Background Social behaviour is essential for the survival of most mammalian species and is shaped by sex-dependent genetic and endocrine factors. However, how sex influences brain-wide neural dynamics during social interactions remains poorly understood. Methods Here, we investigated sex differences in neural activity across a distributed amygdalo-striatal network in freely behaving mice. Using chronically implanted electrode arrays, we simultaneously recorded extracellular activity from multiple amygdalo-striatal regions while mice performed four social discrimination tasks. Neural signals...

Background The pronounced sex disparity in osteoarthritis (OA) risk implicates sex hormones, yet single-hormone studies have yielded inconsistent results. We hypothesized that androgen activity influences OA not in isolation but within a dynamic network defined by sex, menopausal status, and estradiol. Methods We analyzed 13,848 adults from NHANES (2013–2016, 2021–2023) using an integrated framework combining complex-survey regression, two-way restricted cubic splines, generalized additive models (GAMs), and SHAP-based machine learning to model non-linear interactions across the...

Background The sarcopenia index (SI), defined as the ratio of serum creatinine to cystatin C, is a proposed biomarker of muscle mass and sarcopenia, yet its genomic basis and genetic architecture remain largely unexplored. Methods We performed combined-sex and sex-stratified genome-wide association studies of SI in the UK Biobank. We examined the overlap between SI-associated loci and loci previously reported for sarcopenia-related traits. We assessed sexually dimorphic effects and gene–sex interactions, performed fine-mapping, and conducted credible gene prioritization, motif and...

Advancements in cancer biology have increasingly highlighted the crucial role of sex in influencing cancer progression and therapeutic outcomes. Nevertheless, current research remains largely focused on overall populations, overlooking the impact of sex. This gap underscores the need for a detailed understanding of how sex differences manifest within the tumor microenvironment (TME). We performed a comprehensive analysis of sex differences by integrating a large-scale single-cell RNA sequencing atlas comprising 1,662 samples from fourteen human cancer types. Systematic profiling of the TME...

Neurogenic hypertension is characterized by sustained sympathetic activation arising from dysregulation within the central autonomic network. The rostral ventrolateral medulla (RVLM) is a major sympathetic premotor region that integrates reflex, neurohumoral, inflammatory, and metabolic signals. Oxidative stress within the RVLM can increase neuronal excitability, enhance glutamatergic transmission, weaken nitric oxide-dependent GABAergic inhibition, and promote sympathetic activation. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are important sources of reactive oxygen...

Apolipoprotein E ε4 genotype (APOE4), the most significant genetic risk factor for late-onset Alzheimer’s disease (AD), is associated with sexually dimorphic effects whereby higher risks are generally observed in women. Sex differences can arise in part from developmental processes of sexual differentiation, which yield permanent sex-specific phenotypes that can impact adult trajectories and vulnerabilities to various conditions. We investigated the potential contributions of sexual differentiation to the female bias of APOE4 in driving AD pathogenesis. Specifically, using the EFAD...

Obesity and type 2 diabetes mellitus (T2DM) are major burdens on global health today. A novel therapeutic approach could involve increasing postprandial glucose utilization through the activation of brown adipose tissue (BAT). The aim of this study was to determine role of brain uroguanylin (UGN) in sex differences in BAT function. BAT activity was assessed by infrared thermography in wild-type C57Bl/6NCrl mice and UGN KO littermates. The volume of BAT was determined by MRI, while markers of browning were analysed by qPCR. The expression of proUGN in mouse and human brain tissue was...

Background Obesity is a prevalent, systemic metabolic disease affecting not only various adipose depots but also the liver, where lipid accumulation results in metabolic dysfunction-associated fatty liver disease, dyslipidemia, and insulin resistance. While estradiol (E2) has been known to be hepatoprotective for glucose and lipid metabolism in females, whether E2’s effects on individual liver cell types are shared between sexes or are sex-specific with obesity remains poorly defined. Methods We performed single-nucleus RNA sequencing on liver tissue of E2-treated obese, gonadectomized male...

