Biology of Sex Differences最新文献

The global incidence of nephrolithiasis has increased significantly in recent decades. The prevalence remains higher in males than females, the exact mechanisms responsible for this gender-based disparity in nephrolithiasis risk remain incompletely understood. Although dietary and lifestyle factors contribute to this difference, they do not entirely account for the observed variation. Emerging evidence suggests that steroid hormones may play a pivotal role in modulating renal stone formation through their influence on calcium, oxalate, and phosphate metabolism, as well as regulating the renal inflammatory microenvironment. This review synthesizes current knowledge on the interplay between steroid hormones and nephrolithiasis pathogenesis, providing a theoretical framework for understanding gender-specific susceptibility and highlighting potential avenues for tailored preventive and therapeutic approaches.

Background: The gut microbiota significantly influences cardiovascular health by regulating host metabolism and generating bioactive compounds like trimethylamine-N-oxide (TMAO) and indoxyl sulfate (IS), both linked to coronary artery disease (CAD). Emerging research indicates sex-based differences in microbial composition and metabolite production, yet their impact on CAD pathophysiology remains unclear. This scoping review summarizes current findings on sex-specific microbial and metabolic differences in individuals with CAD.

Methods: A systematic search of PubMed and EMBASE was conducted through March 2025 for peer-reviewed studies comparing gut microbiota or metabolite profiles between male and female patients with CAD. Eligible studies used 16S rRNA sequencing, shotgun metagenomics, or metabolite profiling to analyze microbial communities and atherosclerosis-associated metabolites. Mechanistic links from genetics, epigenetics, and hormone-microbiota interactions were integrated to provide a more comprehensive understanding of how gut microbiota may contribute to sex differences in CAD.

Results: Eleven studies met the inclusion criteria for this review. Men with CAD exhibited increased relative abundances of taxa such as Prevotella, Clostridia_UCG_014, UCG_010, and other pro-inflammatory genera, whereas women microbiota was comparatively enriched in Barnesiella, Bifidobacteriales, and other potentially beneficial taxa. Parallel differences emerged in microbial metabolite profiles: men demonstrated elevated plasma levels of TMAO and IS, both associated with heightened cardiovascular risk and disease burden. Conversely, women with CAD had higher circulating levels of secondary bile acids and lower TMAO concentrations.

Conclusion: Preliminary studies suggest sex-related differences in gut microbiota composition and metabolite profiles in CAD patients. Integrating mechanistic links from microbial metabolism, genetics, epigenetics, and hormones supports a potential role of the microbiota in sex-dependent disease pathways. Current evidence is limited and mostly observational; well-designed studies are needed to clarify mechanisms, clinical relevance of sex-specific microbiome signatures and specifically assess whether these sex-specific microbial and metabolic differences influence CAD progression and outcomes.

Background: Exogenous sex hormones have been extensively studied for their influence on stroke risk and outcome. This meta-analysis served to update the pre-clinical acute ischemic stroke (AIS) literature and provide the first synthesis of the intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) literature on how estrogen, progesterone, and testosterone affect post-stroke outcomes.

Methods: This study was pre-registered with PROSPERO (CRD42024544794). Medline, EMBASE, Scopus, and Web of Science were searched; studies using animal models of stroke investigating exogenous estrogen, progesterone, or testosterone, alone or in combination, compared to non-treated controls were included. Assessments of injury volume, edema, and behaviour (neurological deficits, sensorimotor and cognitive outcomes) were analyzed via hierarchical meta-analyses. Risk of bias was assessed via SYRCLE and CAMARADES, and evidence certainty via an adaptation of the GRADE tool.

Results: In total, 211 studies were included. Estrogen and progesterone improved all post-AIS outcomes (SMDs = 0.32-1.30, 95% CIs [0.02, 2.07], very low to moderate certainty of evidence), whereas testosterone had mostly null effects (very low to moderate certainty). Fewer studies investigated hemorrhagic stroke, with null effects of estrogen (very low to low certainty) and conflicting results of progesterone (SMDs = 0.15-1.16 [-2.20, 2.58], very low to moderate certainty) in ICH, as well as benefit of progesterone in SAH (SMD = 2.63 [0.98, 4.30], very low certainty). Uncertainty in our evidence arose from low scientific and translational rigor. Sex and gonadal status were consistent moderators of these effects, and gonadal depletion length (i.e., the 'timing hypothesis') was a significant moderator of estrogen's effect on post-AIS injury volume.

Conclusions: Estrogen and progesterone are promising cerebroprotectants for AIS. Further focussed and rigorous pre-clinical research on remaining research gaps (e.g., dosage parameters) are needed to guide clinical investigations and maximize the likelihood of translational success. The impact of testosterone and sex hormones in hemorrhagic stroke remain inconclusive due to lack of research.

Background: Long COVID (LC) is a post-infectious condition affecting millions worldwide, characterized by persistent multisystem symptoms. Females are disproportionately affected, reporting higher symptom burden, particularly neurocognitive and neurosensory complaints. While short-term immunopathology has been described, the long-term clinical course, immune dysregulation, and sex-specific underpinnings remain poorly understood.

