HR 0.63, 95% CI 0.46-0.86) in females. No such associations were observed in males (P for interaction = 0.047, 0.030, and 0.008, respectively). Mediation analysis revealed that circulating insulin-like growth factor-1 (IGF-1) mediated the association specifically in females, with a sex difference in the indirect effect (FDR < 0.001).</p><p><strong>Conclusions: </strong>Breastfeeding in infancy confers a long-term protective effect against MASH and adverse liver outcomes in women, but not in men. This sex-specific protective association was mediated by circulating IGF-1, suggesting a potential underlying mechanism.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13335326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873255","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 prediction models for aortic aneurysm integrating traditional clinical risk factors and proteomic profiles: a large-scale prospective study from the UK Biobank.","authors":"Xuefei Han, Jiacheng Ding, Suyin Feng, Yunqian Li, Yiyin Gao, Runfeng Sun","doi":"10.1186/s13293-026-00913-w","DOIUrl":"10.1186/s13293-026-00913-w","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to systematically map the sex-specific clinical and proteomic risk profiles of aortic aneurysm (AA), elucidate its molecular mechanisms, and develop a sex-specific protein risk prediction score.</p><p><strong>Methods: </strong>Based on the UK Biobank, we adopted a sex-stratified strategy to assess associations between traditional clinical factors and AA in 471,660 participants, and performed proteomics analysis on 49,887 participants with plasma protein data. Mediation analysis was used to explore the molecular mechanisms by which clinical risks drive AA. Finally, sex-specific protein risk scores were developed via LASSO regression, and their predictive performance was evaluated in an independent validation cohort.</p><p><strong>Results: </strong>Smoking (HR: Male: 2.82; Female: 4.42) and valvular disease (HR: Male: 2.01; Female: 4.62) were the strongest shared risk factors, with women exhibiting significantly higher susceptibility. Incident AA was primarily attributed to smoking (Male: 15.3%; Female: 19.8%) and hypertension (Male: 11.2%; Female: 10.2%). Smoking was associated with AA potentially through the ECM degradation pathway in both sexes. Hypertension may also influence AA risk through this pathway in men, whereas in women, it may primarily operate through metabolic and growth factor regulation pathways. Among LASSO-selected proteins, 4 were shared, 10 were male-specific, and 9 were female-specific. Ultimately, the model integrating traditional risk factors and sex-specific protein scores demonstrated superior predictive performance in an independent cohort (C-statistic: Male: 0.809; Female: 0.832).</p><p><strong>Conclusions: </strong>Smoking and hypertension are primary risk factors for AA. Men may be predisposed to structural destruction potentially mediated by ECM degradation, whereas women may be predisposed to intrinsic failure potentially involving metabolic dysregulation and cell apoptosis. The model integrating age, clinical factors, and protein scores better captures residual risk, significantly improving AA prediction.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13335366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873117","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-biased transcriptomic landscapes in bipolar disorder: integrating neurobiology and clinical heterogeneity through cross-study meta-analysis.","authors":"Omran Davarinejad, Mohammad-Taher Moradi, Arash Safarzadeh, Masumeh Jalalvand, Fatemeh Kazemisafa","doi":"10.1186/s13293-026-00870-4","DOIUrl":"10.1186/s13293-026-00870-4","url":null,"abstract":"<p><strong>Background: </strong>Bipolar disorder (BD) exhibits significant sex differences in its frequency, symptom presentation, and treatment response, suggesting distinct underlying neurobiological mechanisms. However, transcriptomic studies investigating these sex-specific pathways have been fragmented and underpowered.</p><p><strong>Method: </strong>We conducted the first meta-analysis of post-mortem brain RNA-seq data to delineate sex-related transcriptomic landscapes in BD. We integrated data from four public datasets (GSE80336, GSE80655, GSE202537, GSE42546) from GEO and Array Express, comprising an aggregate of 173 individuals (66 BD cases and 117 controls). After preprocessing and correcting for batch effects, sex-stratified expression analysis was performed using DESeq2. A meta-analysis was conducted with the metafor package to identify differentially expressed genes (DEGs) at an FDR < 0.05. We also performed functional enrichment, protein-protein interaction (PPI) network analysis, hub gene identification, regulatory network reconstruction, and supplementary quantitative analyses of sex-specific interaction effects.</p><p><strong>Results: </strong>Our results reveal striking differences in transcriptomic signatures between men and women with bipolar disorder, with the most pronounced changes occurring in the brain. A meta-analysis across brain regions identified 34 significantly dysregulated genes. In females, upregulated genes were enriched for hormonal signaling (FSHR pathway, G-protein signaling) and transcriptional/epigenetic regulation (GLIS1, neural plasticity). In males, upregulated genes were involved in synaptic calcium signaling (PDLIM5, dendritic spine regulation) and DNA mismatch repair pathways (PMS1). Analysis of the striatum identified 289 differentially expressed genes. The most significantly upregulated genes in females were implicated in immunity and synaptic plasticity, while the male-specific pattern pointed to alterations in basic cellular functions like structure, internal communication, and genetic regulation. A quantitative interaction analysis revealed a negligible correlation (r = -0.122) between disease effect sizes in females and males and identified one gene with opposing, sex-dependent dysregulation (MEF2C).</p><p><strong>Conclusion: </strong>This study provides robust evidence that bipolar disorder engages fundamentally distinct molecular pathways in males and females, underscoring the necessity of integrating sex as a biological variable in psychiatric research and advancing toward personalized therapeutic strategies.