Major depressive disorder (MDD) is associated with metabolic disturbances (elevated TyG index), peripheral inflammation (IL-6, TNF-α, CRP), and cognitive deficits. Serum NPY levels vary by sex and reproductive aging, influencing appetite changes in MDD. However, the interplay between NPY, metabolic dysfunction, inflammation, and cognition stratified by sex and menopausal status remains unexplored. This study investigated whether NPY mediates the TyG index–cognitive impairment relationship, moderated by inflammation and sex/reproductive status. In a cross-sectional study (February 2021–September 2024), 300 MDD patients (100 males, 100 premenopausal females, 100 postmenopausal females) and 150 age- and BMI-matched healthy controls were recruited. Assessments included TyG index, serum NPY (ELISA), inflammatory markers, MoCA, VAS appetite, and HAMD-17. Analysis used Pearson correlations, multiple linear regression, moderated mediation (PROCESS Model 58), and ROC curves for a combined biomarker panel (TyG + NPY + IL-6 + TNF-α). MDD patients showed higher TyG, NPY (especially premenopausal females), inflammation, and lower MoCA scores than controls (all P < 0.001). NPY positively correlated with TyG and VAS appetite (r = 0.43–0.52, P < 0.001) and negatively with MoCA (r = − 0.35 to − 0.46, P < 0.001), strongest in premenopausal females. Inflammation partially mediated NPY–MoCA (indirect effect = − 0.046, 95
As there has been increased focus on sex differences in neuroscience research, perineuronal nets have come forward as a possible piece in the sex difference puzzle. There are sex differences in neurodevelopmental disorders such as autism spectrum disorder (ASD) as well as sex differences in perineuronal net development. Day to day changes in perineuronal net density in the developing hippocampus may be relevant to further understanding a relationship between neurodevelopmental disorders and perineuronal nets. In this study we aimed to determine a timeline of perineuronal net onset in juvenile Sprague Dawley rats aged postnatal day (p) p14, p16, p18, and p22 in the subiculum and regions cornu-ammonis − 1 (CA1), CA2, CA3 and the dentate gyrus (DG) of the hippocampus, and whether that timeline differed between males and females. Animals were perfused at the given ages and the tissue was processed for immunofluorescence staining of perineuronal nets and parvalbumin interneurons. We found males to generally have fewer perineuronal nets than did females across subregions of the hippocampus; but importantly, we also found that males and females demonstrated different patterns of perineuronal net development over the time course investigated, with females showing a decrease in PNN count at p16 before rebounding, and males showing a steep decrease in perineuronal net count two days later at p18 before rebounding. These data suggest that perineuronal net development is not a steady linear increase over time, but rather a process that fluctuates according to sex and developmental stage. This may translate to the development of developmental disorders that also show a sex difference such as ASD, and suggest windows of both increased and decreased vulnerability to neurons and neuronal circuitry during early neurodevelopment specific to sex. There are extracellular matrix structures in various regions of the brain that surround the cell body and proximal projections of certain types of interneurons, and these structures are called perineuronal nets, or PNNs. These PNNs are thought to be involved in the regulation of excitation and inhibition and plasticity in the brain; processes that, when altered, are also associated with the development of neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). As ASD is more prevalent in biologically male children and adults, we investigated and compared the very early development of PNNs in male and female rat brains. We found that females overall have a greater number of PNNs in a region of the brain called the hippocampus. We also demonstrated that the numbers of PNNs did not increase in a linear fashion across development, but rather in a consistent pattern wherein PNN numbers dropped and then rose throughout the age window we investigated. Females showed an earlier pattern of decline and recovery with males following the same pattern, though delayed by a few days when compared with females. We believe this indicates an increased vulnerability to insults in the developing brain at different time points dependent on sex. - Perineuronal nets are usually studied in adolescent and adult rats, and there is very little research on the typical development of perineuronal nets and parvalbumin interneurons during earlier developmental timepoints. - Male and female rats show the same general pattern of perineuronal net development between p14 and p22 though differ in the timing. - Female rats appear to have an accelerated development of perineuronal nets and parvalbumin interneurons when compared with males.