Methods: We analyzed 34 participants experiencing persisting symptoms from 9 months to 5 years post-SARS-CoV-2 infection, alongside 26 SARS-CoV-2-infected controls without symptoms. Clinical assessments, symptom inventories, comorbidity analysis, and work capacity evaluation were performed. Immune profiling included flow cytometry of CD4⁺ and CD8⁺ T cells, NK cells, and B cells, as well as quantification of plasma cytokines, soluble factors, and cytotoxic molecules, analyzed in a sex-disaggregated manner.

Results: Females with LC exhibited higher symptom burden, particularly persistent fatigue, neurocognitive and neurosensory complaints, which increased with age and tended to increase with disease duration, whereas males showed no clear age- or duration-related patterns. Comorbidities, especially affecting endocrine, metabolic, and circulatory systems, were more frequent in females and aligned with symptom severity. Immune profiling revealed subtle but sex-specific differences: females had reduced CD8⁺ T cell cytotoxic profile, lower NKG2D and granzyme K expression, increased sCD40L and sFAS, and decreased perforin, whereas males displayed elevated TNF-α. NK cell function, B cells, and humoral immunity remained largely intact. Over half of participants reported functional impairments affecting work capacity.

Conclusions: Even though our cohort is small it suggests that prolonged LC is characterized by sex-specific differences in symptom burden and immune profiles. Reduced cytotoxic CD8⁺ T cell profile in females may contribute to viral persistence and neurological symptoms, whereas elevated inflammatory markers in males suggest distinct immune pathways. These findings highlight the need for sex- and duration-specific management strategies, the identification of biomarkers, and the development of personalized therapies targeting specific LC endotypes.

Alzheimer's disease (AD) displays striking sex differences in incidence, progression, and resilience, yet the mechanisms that drive female-biased vulnerability remain incompletely understood. Emerging evidence indicates that gut dysbiosis, increasingly prevalent with ageing, acts as a systemic amplifier of neuroinflammation, vascular instability, and metabolic dysfunction. Here, we synthesize converging findings linking gut microbial alterations to noradrenergic pathology in the locus coeruleus (LC), one of the earliest brain regions affected in AD. We outline how dysbiosis-associated inflammatory signaling, including endotoxin exposure and impaired vagal-neuroimmune regulation, targets LC circuits. In parallel, disruptions in microbial metabolite pathways involving short-chain fatty acids, bile acids, and tryptophan metabolism further promote oxidative stress, tau phosphorylation, and neurodegeneration. We further argue that sex-dependent differences in immune reactivity, autonomic regulation, and hormonal transitions, particularly peri- and post-menopausal estrogen decline, render female LC neurons uniquely vulnerable to microbial and inflammatory perturbation. We propose a mechanistic framework in which gut dysbiosis destabilizes LC integrity through parallel immune-vascular, metabolite, endocrine, and vagal neural pathways, thereby accelerating cognitive decline and AD progression. Understanding how microbial signaling intersects with sex biology and neuromodulatory circuitry may reveal therapeutic windows for early intervention, including microbiome restoration, neuromodulatory tuning, and sex-specific metabolic targeting.

Background: Peptic ulcer disease (PUD) is a common digestive system disorder and an important risk factor for gastric cancer. While previous studies have extensively focused on using traditional indicators, lifetime risks of PUD remain relatively scarce.

Methods: Using Global Burden of Disease (GBD) 2021 data, we estimated lifetime risks of developing and dying from PUD by lifetable method.Trends were assessed by calculating the average annual percent change (AAPC) from 1990 to 2021. By computing the sex ratios(male to female) of lifetime risks and plotting time-trend graphs, we analyzed the dynamic evolution of sex differences.

Results: In 2021, the global lifetime risk of developing from PUD was 3.21% (95% CI, 3.20%-3.22%), declining from 1990 (AAPC: -1.24; 95% CI, -1.37 to -1.11), with a more pronounced decrease among males (AAPC: -1.43; 95% CI, -1.53 to -1.33) than females (AAPC: -1.00; 95% CI, -1.10 to -0.89). The lifetime risk of dying from PUD was 0.35% (95% CI, 0.34%-0.35%), with a faster decline (AAPC, -2.25; 95% CI, -2.57 to -1.93), again with greater in males (AAPC: -2.73; 95% CI, -2.86 to -2.60) than in females (AAPC: -1.80; 95% CI, -2.00 to -1.60). Marked socioeconomic disparities were observed: high-SDI regions had the highest lifetime risk of developing but the lowest risk of dying, whereas low-SDI regions showed the opposite pattern. Across different SDI regions, the sex ratios of lifetime risk of PUD exhibited unique inflection points over three decades.

Conclusion: Despite substantial global declines in lifetime risks of PUD over the past three decades, our findings reveal persistent inequities by SDI, geography, and sex. These disparities underscore that access to timely diagnosis, eradication therapy, and advanced endoscopic care remains uneven, particularly in low-SDI regions and among females.