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13321544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855617","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":"Highlight on Dr. Rhonda Voskuhl: a pioneer in the exploration of sex differences in the immune response.","authors":"Shannon E Dunn","doi":"10.1186/s13293-026-00910-z","DOIUrl":"10.1186/s13293-026-00910-z","url":null,"abstract":"","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":"17 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13154545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855797","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":"Artificial intelligence predicts sex-specific risk of metabolic dysfunction-associated steatotic liver disease.","authors":"Mohamad Jamalinia, Giovanni Targher, Amedeo Lonardo, Seyed Taghi Heydari, Kamran Bagheri Lankarani","doi":"10.1186/s13293-026-00917-6","DOIUrl":"10.1186/s13293-026-00917-6","url":null,"abstract":"<p><strong>Background & aims: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD) exhibits well-established sex differences across its risk factors, disease progression, and liver-related and extrahepatic outcomes. We trained sex-specific machine learning (ML) algorithms using routine clinical data to evaluate sex-specific learning patterns and diagnostic performance.</p><p><strong>Methods: </strong>In this cross-sectional study conducted at a cardiology referral center, 446 adults were enrolled. Participants were divided into training (127 men, 185 women) and test sets (55 men, 79 women). Eight ML classifiers were trained on the overall dataset and separately for men and women to predict MASLD presence and steatosis severity (no/mild/moderate-to-severe) as assessed by ultrasonography. Hyperparameters were tuned using grid search cross-validation, and model performance was evaluated on an unseen test set.</p><p><strong>Results: </strong>The prevalence of MASLD was 63.6% among participants; 41.2% had mild, and 22.4% had moderate-to-severe steatosis. Compared to models trained on the overall dataset, sex-specific modeling improved diagnostic performance in men but remained suboptimal in women. For MASLD presence, top-performing models achieved AUC/F1 scores of 0.769/0.856 overall, 0.793/0.897 in men, and 0.681/0.794 in women. For steatosis severity, respective AUC/F1 scores were 0.761/0.671 overall, 0.723/0.608 in men, and 0.718/0.571 in women. Sensitivity analyses using stratified cross-validation confirmed the performance gap between men and women. Threshold analyses showed acceptable rule-in and rule-out performance in men but suboptimal performance in women. Feature-importance rankings differed substantially between sexes, indicating distinct sex-specific learning patterns.</p><p><strong>Conclusions: </strong>Artificial intelligence-based algorithms identify sex-specific learning patterns in MASLD steatosis risk prediction. Routine clinical variables appear more informative for men, while showing weaker algorithmic performance in women. This finding suggests that failure to train MASLD risk algorithms with sex-specific risk factors may increase the risk of misclassification in women. Therefore, achieving more equitable and clinically reliable models will require integrating women-specific risk factors and adopting sex-stratified data processing strategies within MASLD prediction frameworks to reduce diagnostic inequities and support more personalized care.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13321611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855683","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":"Reproductive history differentially shapes the neural response of middle-aged hAPOEɛ4 female rats to estradiol therapy after a metabolic challenge.","authors":"Jennifer E Richard, Ahmad Mohammad, Stephanie E Lieblich, Kimberly A Go, Soda Wang, Rebecca K Rechlin, Tallinn F L Splinter, George E Barreto, Liisa A M Galea","doi":"10.1186/s13293-026-00911-y","DOIUrl":"10.1186/s13293-026-00911-y","url":null,"abstract":"<p><strong>Background: </strong>Advancing age, the APOEɛ4 allele, and female sex are the top nonmodifiable risk factors for Alzheimer's disease (AD). Female-specific experiences, such as parity and hormone therapy (HT) affect aging biomarkers such as metabolism and immune signaling, and may affect AD risk. Estradiol (E2), a component of many HTs, affects cognition and brain health in aging females although studies suggest the effects can vary depending on parity, genotype, and metabolic status which may account for some of the inconsistencies in the literature. We hypothesized that prior parity influences brain and metabolic health, including response to E2, depending on APOE genotype.</p><p><strong>Methods: </strong>Middle-aged female (10 month) wildtype (WT) or humanized (h) APOEɛ4 expressing rats, with different reproductive experience (nulliparous or primiparous) were fed a Western (WD) or standard diet (SD) for 2 months. In the second month, rats were given E2 or vehicle (oil) injections daily. Fear associative learning, plasma metabolic hormones, hippocampal inflammatory cytokine expression, and neuroplasticity (neurogenesis, synaptic protein) were assessed.</p><p><strong>Results: </strong>Females fed a WD gained weight and displayed metabolic dysregulation, regardless of genotype. E2 treatment reduced WD-induced weight gain and reduced metabolic hormones, with stronger effects in WT rats. E2 treatment increased dorsal hippocampal inflammatory cytokine expression selectively in primiparous hAPOEɛ4 females fed a WD. Previous parity increased neurogenesis and reduced certain cytokine expression in the hippocampus of middle-aged WT rats under a SD. Both E2 treatment and previous parity decreased dorsal neurogenesis in hippocampus of hAPOEɛ4 rats. In hAPOEɛ4 females, higher weight was associated with reduced contextual fear memory, an effect driven by primiparous females. In the cued fear conditioning task, hAPOEɛ4 females displayed better cued fear memory than WT, however, WD exposure reduced cued fear memory only in this group. Together, this indicates that diet and weight gain may be more detrimental to associative memory in hAPOEɛ4 females and that E2 treatment has more favourable outcomes in WT rats.</p><p><strong>Conclusions: </strong>Previous parity alters how females respond to E2 and metabolic stress in midlife. Primiparous hAPOEɛ4 females were especially vulnerable to the effects of WD and E2, exhibiting more inflammation, impaired memory, and reduced weight-loss. These findings highlight the importance of considering parity and genotype when evaluating midlife metabolic and cognitive risk.</p>","PeriodicalId":8890,"journal":{"name":"Biology of Sex Differences","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13285403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810385","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}