Imprinted genes are expressed from one parental allele as a result of epigenetic events initiated in the male and female germlines. We previously identified a role for imprinted genes as master regulators of placental endocrine lineage development in mice. We further reported that loss-of-function of the paternally expressed imprinted gene Peg3 resulted in sexually dimorphic placental and behavioural phenotypes, with the male being relatively more impacted in both cases. Here, we asked whether loss-of-imprinting of the maternally expressed imprinted gene Phlda2 similarly had a sexually dimorphic impact on placental endocrine lineages, potentially underlying male-biased behavioural outcomes that arise when this gene is abnormally expressed. C57BL/6 wildtype (WT) female mice were mated with Phlda2BACx1 transgenic studs to generate WT control and loss-of-imprinting model samples overexpressing Phlda2. Placental and fetal weight, placental endocrine lineages and hormone gene expression were characterised at embryonic day (E) 14.5, together with fetal and placenta weight data at E18.5. RNAscope-aided identification of the placental endocrine lineages revealed a significant loss of spongiotrophoblast cells from the junctional zone, with a substantially greater impact on female mutant placenta compared to male. Glycogen cell and parietal trophoblast giant cell number was also diminished but without detectable sexual dimorphism. Reverse-transcription quantitative PCR (RT-qPCR) and RNA sequence analysis supported a female-biased reduction in the expression of placental hormones expressed by the spongiotrophoblast in response to Phlda2 “loss-of-imprinting”. Placental changes were associated with reduced fetal growth in females but not in males late in gestation. Phlda2 expression is known to increase in response to maternal adversity, including nutritional deficiencies, thereby reducing placental “demand” signalling by limiting hormone production. Our new findings identify a striking biological asymmetry whereby female fetuses reduce their demands on the mother in response to Phlda2 loss-of-imprinting, whereas male fetuses do not. Such asymmetries may be linked to sex-specific reproductive strategies in mammals in response to prenatal adversity. Our findings also have implications for human pregnancy research. Elevated placental PHLDA2 has repeatedly been linked to fetal growth restriction and low birthweight but without consideration of the sex of the infant. Our findings that this imprinted gene can exert sex-specific effects on fetal growth may therefore be of translational importance. During pregnancy, the placenta produces hormones that signal to the mother to secure nutrients and prime her for her role as a caregiver. Some of the genes that control how the placenta works are imprinted - meaning that only the copy from the mother or the father is active. Previously we have shown in mice that increased expression of the normally maternally expressed Phlda2 gene, modelling loss-of-imprinting, results in placenta that produce lower levels of hormones resulting in fetal growth restriction and mothers that neglect their offspring. In this study, we compared males and females. We found that that this genetic modification resulted in far fewer hormone-producing cells and much lower expression of hormone-related genes in female mutant placenta compared to male. Critically, female fetuses were growth restricted while male fetal growth was preserved. Phlda2 is known to be a gene which responds to adverse pregnancy conditions. This suggest that female fetuses reduce their demands on the mother during times of adversity. Male fetuses, however, maintain their growth demands even under adverse conditions. This supports the idea that sex-of-offspring effects on maternal resource allocation in pregnancy are mediated by imprinted genes which respond to different environmental conditions with greater benefits to male or female offspring depending on parent-of-origin status of the gene. Of clinical relevance, in human pregnancies, higher levels of placental PHLDA2 have repeatedly been linked to babies being born smaller. Our results further highlight the importance of considering fetal sex when studying pregnancy complications driven by imprinted genes. Loss-of-imprinting of Phlda2 (two-fold expression) causes a more severe loss of endocrine cells in female murine placenta Mutant female placenta express significantly lower levels of key placental hormones Despite carrying the same genetic modification, mutant female fetuses are growth restricted late in gestation, but male fetal weight is preserved. Sex differences in the placental function of Phlda2 support a mechanism whereby females reduce demands on mothers in response to prenatal adversity, but their male siblings do not. Imprinted gene can exert sex-specific effects on fetal growth with potential translational impact
While sex differences in behaviour have attracted considerable scientific interest, their underlying causes are complex and remain poorly understood. One approach to understand whether early biological factors might play a partial role is to study newborns, who have limited postnatal experiences. Previous research on neonatal sex differences is extremely limited, and studies that do exist have yielded mixed results, raised methodological concerns, and are yet to be replicated. To assess these gaps, the present study aimed to reevaluate sex differences in neonatal attention. 130 neonates (67 males, 63 females; mean age = 33 h) were presented with a video of a human face and a non-social object. When analysing percentage looking times, on average, females allocated a greater percentage of time looking at the face relative to males (d = 0.40). When analysing absolute looking times, females showed a preference for the face compared to the non-social object, while males showed no preference for either. However, no differences were observed between males’ and females’ absolute looking times for the face or object, indicating that sex differences are most prominent in the relative allocation of attention. Since sex differences in relative attentional patterns are present from the earliest days of life, one possible explanation for this effect may be due to contributions from prenatal factors (e.g., sex hormones). However, alternative explanations may be that these differences reflect general maturational differences between males and females or arise from low-level visual properties of the stimuli rather than their social versus non-social content. Research on neonatal sex differences remains limited and inconsistent, making it challenging to identify the factors that drive behavioural sex differences. The present study found that female newborns spent a greater percentage of time looking at a face relative to a non-social object compared to male newborns. Since these differences are present soon after birth, one possible explanation is that prenatal factors (e.g., sex hormone levels) may contribute to sex differences in behaviour, though alternative explanations remain possible. The findings may help to understand why several psychiatric and neurodevelopmental conditions, such as autism, show sex differences in prevalence. Previous research suggests that males and females show psychological and behavioural on-average differences, though there remains debate regarding whether these differences emerge purely due to environmental factors (e.g., gender socialisation) or whether biological factors might also play a partial role. Studying newborn babies may help to address this question, since they have limited exposure to the environment. In this study, 130 newborn babies, who were on average 33 hours old, were shown a video of a human face alongside a video of a non-social object. Female newborns spent a greater proportion of their time looking at the face than male newborns, suggesting that sex differences in attention may be present from the first days of life. One possible explanation is that factors acting before birth, such as prenatal sex hormones, may contribute to these differences. However, other explanations are also possible, including differences in developmental maturity between male and female newborns or differences in the visual characteristics of the videos used.