Background Sex and gender (S/G) differences in cognitive performance are well documented, yet how they relate to brain organization and interact with educational experience during early adulthood, a period of ongoing cognitive maturation, remains unclear. University training exposes young adults to distinct cognitive and social demands, providing a natural context to test whether brain functional connectivity (FC) mediates S/G cognitive differences in an education-dependent manner. Methods The cohort included students enrolled in declarative fields (formalized, context-independent...

Background Bone formation during skeletal growth and repair is divergently modulated by osteoblast-derived vascular endothelial growth factor (VEGF), which contributes to the sexual dimorphism of the bone vasculature. While the extracellular matrix (ECM) provides structural and instructive cues to developing vasculature, whether the osteoblast-derived matrix contributes to this dimorphism remains unclear. Methods Primary osteoblasts from the long bones of neonatal female and male C57BL/6J mice were cultured under basal or osteogenic conditions for compositional ECM analysis by Raman...

Background One of the major challenges in addressing multiple sclerosis is to understand its progression trajectory. The pathological process transitions from acute phases predominantly driven by inflammation to progressive clinical profiles where neurodegeneration takes precedence. It is known that sex plays a crucial role in this heterogeneity; females are two to three times more likely to suffer from multiple sclerosis, while males suffer from more rapid neurodegeneration with greater severity. Results To gain insight into the sex-based molecular differences, we processed single cell...

Background Epigenetic age acceleration (EAA) is a critical biomarker of aging. Hormone replacement therapy (HRT) is commonly used to alleviate age-related diseases, while glycemic status also influences the aging process. We aimed to investigate the association between estrogen and EAA, and the effects of HRT, EAA, and glycemic status on mortality. Methods Mendelian randomization (MR) established causal relationships between genetically predicted estrogen receptor expression and EAA markers (HorvathAA, HannumAA, PhenoAA, and GrimAA). Using data from the National Health and Nutrition...

Background In the Pacific oyster Crassostrea gigas, triploidization—a well-established technique for generating sterile organisms—provides a promising model to study reproductive dysfunction, as it causes severe and sex-specific impairments in gametogenesis. Specifically, triploid males produce abundant spermatocytes and spermatids but fail to generate mature spermatozoa, while oogenesis in triploid females presents a more complex and heterogeneous picture. The molecular basis for this differential gametogenesis impairment, however, is not fully understood. Methods To investigate the roles...

Background In the landscape of sexual health, sex, gender, and sexuality are inextricably linked and highly relevant to sexually transmitted infections (STIs). Globally, key sexual and reproductive health concerns of women have been associated with the socioeconomic status of their country, indicating that social context bears influence over sexual health outcomes. Further, the increasing prevalence of antimicrobial resistant STIs (AMR-STIs) in the sexual networks of gay and bisexual men-who-have-sex-with-men (GBMSM) suggests an implicit connection between microbiological and social...

Hypoxia research has significantly advanced our understanding of how the human body responds to low-oxygen environments, yet women are still frequently studied without adequate consideration of hormonal status or reproductive life-course stage. This review examines the complex interactions between hormonal status across the female life course and the specific physiological responses of women to acute and chronic hypoxia, focusing on the menstrual cycle, hormonal contraception, pregnancy, menopausal status, hormone replacement therapy, gender-affirming hormone therapy, and reproductive...

Background Cardiovascular diseases remain the leading cause of global mortality, with risk increasing significantly in women post-menopause. Identifying accessible biomarkers for subclinical risk stratification is a clinical priority. The uric acid to HDL-cholesterol ratio (UHR) has emerged as a composite marker reflecting metabolic burden and reduced vascular protection. This study investigates the independent association between UHR and subclinical organ damage, exploring sex-specific differences. Methods We analyzed 1,198 Caucasian subjects. Subclinical cardiovascular damage was...