Background: Sex differences are evident in anxiety and depression, and women more frequently present with comorbid anxiety and depression alongside gastrointestinal disturbances. This pattern suggests contributions from sex-specific biological mechanisms and gut-brain communication. Negr1, a molecule regulating neuronal growth and connectivity, has been linked to depression-relevant behaviors in animal models. However, its mechanisms and potential sex-specific effects remain unclear.

Methods: Behavioral tests were used to assess phenotypes related to depression, anxiety, and learning in male and female wild-type (WT) and Negr1^-/- mice, and molecular assays were performed to evaluate endoplasmic reticulum (ER) stress and apoptosis in the brain, liver, and colon. Behavioral test data were analyzed using a three-way mixed repeated-measures analysis of variance (RM-ANOVA), and molecular data were analyzed using two-way or three-way ANOVA.

Result: Negr1^-/- mice exhibited sex-dependent phenotypes in both central and peripheral systems. Baseline analyses revealed increased intestinal permeability in Negr1^-/- mice and sex-specific patterns of brain-derived neurotrophic factor (Bdnf) mRNA expression across multiple time points. Behaviorally, Negr1^-/- mice showed increased anxiety-like behavior, decreased social interaction, and impaired spatial learning in the Morris water maze, regardless of sex. Female Negr1^-/- mice displayed impaired fear learning and increased depression-like behavior, while male Negr1^-/- mice exhibited heightened anxiety-like responses. At the molecular level, ER stress marker spliced X-box binding protein 1 (Xbp1s) mRNA was upregulated in peripheral tissues of males but downregulated in females. Apoptosis analysis revealed enhanced caspase-3 activation in peripheral tissues of female Negr1^-/- mice, while males showed no significant changes. Brain tissue showed no significant apoptotic alterations in either sex.

Conclusions: This study demonstrates that, in Negr1^-/- mice, both sexes show general behavioral alterations. However, female Negr1^-/- mice exhibit greater vulnerability to fear learning impairments and depression-like behavior, whereas males Negr1^-/- mice show heightened anxiety responses. These behavioral differences were associated with opposing ER stress responses and differential apoptotic signaling between the sexes in peripheral tissues. Our findings highlight the importance of considering sex as a biological variable in depression research and suggest that Negr1 plays a crucial role in the sex-specific pathophysiology of psychiatric disorders through complex mechanisms spanning central and peripheral systems.

Menopause is an important life-stage transition with substantial implications for health and quality of life. Menopausal hormone therapy (HT) remains among the most effective treatments for menopausal symptoms, yet clinical uptake has varied markedly over time as evidence regarding benefits and risks has evolved. The Organization for the Study of Sex Differences and the Society for Women's Health Research outline our support for the US Food and Drug Administration's (FDA) removal of the "black box" warning on menopausal HT labels. This important shift in federal policy supports evidence-based menopause care and reflects an evolving, evidence-responsive regulatory practice. We further call for consistent, evidence-based FDA review of whether approved product labeling adequately incorporates sex-related differences in pharmacokinetics, pharmacodynamics, and adverse event profiles, with updates to indications, dosing, and warnings where supported by robust data.

Background: Bladder cancer affects men and women differently: men are diagnosed more frequently, but women often present with advanced disease and have worse survival. The biological mechanisms underlying these disparities remain unclear. This study aimed to identify sex-specific molecular features and regulatory interactions that shape tumor biology and outcomes.

Methods: We performed an integrative multi-omics analysis combining bulk messenger RNA and microRNA expression, survival modeling, and single-cell transcriptomic profiling. Data were obtained from The Cancer Genome Atlas, Gene Expression Omnibus, and the Genome Sequence Archive. Differential expression analyses were conducted separately in tumors and in normal samples to compare males and females. Experimentally validated microRNA-mRNA target pairs were tested for correlation, and survival associations were evaluated using Kaplan-Meier and Cox models. Single-cell RNA-seq data were analyzed to assess sex-biased expression across tumor and immune cell populations.

Results: We identified 48 tumor-specific sex-biased microRNAs and 456 tumor-specific sex-biased genes, the majority located on autosomes rather than sex chromosomes. Correlation analysis revealed 82 experimentally supported, negatively correlated microRNA-mRNA pairs, including 63 discordant pairs with opposite sex-biased expression, suggesting sex-specific regulatory interactions. Several of these features were significantly associated with overall survival in a sex-dependent manner. For example, the male-upregulated microRNA miR-1270 showed repression of the female-biased targets CYP26B1 and FAM180A, both of which were associated with poor survival, highlighting potential prognostic and therapeutic relevance. Single-cell analysis revealed widespread sex-biased expression across epithelial, stromal, and immune cells, with female tumors showing stronger signals in stromal and immune compartments, which may contribute to the more aggressive clinical course observed in females.

Conclusions: Our findings indicate that sex disparities in bladder cancer are largely driven by post-transcriptional regulation of autosomal genes, rather than sex chromosome dosage. By linking sex-biased microRNAs, target genes, and patient survival with cell type-specific expression, this study provides new insight into the biological basis of sex differences in bladder cancer. These results underscore the importance of incorporating sex as a critical variable in biomarker development, therapeutic targeting, and clinical trial design.