To examine the effect of biological sex on mortality, inflammation, organ dysfunction, and bacterial burden in preclinical sepsis models. MEDLINE and Embase from January 1, 2011, to May 13, 2025. We included in vivo animal models of experimentally- induced sepsis with or without intervention that reported sex-stratified data. We excluded non-infectious models and interventions hypothesized to worsen sepsis outcomes. We performed full-text screening and data extraction on mortality (primary outcome), inflammation, organ dysfunction, and bacterial burden. We applied a novel three-level analytic framework to determine: (1) baseline sepsis effect (female versus male differences), (2) unadjusted treatment effect (post-treatment risk differences), and (3) adjusted treatment effect (post-treatment risk differences accounting for baseline sepsis differences). Using random-effects models, we pooled outcomes as risk differences (RDs) or difference of standardized mean differences with differences > 0 indicating worse outcomes in males. We screened 7,896 citations; 94 studies met eligibility criteria, and 83 studies were analyzed quantitatively. Cecal ligation and puncture (CLP) was the most common model (46
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 species in this region. Direct anatomical evidence is the strongest for components of the NADPH oxidase 2 (NOX2) complex, whereas the cellular distribution and functional roles of Nox1, Nox4, and other isoforms remain less clearly defined. Current evidence more strongly supports RVLM Nox-related oxidative stress as a mechanism that amplifies and maintains established hypertension than as an independent initiator of chronic hypertension. Sex and ovarian hormone status modulate these redox and autonomic mechanisms. Estrogen signaling can influence neuronal excitability, inflammation, and oxidative balance, but its effects depend on receptor subtype, endocrine state, exposure pattern, age, and hypertensive background. Estradiol replacement after ovarian hormone loss may reduce RVLM oxidative stress, whereas prolonged exposure in intact cycling animals may increase superoxide production and Nox-related gene expression. Human studies also associate menopause with altered blood pressure, arterial stiffness, sympathetic activity, and baroreflex regulation, although direct evidence for estrogen receptor and Nox signaling within the human RVLM remains lacking. This review summarizes current evidence and highlights priorities for mechanistic and translational research.
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 transgenic mouse model of AD that includes knock-in of human APOE3 or APOE4, we examined the effects of experimental masculinization in perinatal female mice on adult patterns of AD-related pathology relative to control male and female mice. Both female sex and APOE4 genotype were associated with increased levels of β-amyloid pathologies. Masculinization resulted in expected systemic and neural phenotypes in adult animals. The effects of masculinization differed depending upon both outcome measure and APOE genotype. Intermediate phenotypes were the most common response to masculinization, though select aspects of AD-related endpoints, including the numbers of mature amyloid plaques, were reduced by masculinization of APOE4 female mice. These findings suggest that sexual differentiation in early life has modest effects on adult development of AD in females, a relationship that appeared stronger in the context of APOE4. The results complement prior work establishing roles of sex chromosomes and age-related depletion of sex hormones in the sexual dimorphisms characteristic of AD and provide new insights into the organizational actions of sex hormones and how these interact with APOE genotype. Vulnerability to Alzheimer’s disease (AD) is affected by several risk factors. Women show higher prevalence and lifetime risks of AD than men. The most significant genetic risk factor for late-onset AD is APOE4, a normal genetic variation that is present in 25
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 determined by ELISA. In the human brain, decreased proUGN expression in subjects with obesity was observed only in the male hypothalamus, BA10, and BA11. The effects of centrally applied UGN depend not only on sex, but also on the phase of the estrous cycle. Sex differences in the postprandial regulation of BAT activity in mice may be caused by differential postprandial regulation of hypothalamic proUGN expression, which was observed only in male mice. In young male mice, intranasal administration of a GLP-1 analogue, as possible regulator of UGN expression in the brain, increased BAT activity and decreased hypothalamic proUGN expression only in males. Although chronic UGN administration also increased postprandial BAT activation in both sexes, increased BAT volume was observed only in male mice. Due to the different physiological and pathophysiological functions of BAT and its activators, the introduction of brain BAT activators as a therapy for obesity and T2DM must take sex into account. Obesity and type 2 diabetes are major health problems. A new way to treat them is by activating “brown fat” (a type of fat that burns energy to create heat) to improve blood sugar control after meals. Specifically, researchers studied how a brain hormone called uroguanylin (UGN) affects brown fat, and how this process differs between men and women. In human brains, source of UGN (proUGN) is decreased only in men with obesity, which was not observed in female brains. In mice, activating brown fat after eating depended on the sex. The mechanism that links eating to brown fat activation via UGN was shown only in male mice. While chronic UGN treatment helped both sexes, only in males there was an increase in the total amount of brown fat. When GLP-1 analogue was applied in the brain, it increased brown fat activity in both male and female mice, but affected brain UGN levels only in male mice suggesting completely different mechanism of GLP-1 function in the brain. Targeting brain-activated brown fat to fight obesity and diabetes may work differently in men and women. Future therapies need to take sex differences into account to be effective. Expression of the BAT-regulating hormone UGN in the mouse and human brain is sex-dependent. Regulation of BAT activity by UGN depends on sex and the phase of the estrous cycle. The role of brain UGN in obesity differs between the male and female human brain.