Background The prevalence, timing and disease course of mental and neurological disorders vary according to sex, yet the neurogenetic mechanisms underlying sex differences in brain disorders remain poorly understood. While sex chromosomes and hormones contribute to sex differences in brain biology, previous studies suggest a role for autosomal genetic variation as well. Methods We investigated autosomal genetic associations with brain volumes in 15,740 females and 15,740 males from the UK Biobank, matched for age and scan site, using sex-stratified genome-wide association analyses. We...

Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major risk factor for atherosclerotic cardiovascular disease (ASCVD). Emerging evidence suggests that the vascular manifestations of MASLD differ substantially between men and women. We therefore hypothesized that the mechanisms, plaque phenotypes, and clinical implications of MASLD-related ASCVD are sex-specific. Methods and results In this narrative review, we searched PubMed/MEDLINE for studies published up to April 2026 and synthesized current evidence regarding sex differences in MASLD-related...

Chronic pain–depression comorbidity is characterized by sensory hypersensitivity and emotional dysregulation, and has been linked to alterations in prefrontal network connectivity. It represents a major therapeutic challenge due to its pronounced sex differences in symptom manifestation and increased treatment resistance. Nitrous oxide (N₂O), an inhalational anesthetic traditionally used for its analgesic properties, has recently emerged as a potential rapid-acting antidepressant, with evidence suggesting both rapid and sustained antidepressant effects. Here, we evaluated the behavioral and...

Background Pregnant individuals may receive antenatal corticosteroids for various conditions, including congenital adrenal hyperplasia (to prevent virilisation in female fetuses) and preterm birth risk (to hasten fetal maturation and improve perinatal survival). This narrative review aimed to evaluate the evidence of sexually-dimorphic offspring outcomes following antenatal corticosteroids for such conditions and explore the potential underlying mechanisms. Methods A comprehensive MEDLINE search identified twenty-eight studies for inclusion: seven focused on congenital adrenal hyperplasia...

Background Sex differences in obstructive sleep apnea (OSA) may extend beyond the apnea–hypopnea index (AHI), the standard measure of OSA severity, and involve differences in sleep architecture and nocturnal oxygenation. We compared these characteristics between women and men across OSA severity categories in a large Chinese clinical cohort. Methods This single-center, hospital-based observational study included adults referred for overnight polysomnography at a sleep center in Fujian, China. OSA severity was classified as mild, moderate, or severe according to AHI. Outcomes included total...

Background Liver metabolism is under tight control of the circadian system. Disruption of key clock gene expression (desynchronosis) leads to the misalignment of metabolic pathways. However, the relationship between circadian dysregulation and hepatic protein-synthetic function, as well as its sexual dimorphism, remains poorly understood. To evaluate the effect of chronic photoperiod disruption on hepatic protein-synthetic function (total protein, albumin) and to establish its relationship with the expression of key circadian proteins (BMAL1, CLOCK, PER2) in male and female rats, as well as...

Background There is a gap in understanding the predominance of males with idiopathic pulmonary fibrosis (IPF). While gonadal hormones contribute to fibrosis susceptibility, evidence suggests a role for sex chromosomes. Methods We used The Four Core Genotypes (FCG) mouse model, which uncouples gonadal sex from sex chromosomes, in aged mice before and after bleomycin (BLM)-induced lung injury. Fibrosis severity was assessed by histology, collagen content, and profibrotic gene expression, along with analysis of estrogen receptor (ER)α and ERβ signaling, matrix metalloproteinase activity,...

Background As algorithm-based decision support tools become increasingly integrated into clinical workflows, particularly with the popularization of artificial intelligence, the conceptualization and operationalization of demographic variables such as sex and gender have implications for how these variables are measured and interpreted. Misalignment between variable labels, response categories, and underlying data sources may introduce measurement error or ambiguity in algorithm inputs, potentially affecting clinical interpretation and downstream decision-making. This concern reflects...