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. We performed single-nucleus RNA sequencing on liver tissue of E2-treated obese, gonadectomized male (XY) and female (XX) mice with diet-induced obesity to evaluate the sex-concordant and discordant effects of chronic E2 treatment. Differential gene expression, pathway analysis, intracellular and intercellular regulatory network modeling, and human metabolic disease/trait association analysis were conducted. E2-induced transcriptional effects among hepatocyte subtypes were largely sex-concordant in both males and females, along with sex-specific E2 changes. In pericentral hepatocytes, E2 concordantly reduced the expression of genes involved in insulin resistance, FOXO signaling, and lipid biosynthesis; in periportal hepatocytes, E2 treatment enhanced cholesterol efflux genes and suppressed oxidative stress response genes. XY-specific effects of E2 included additional suppression of lipid and energy metabolic pathways in pericentral hepatocytes and oxidative phosphorylation in periportal hepatocytes, while in XX mice E2 showed unique regulation of glucose and lipid utilization programs. Network analysis revealed that E2-responsive genes in hepatocyte subtypes in both sexes showed enriched transcription factors associated with estrogen receptor signaling and lipid sensing and metabolism, alongside sex-specific regulators. Intercellular signaling affected by E2 showed more changes in XY mice than in XX mice across hepatocyte subtypes. Lastly, while E2-responsive genes in hepatocyte subtypes of both sexes were enriched for human genetic signals associated with lipid profiles and coronary artery disease, we also identified sex-specific associations, such as the link of E2-downregulated genes in XY hepatocytes to body mass index in men. Our findings revealed that chronic E2 administration remodels gene regulatory programs in individual liver cell types through both shared and sex-specific mechanisms, highlighting the importance of considering sex chromosome-dependent E2 responses when developing therapeutic strategies for obesity and associated hepatic metabolic dysfunction. Obesity is a growing global health concern that has negative impacts on a broad spectrum of organs, including the liver. Estradiol (E2) is a sex hormone that generally plays a protective role in both sexes against liver dysfunctions. However, whether and how E2 effects differ between sexes and across various liver cell types remains understudied. Here, we compared and contrasted how liver cells responded to chronic E2 treatment between obese female and male mice. We found that hepatocytes, the major liver cell type, generally responded to E2 in similar ways in both sexes. In hepatocytes located near the liver’s central vein, E2 dampened shared pathways related to insulin resistance and lipid synthesis in both sexes, while additionally suppressing lipid and energy metabolic processes in males only. In hepatocytes near the portal triad, where oxygenated and nutrient-rich blood arrives, E2 enhanced cholesterol processing and reduced oxidative stress response in both sexes. E2 also induced more cell–cell communication changes in male mice than in female mice across hepatocyte subtypes. Lastly, E2-responsive genes in hepatocyte subtypes of both sexes were largely associated with lipid profiles and heart disease, with additional sex-specific obesity and diabetes associations also observed. Single-nucleus RNA sequencing revealed sex-concordant and discordant genes and pathways in hepatic cell types of obese gonadectomized mice, with hepatocyte subtypes showing greater concordance between sexes. Shared E2 effects include dampened insulin resistance, FOXO signaling, and lipid biosynthesis in pericentral hepatocytes, along with enhanced cholesterol efflux and suppressed oxidative stress response in periportal hepatocytes. Sex-discordant effects were also observed: in XY mice, lipid and energy metabolic pathways were additionally suppressed in pericentral and periportal hepatocytes, while in XX mice, unique regulation of glucose and lipid utilization programs was observed. Cell–cell communication analysis revealed more E2-induced signaling changes in XY mice than in XX mice across hepatocyte subtypes. E2-responsive genes in hepatocytes of both sexes were enriched for human genetic signals associated with lipid profiles and heart diseases, while cell type- and sex-specific associations with obesity and diabetes were also observed.
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. The cohort included students enrolled in declarative fields (formalized, context-independent knowledge, e.g., STEM, law, business administration, philosophy) or situated fields (knowledge embedded in social practice, e.g., psychology, education, medicine). Individual FC networks were derived using the GINNA atlas; edges significantly differing between S/G groups were identified and aggregated into sex-differential nodal FC indices (sdNFIs). Moderated mediation models tested whether academic training fields shape the contribution of these sdNFIs to S/G differences in cognitive performance. Additional exploratory analyses tested whether effects varied across academic stages by including study level as a second moderator. Baseline S/G differences in cognitive performance and sdNFIs were preserved across academic training. Yet sdNFI-mediated pathways linking S/G to cognitive performance varied strongly by knowledge domain. In declarative fields, sdNFIs spanning parietal and medial temporal networks supported male advantages in visuospatial and arithmetic tasks. In situated fields, sdNFIs spanning medial prefrontal and temporo-parietal networks supported female advantages in socio-emotional and verbal tasks. Study-level analyses revealed distinct profiles of sdNFI mediation across tasks. sdNFI-mediated effects were observed primarily at later academic stages (Y2 +) for arithmetic fact retrieval, mental rotation, and emotion recognition, whereas they were present at Y1 but absent at later stages for verbal list learning. These findings demonstrate that academic training selectively shapes FC-cognition relationships in a S/G-specific manner, with declarative and situated knowledge domains recruiting distinct, context-sensitive networks to support performance. By guiding the recruitment of functional networks to meet specific cognitive demands, higher education may constitute a formative period during which the brain architecture supporting S/G cognitive differences is dynamically reorganized. Plain English summary Men and women often differ in certain cognitive skills: women tend to perform better in tasks involving language and recognizing emotions, while men tend to show advantages in spatial reasoning and arithmetic. These differences are well established, but their origins, biological, environmental, or both, remain debated. In this study, we asked whether the type of university education a person follows influences how the brain supports these cognitive differences. We compared students enrolled in fields centered on formal knowledge, such as STEM, law, or philosophy, with students in fields where learning is deeply embedded in human interaction and social practice, such as psychology, education, or medicine. We found that men and women showed similar cognitive differences regardless of their field of study. However, the brain pathways supporting these differences varied depending on the type of training. In formal knowledge fields, brain connections in spatial and memory-related regions supported male advantages in arithmetic and visuospatial tasks. In socially oriented fields, brain connections in regions involved in language and social processing supported female advantages in verbal memory and emotion recognition. Examining these relationships across academic stages revealed different patterns: some brain-performance associations emerged with university training, whereas others faded after the first year, highlighting how flexibly the brain adapts to educational experience. These findings suggest that higher education does not eliminate cognitive differences between men and women, but shapes how these differences are reflected in the brain. Understanding how education interacts with brain development may help design learning environments that better support all students.
The incidence and clinical manifestations of major depressive disorder (MDD) differ between sexes. This implies distinct neuropathological mechanisms. This study aimed to investigate sex-specific brain patterns in MDD by stratifying patients according to both sex and disease course. We recruited 1170 participants (811 MDD patients and 359 healthy controls) who underwent T1-weighted and resting-state functional magnetic resonance imaging. We explored duration-stage-related, sex-specific differences in gray matter (GM), amplitude of low-frequency fluctuation (ALFF), and structural-functional coupling. We also used the structural covariance network (SCN) to assess morphological connectivity reorganization. Finally, we explored the relationship between key brain measures derived from the preceding multimodal analyses and clinical features. GM abnormalities in both sexes were observed first appeared in areas supporting sensorimotor and interoceptive functions, and later extended to areas involved in cognitive and emotional processing. Critically, we found distinct sex-specific epicentres of pathology. In male patients, the right postcentral gyrus (PoCG) exhibited early GM atrophy and decreased betweenness centrality within the SCN. In female patients, the left inferior temporal gyrus (ITG) showed early GM atrophy, increased degree centrality within the SCN, reduced ALFF values, and a two-stage evolution of structural-functional coupling with a transition lasting 3 years. Clinically, GM volumes of the right PoCG in male patients were negatively associated with insomnia-early, genital symptoms, and weight loss, while in female patients, GM volumes of the left ITG were negatively associated with depressed mood, work and interest, and psychic anxiety. This study shows a sex-specific neuropathological origin in MDD, with the left ITG serving as the core pathological area in females and the right PoCG in males. These conclusions not only advance our insight into the sex-dependent mechanisms underlying MDD but also provide a stage-informed framework for individualized interventions, suggesting that the early years of the disease may be a critical period for structure-targeted therapies. Sex-specific hub pathological regions identified: left ITG in females, right PoCG in males. Atrophy begins in sensorimotor areas and later extends to cognitive regions, following sex-divergent trajectories. The female left ITG uniquely shows atrophy, increased centrality, reduced ALFF, and a pattern of structural-functional over-coupling. Male PoCG atrophy correlates with insomnia and somatic symptoms; female ITG atrophy correlates with mood, interest, and anxiety symptoms.
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. 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 spectroscopy. Primary murine bone marrow-derived endothelial cells (BMECs) were seeded onto established osteoblast layers and maintained in heterotypic cocultures to assess contact-mediated effects of osteoblast ECM on BMEC survival and expansion. Osteoblast-derived conditioned media (CM) were used to evaluate soluble-factor contributions, with VEGF-A concentration quantified by ELISA. Raman spectroscopy of monocultured osteoblasts revealed sexually dimorphic ECM signatures independent of cellular growth profiles. Female matrices were enriched with type I collagen-associated proline and hydroxyproline and octacalcium phosphate, consistent with a matrix-dominant signature. Male matrices exhibited lower levels of collagen-associated components and instead adopted a more mineral-mature profile, reflected by CAP accumulation and an elevated mineral/matrix ratio. In heterotypic cocultures, BMEC numbers were 1.39-fold higher with male than female osteoblasts. CM treatment of BMECs did not recapitulate these effects despite higher VEGF-A release from male osteoblasts. Sex differences in osteoblast-derived ECM are linked to divergent, contact-dependent modulation of BMEC behaviour. These findings indicate that intrinsic sex differences in osteoblast matrix maturation may contribute to sex-specific regulation of the skeletal vascular niche. Defining how osteoblast-derived ECM regulates skeletal vascularisation may reveal targets for selectively modulating pathological skeletal angiogenesis in women and men. Bone is a sexually dimorphic organ, with women and men differing in bone size, strength and risk of fracture. The skeletal vasculature is essential for bone growth and repair, with bone forming osteoblast cells influencing blood vessel development through the skeletal extracellular matrix (ECM). Although the interactions between osteoblast and vascular cells are crucial for lifelong skeletal health, whether sex differences in bone structure between women and men arise from differences in osteoblast activity or sex differences in blood vessel growth remains unknown. Here, we show that female and male mouse osteoblasts deposit compositionally distinct ECMs that differentially influence vascular endothelial cell behaviour. Female osteoblasts produce a collagen-rich matrix with low mineral content. In contrast, male osteoblasts produce matrices containing less collagen and more mineral, while releasing elevated levels of the blood vessel-promoting factor, VEGF-A, compared with female osteoblasts. When placed directly onto these osteoblast layers, vascular cell growth was greater in cocultures with male than female osteoblasts and could not be reproduced by exposure to osteoblast-derived soluble factors alone. These findings identify a contact-dependent relationship through which sex differences in osteoblast ECM composition influence vascular cell behaviour in bone. Understanding how osteoblast-vascular interactions differ by sex may explain the variability in bone health, healing capacity and disease risk between women and men. Further, our approach may inform the discovery of new therapeutic targets that support bone growth and repair while targeting abnormal blood vessel growth in a sex-specific manner. Primary osteoblasts from female and male C57BL/6J mouse long bones synthesise compositionally distinct ECMs. ECM produced by female osteoblasts contains raised type I collagen-associated components and OCP, whereas the male osteoblast ECM comprises relatively lower levels of type I collagen-associated species and CAP accumulation. BMEC growth is markedly enhanced in heterotypic direct-contact cocultures with male than female osteoblasts. Male osteoblasts release higher levels of the pro-angiogenic factor, VEGF-A, than female osteoblasts. The sex-specific effects of the osteoblast ECM on BMECs are contact-dependent and are not reproduced by treatment with osteoblast-derived CM.