Background Autism spectrum disorder (ASD) is a pervasive neurodevelopmental condition characterized by social communication deficits, exhibiting a male bias in prevalence. Emerging evidence suggests that prenatal exposure to bisphenol A (BPA) may perturb neurodevelopmental trajectories relevant to ASD. While the cerebellum is increasingly recognized as a brain region implicated in ASD pathophysiology, the impact of gestational BPA exposure on its post-transcriptional alternative splicing machinery remains fundamentally undefined. Methods Here, we investigated sex-dependent effects of...

Lipid traits are known to be sex-differential, but the underlying molecular players are largely unknown. Herein, we aim to highlight differential molecular signatures in lipid metabolism between males and females by identifying proteins that are causally linked to lipids in a sex-specific or sex-differentiated manner. Since protein levels are downstream products of gene expression, proteomics data can be crucial to understand etiology of sex-differences in lipids metabolism.We used sex-specific pQTL summary statistics for 2,923 circulating proteins measured in the UK Biobank Pharma...

Background NR5A1 encodes a transcription factor essential for adrenal and gonadal development. Gene variants are a known cause of heterogeneous 46,XY disorders of sex development (DSD), but the mechanisms underlying the phenotypic variability remain unclear. We investigated how different NR5A1 variants affect downstream gene regulation and contribute to DSD pathogenesis. Methods We analyzed four naturally occurring NR5A1 variants identified in patients with 46,XY DSD—two novel (p.Cys65Ser, p.His310Arg) and two previously reported (p.Cys30Ser, p.Gln329*). We performed protein and...

Background Small differences between females and males in cognitive abilities have been consistently reported, but the factors underlying these sex differences remain unclear. Social and cultural factors are thought to play a key role, but studies on this topic have been inconclusive. Examination of genetic factors may shed some light on the mechanisms underlying cognitive sex differences. Methods Using data from the Philadelphia Neurodevelopmental Cohort, a large, general population sample of individuals aged 8 to 21 years old (N = 4,694), we tested for sex differences in the genetic...

Background Early-life stress constitutes a major risk factor for the development of neuropsychiatric and substance use disorders, exerting enduring effects on stress responsivity and emotional behavior. Maternal deprivation (MD) is a well-established model of early adversity that induces persistent neurobiological alterations. During adolescence, alcohol exposure presents an additional challenge that may interact with early-life stress, potentially influencing long-term adaptations in a sex-dependent manner. Among the systems involved, lipid signaling pathways, including the endocannabinoid...

Background CD38, an NADase implicated in aging and metabolic stress, promotes cardiac dysfunction via NAD⁺ depletion. Whether circulating CD38 is associated with incident heart failure (HF), whether this association differs by sex, and how it relates to kidney-function context remain unclear. Methods We measured plasma CD38 in 42,584 UK Biobank participants (1,659 incident HF events) and evaluated its association with HF using sequential Cox models, attenuation analyses, competing-risk models, and incremental prediction metrics. Complementary mouse studies employed chronic β-adrenergic...

In a large Human Connectome Project dataset of 504 females and 452 males performing a 0-back memory task with visual images using the HCP-MultiModalParcellation, faces activated some key cortical regions more (using FDR correction) in females than males, including in the left hemisphere the fusiform face cortex and inferior temporal visual cortex TE2p; and visual motion regions in the MT+ complex. The sight of scenes activated more in males than females scene-related cortical regions including the medial parahippocampal scene (or place) regions such as PHA2 and earlier regions in the...

Male sex is recognized as a risk factor for cerebral palsy (CP), but the magnitude and consistency of this association across gestational ages remain unclear. To quantify sex-specific CP risk across gestational age categories and assess whether male excess risk varies by gestational age or temporal period, we conducted a systematic review and meta-analysis following PRISMA guidelines. Studies reporting sex-specific CP prevalence stratified by gestational age were included. Random-effects meta-analyses were performed stratified by gestational age (< 28 weeks, ≤ 31 weeks, 32–36 weeks, ≥ 37...