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. 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 Examination Survey, we employed Cox proportional hazards models to analyze the association between HRT and mortality, exploring whether it was modified by EAA and glycemic status. Elevated estrogen receptor α (ESR1) expression significantly decelerated PhenoAA (β -1.26; 95
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. To gain insight into the sex-based molecular differences, we processed single cell datasets from the central nervous system and the peripheral blood, covering the different courses of multiple sclerosis. We generated cell-type specific landscapes, including gene signatures from differentially expressed genes, functional profiling, pathway activation, and cell-cell communication networks for females, males, and their sex differential profiles. Among our findings, we revealed that female neurons may exhibit protective mechanisms against neurodegeneration. In the inflammatory-predominant forms, female immune cells present an inflammatory core driven by the AP-1 transcription factor, while male adaptive immune cells exhibit higher mitochondrial impairment. Conversely, larger differences are reported in CD8 + T cells progressive forms, with males exhibiting cytolytic profiles that may promote neurodegeneration. Complete results can be explored in the interactive webtool https://irsoler.shinyapps.io/cbl-atlas-ms/. We identified cell-type specific sex differences in brain and immune cells that vary in the spectrum of multiple sclerosis. We consider this molecular description a valuable resource to promote future targeted approaches considering the sex of the individual.
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. To investigate the roles of circRNA and ceRNA networks in the sex-specific gametogenesis impairment of triploid oysters, gonadal circRNAs were identified and their expression was profiled from whole transcriptome data of diploid and triploid oysters. Differentially expressed circRNAs were then subjected to functional enrichment analysis. Competitive endogenous RNA (ceRNA) networks were constructed from the interactions of differentially expressed RNAs. Key candidate genes implicated in gametogenesis impairment were then identified and characterized through integrated bulk and single-nucleus RNA-seq analyses. Differential expression analysis revealed substantial alterations in circRNAs expression between diploid and triploid gonads. Functional enrichment of circRNA source genes implicated global metabolic and cell proliferation pathways associated with oogenesis impairment, while it implicated lipid/steroid metabolism, cell proliferation, and apoptosis pathways associated with spermatogenesis disruption in triploid oysters. Sex-specific ceRNA networks were constructed for oogenesis and spermatogenesis, revealing extensive regulatory rewiring in triploid gonads. Analysis of bulk and single-nucleus RNA-seq data identified key candidate genes within these ceRNA networks. Specifically, upregulation of FoxG1, Sox11, Cyp2J6, and Tra2A in somatic cells, combined with downregulation of Uhrf1, Ccna2, Sox2, and Bre1 in germ cells, was implicated in oogenesis impairment of triploids. Similarly, the ceRNA-mediated suppression of Iqch, Ccdc173, Srebp1, and Gtpbp2 was linked to disrupted spermatogenesis. These findings highlight that circRNA-mediated ceRNA dysregulation is potentially associated with gametogenesis impairment in triploid oysters, and offer novel insights into post-transcriptional regulatory mechanisms underlying molluscan reproduction. Owing to their sterile and fast-growing nature, triploid oysters are now a staple of global oyster aquaculture. This impaired reproductive function provides an important model to study reproductive dysfunction. However, the potential mechanisms regulating the differential impairment of gametogenesis in female versus male triploid oysters are not fully understood. This study identified circRNAs and profiled their expression using whole transcriptome data of diploid and triploid oyster gonads. Many differentially expressed circRNAs were identified between diploid and triploid gonads. In females, functional enrichment analysis of differentially expressed circRNA source genes revealed the involvement of global metabolic and cell proliferation pathways in oogenesis impairment in triploid oysters. In males, the analysis revealed the association of lipid/steroid metabolism, cell proliferation, and apoptosis pathways with spermatogenesis disruption. The research constructed sex-specific competitive endogenous RNA (ceRNA) networks. Significant perturbations in the regulatory landscape of triploid gonads were found, which is potentially associated with impairment of gametogenesis. This study further identified key candidate genes within ceRNA networks by using gonadal bulk and single-nucleus RNA-seq data. Detailly, the expression of FoxG1, Sox11, Cyp2J6, and Tra2A increased in somatic cells, while expression of Uhrf1, Ccna2, Sox2, and Bre1 decreased in germ cells. These expression alterations potentially lead to oogenesis impairment of triploids. Meanwhile, the expression of Iqch, Ccdc173, Srebp1, and Gtpbp2 was suppressed via ceRNA mechanism, which likely contribute to spermatogenesis disruption. Importantly, these genes are highly conserved across species, from humans to oysters, thereby providing new insight with potential implications for understanding reproductive dysfunction broadly. Oogenesis impairment was associated with circRNA-mediated alteration of global metabolic and cell proliferation pathways. Spermatogenesis disruption was linked to circRNA-mediated dysregulation of lipid/steroid metabolism, cell proliferation, and apoptosis pathways. The ceRNA networks implicated in sex-specific gametogenesis impairment of triploid oysters were established. The ceRNA-mediated upregulation of somatic cells-expressed genes (FoxG1, Sox11, Cyp2J6, Tra2A, et al.), and downregulation of germ cells-expressed genes (Uhrf1, Ccna2, Sox2, Bre1, et al.) potentially triggered impaired oogenesis. Suppression of Iqch, Ccdc173, Srebp1, Gtpbp2, et al. by ceRNA mechanism likely result in disrupted spermatogenesis.
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. We analyzed 1,198 Caucasian subjects. Subclinical cardiovascular damage was evaluated via carotid intima-media thickness (c-IMT) and left ventricular mass index (LVMI). Multivariate linear regression and formal interaction analyses were employed to assess the independent association of UHR with organ damage, adjusting for traditional cardiometabolic risk factors. UHR correlated significantly with adiposity, insulin resistance, blood pressure, and lipid profiles. In the total population, UHR was independently associated with both c-IMT (β = 0.093, p = 0.003) and LVMI (β = 0.194, p < 0.0001). A significant sex-UHR interaction was observed for LVMI (p = 0.024). Sex-stratified analyses revealed that UHR was linked to LVMI in women, particularly those postmenopausal, but not in males. In postmenopausal women, UHR remained an independent determinant of LVMI (β = 0.164, p = 0.033). UHR is independently associated with subclinical cardiovascular damage, displaying a sex-specific relationship with myocardial remodeling after menopause. As an inexpensive and easily accessible biomarker, UHR may represent a practical tool to combat clinical inertia and improve the early selection of postmenopausal women warranting targeted diagnostic workups. Heart disease is the leading cause of death worldwide, and women face a particularly sharp rise in risk after menopause. To prevent cardiovascular events, it is vital to find simple ways to spot early, hidden signs of trouble before a person even feels sick. In our study, we looked at an accessible tool called the Uric Acid to HDL-Cholesterol Ratio (UHR). This is a simple value that doctors can easily calculate at no extra cost using two common markers found in routine blood tests: uric acid and HDL (“good”) cholesterol. We studied nearly 1,200 individuals to see if a high UHR score was associated with early, subclinical damage to the heart muscle and the arteries in the neck. Our results showed that while a higher score is generally linked to poorer artery health across the entire population, it has a very specific meaning for women. Indeed, the link between this blood marker and an enlarged heart is remarkably strong in women who have gone through menopause, whereas no such significant association was detected in men. This discovery is important because it suggests that menopause triggers metabolic changes that make the female heart more vulnerable to certain types of stress. By using this simple blood test ratio as an early biochemical indicator, doctors may more easily recognize postmenopausal women who exhibit silent changes in their heart structure, allowing clinicians to facilitate early intervention and prioritize them for deeper diagnostic checkups. Because this calculation is inexpensive and easily accessible, it offers a highly practical way to help women protect their heart health as they age. UHR serves as a novel, sex-specific biomarker for identifying subclinical cardiovascular organ damage. Elevated UHR is independently associated with both carotid wall thickening and increased left ventricular mass in a large Caucasian cohort. Formal interaction analysis confirms that the impact of UHR on cardiac structure is affected by biological sex. The association between UHR and myocardial remodeling is particularly prominent in postmenopausal women.
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 health in high-altitude environments. Estrogen and progesterone significantly modulate ventilatory, cardiovascular, hematological, vascular, and muscular/metabolic responses to hypoxia, with distinct effects across different menstrual cycle phases, contraceptive regimens, and life-course states. Menopause introduces additional complexities, as declining hormone levels alter the body’s ability to acclimatize to low-oxygen conditions. Additionally, we examine how chronic and lifelong hypoxia impacts reproductive health, including fertility and pregnancy outcomes, in women living at high altitudes, highlighting both physiological adaptations and contextual factors. While current research has made progress, further studies are needed to better understand these sex-specific responses. We propose that future research should integrate stratified approaches, accounting for hormonal status (cycle phase, contraceptive use, pregnancy, HRT, GAHT) and reproductive status, to optimize health and performance recommendations for women exposed to hypoxic environments. Hormonal status and reproductive life-course stage may modulate women’s physiological responses to hypoxia. Hypoxic exposure models differ in dose, duration, mechanisms, and physiological interpretation. Menstrual cycle phase, hormonal contraception, pregnancy, menopause, hormone replacement therapy, and gender-affirming hormone therapy represent distinct hormonal contexts. Hormonal modulation may affect ventilatory, cardiovascular, vascular, hematological, metabolic, and placental responses. Stratified study designs should report hormonal status, hypoxic dose, oxygen saturation response, exposure duration, and rest, exercise, or sleep context.