Aortic stenosis (AS) presents with distinct sex-related differences in clinical manifestation, pathophysiology, and response to treatment. Women typically present at an older age, with greater frailty, more pronounced symptoms, and paradoxical low-flow AS, often associated with concentric left ventricular remodeling and fibrotic valve changes. In contrast, men show a predominance of calcific AS, eccentric remodeling, and more extensive aortic valve calcification. These differences are not solely anatomical or hemodynamic; they extend to molecular pathways and emerging contributors such as...

Background The amygdala is involved in the emotional expression, memory processing and managing stimulatory input. Although amygdala atrophy is early evidenced in Alzheimer’s Disease (AD), the molecular mechanisms disrupted in initial neuropathological stages are still unknown. In the present study, we investigated the proteomic impairment of the amygdaloid region from AD-Braak stage I-II and III-IV subjects to better understand the neuropathological processes occurred early in this area and to identify potential targets that may face AD from the beginning of the disease. Methods Label-free...

Consistent with differences in behaviors between sexes, studies reveal sex differences in the organization of neural circuits, synaptic function, and neuronal excitability, as well as sex-dependent recruitment of specific neuronal subtypes during behavior. These studies demonstrate sex differences in cell numbers, brain region volumes, cellular composition of brain areas, and density and strength of synapses in many brain regions, innervation of neuronal subtypes, receptor-mediated transduction mechanisms, neurotransmitter and neuropeptide release, and the influence of neuronal growth...

Background Adolescence is a critical developmental period characterized by increased vulnerability to social stress, closely associated with the emergence of long-term neurobiological alterations. The present study aimed to investigate the short- and long-term effects of social stress during adolescence in mice, using the classical social defeat (SD) model in males and the vicarious social defeat (VSD) model in females, and examining the role of the kynurenine (KYN) pathway in resilience and susceptibility phenotypes. Methods A total of 264 OF1 mice were exposed to SD or VSD between PND 26...

Background Pregnancy zone protein (PZP) is a highly glycosylated macromolecular protein involved in energy metabolism, fibrinolysis, and immunomodulation. However, its association with acute coronary syndrome (ACS), particularly regarding sex differences, remains to be fully elucidated. Methods ACS patients were enrolled from the Department of Cardiology, and control subjects were recruited from the Health Examination Department. Plasma levels of PZP were quantified using a sandwich enzyme-linked immunosorbent assay (ELISA). Spearman’s correlation was used to analyze the association between...

Background Glioblastoma or GBM (IDH wild-type) is an aggressive brain tumor that is notoriously resistant to treatment, with an average survival time of 17 months. While the overall outcome is poor for both males and females, sex differences in GBM incidence and outcome suggest sex-specific biological mechanisms underlie tumorigenesis. In contrast, low-grade glioma (LGG) is a less aggressive brain tumor that tends to have a better prognosis and a longer survival time. Methods To understand mechanisms contributing to treatment resistance in GBM in both males and females, we inferred gene...

Background Sex differences in aortic dissection (AD) have been consistently reported in epidemiological studies and experimental mouse models, with males showing markedly higher susceptibility. However, the molecular basis underlying these sex-specific differences remains insufficiently understood. Methods Three-week-old male and female C57BL/6J mice were administered 0.4% β-aminopropionitrile (BAPN) in drinking water for 28 d to induce AD. After the induction period, fecal samples, serum, and aortic tissues were collected from all surviving animals. Integrated analyses included...

Background & Aims The influence of sex hormones on chronic liver disease (CLD) progression remains unclear, despite sex-related differences in disease susceptibility and outcomes. This study aimed to investigate the associations of total testosterone (TT) and sex hormone-binding globulin (SHBG) levels with CLD-related outcomes across sex and menopausal status. Methods A retrospective cohort study was conducted using UK Biobank data. Serum TT and SHBG levels were measured at baseline. Participants were followed for incident liver fibrosis and cirrhosis, hepatocellular carcinoma (HCC), and...