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 phenomena, although research to date is relatively limited and often fails to reflect the complexity and nuance of sexual networks. Vulval and vaginal microbiome composition may influence STI acquisition and transmission, yet the relationships between composition, microenvironment, and STIs remain largely overlooked, especially in the context of women and gender-diverse people. In this article, we explore the possibility that a combination of social, sexual, and behavioural factors, combined with biological features, shape the microbiological context of STIs within the vaginal microenvironment. The human vaginal microbiome (VMB) forms an ecological niche home to a complex ecosystem of microorganisms. The microbial composition of the VMB is diverse between individuals, with variations observed across racial and ethnic groups, and intrapersonal fluctuations linked to a plethora of factors both within and outside of personal control. Importantly, VMB health is a crucial component of wellbeing for people assigned female at birth (AFAB), transgendered women with neovaginas, and their sexual partners. Clinical context also remains important; in Australia, doxycycline prophylaxis (Doxy-PEP) has recently become available to GBMSM networks aimed to protect against the acquisition of STIs. However, Doxy-PEP guidelines exclude AFAB people and fail to specify regarding use among gender diverse individuals. Given the high prevalence of AMR-STIs within GBMSM networks, the impact of this intervention on excluded partners should be thoroughly investigated. Factors in the VMB such as biofilm formation and necessary microbial balance with opportunistic pathogens renders this ecological microbial niche a hypothetically perfect platform for AMR development and emergence within the social context. This review explores the social context of vaginal microbiomes, their potential influence on AMR-STI development, and highlight several important knowledge gaps to benefit from further research. Sexual health is shaped by both social factors, such as sex, gender, and sexuality, and biological factors, including anatomy, microbial ecosystem present in genitalia, and exposure to sexually transmitted infections (STIs). Globally, STIs are becoming increasingly drug-resistant, partially due to antibiotic overuse, producing ‘AMR-STIs’ (STIs with antimicrobial resistance properties). Because STIs are highly prevalent in gay and bisexual men, and vaginal infections with STIs are less likely to display symptoms, women and gender diverse people have been largely overlooked as STI reservoirs. This is worrying given that treatments are provided based on available research, raising concerns about their effects on those key groups without sufficient research to confidently inform treatment. For instance, in Australia, Doxy-PEP (proactively using an antibiotic to prevent STIs) is available to gay bisexual and other men who have sex with men, but excludes people with vaginas and fails to address gender diverse individuals. This review explores how social and biological factors interact with the vaginal microbiome (the community of microbes in the vagina) to influence the spread of both STIs and the genetic material which leads to AMR-STIs. We discuss the context of multiple types of vaginal microenvironment and highlight how race, menstrual milestones, and lifestyle factors may shape the balance of the vaginal microbiome, influencing STI risk. We argue that these intersecting biological and social factors likely play a key role in how STIs develop and spread. Hence, this review calls for more research into how these factors shape STI risk in the vaginal microbiome, how these factors shape risk for sexuality and gender diverse individuals, and ultimately how these factors influence the rise of AMR-STIs. Vaginal microbiome (VMB) composition influences sexual health and forms a crucial component of wellbeing for people with vaginal physiology and their sexual partners. Intersecting social, sexual, behavioural and biological factors shape the microbiological context of sexually transmitted infections (STIs) and can select for antimicrobial resistance (AMR-STIs) Antimicrobial treatments applied to specific population groups can act as selective pressure for AMR-STIs and require significant pragmatic study with consideration to downstream effects. Systematic historical neglect has led to gaps in understanding and medical treatment options for women and sexuality and gender diverse minorities seeking sexual and reproductive health care Vaginal microenvironments form a key ecological niche for AMR-STI development and emergence due to differential clinical treatment, vaginal physiology, VMB ecology, social contexts, and intersecting knowledge gaps.
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 to assess the efficacy of exogenous melatonin in correcting the identified disturbances. The study was performed on 240 adult Wistar rats (120 males, 120 females). Animals were divided into 3 groups: control (light: dark 10:14 h), dark deprivation (LL, constant light for 21 days), and LL + melatonin (12 mg/L drinking water). Plasma levels of total protein and albumin were measured. Immunohistochemistry was used to assess the percentage of positively stained hepatocytes for BMAL1, CLOCK, and PER2. Statistical analysis included two-way ANOVA, Pearson correlation analysis, ANCOVA, and ROC analysis. Dark deprivation reduced albumin levels by 15.7
Alzheimer’s disease (AD), the most prevalent form of dementia, exhibits a strong sex bias, with women comprising two-thirds of all patients, for reasons that remain unclear. Microglia, as the brain’s resident immune cell, are key players in AD pathogenesis and are increasingly understood as being sex-specific. However, the mechanisms underlying these differences, and how they may in turn contribute to distinct pathogenesis has not been well examined. Therefore, this study aimed to investigate the organizational role of neonatal estradiol (E2) in early-life sex-patterning of microglia for disease onset and progression. We assessed the effect of neonatal estradiol exposure on microglial and neuronal density, microgliosis, and gene expression related to microglial identity and responses using immunohistochemistry, qPCR, and ProteinSimple Jess on-capillary immunoblotting. We find neonatal estradiol administration influences the expression of genes and proteins involved in inflammation and X chromosome inactivation, without affecting cellular composition of the cortex and hippocampus. Additionally, we observed genotype-dependent changes to the female reproductive cycle in E2 treated 5xFAD females. Overall, the results of the present study provide novel insight into the role of steroid sex hormones in neonatal microglial programing, and how this programming may set the stage for further sex- and disease-linked alterations later in life. Women are disproportionally affected by Alzheimer’s disease (AD), the most prevalent form of dementia, for reasons that have yet to be defined. Classical AD pathology is accompanied by a robust immune response mediated by microglia, which exhibit sex-specific characteristics. As steroid sex hormones like estradiol (E2) drive lasting changes to the brain during neurodevelopment, and previous studies have identified that estradiol administration during early postnatal development can masculinize both brain and behavior, we investigated the impact of E2-mediated masculinization on microglia in AD-relevant brain areas. We report E2 does not alter brain cytoarchitecture in the hippocampus or cortex, instead driving changes at the molecular level, with subtle shifts in microglial gene expression and changes in the expression of the molecular machinery responsible for X chromosome inactivation (XCI). Taken together, these results suggest that neonatal steroid sex hormones may exert effects beyond classical sexually dimorphic brain regions through the regulation and maintenance of XCI for sex-specific immune responses, leading to biased disease onset and progression. The absence of changes to cytoarchitecture in the cortex and hippocampus suggests a potential limitation of cytoarchitectural change to the canonical sexually dimorphic brain nuclei. Microglial gene expression is altered in response to neonatal estradiol treatment, when paired with the absence of cytoarchitectural changes, this suggests estradiol-mediated brain masculinization occurs primarily at the molecular level beyond the sexually dimorphic nuclei. Neonatal estradiol changes patterns of X chromosome inactivation. Changes to molecular messengers in X chromosome inactivation constitute a potential novel mechanism of action for the estradiol masculinization paradigm.
