Characterize Sex Differences Research Articles

Age stratified differences in coronary artery plaque phenotype in women and men with non-obstructive coronary artery disease

Abstract Background Development of coronary artery disease (CAD) and risk of acute cardiac events differ between women and men during the life span. The aim of this study was therefore to characterize sex differences in coronary artery plaque phenotype among patients with symptomatic non-obstructive CAD in different age groups. Methods Advanced coronary artery plaque phenotyping by coronary computed tomography angiography was performed in 606 patients (31% women) with symptomatic non-obstructive CAD from the Norwegian Registry of Invasive Cardiology. A 1:1 sex-matched study design ensured equal distribution of the sexes in the different age groups. We assessed total plaque burden adjusted for vessel volume and plaque composition consisting of dense calcium, fibrous, fibro-fatty, and necrotic core. Patients were further stratified into age groups of ≤50, 51-64, and ≥65 years to explore the relationship between age and sex on coronary artery plaque phenotype. Results In the study population, patients ≥65 years had a higher prevalence of hypertension, higher calcium score, coronary artery segment involvement score and total plaque burden, whereas the prevalence of obesity was lower compared to patients aged 51-64 and ≤50 years (all p<0.05). The prevalence of smoking, diabetes and statin treatment was similar between groups. A two-way analysis of variance demonstrated an interaction between sex and age group on total plaque burden (F [2, 600] =3.431, p=0.33), where women aged 51-64 and ≥65 years had a higher total plaque burden compared to men (p=0.002 and p<0.001, respectively, Figure 1). Plaque composition in women ≥65 years was characterized by an increased proportion of stable dense calcified plaques compared to men and younger women (all p<0.05), whereas men ≥65 years had a higher proportion of vulnerable necrotic core plaque phenotype (p<0.001). Women showed consistently lower proportions of more vulnerable fibro-fatty plaques compared to men across all age groups (all p<0.05, Figure 2). Conclusions In non-obstructive CAD, higher total plaque burden was associated with older age and female sex. Women had a lower proportion of vulnerable fibro-fatty plaques across all age groups and a higher proportion of stable dense calcified plaques at an older age compared to men. Future longitudinal studies on coronary artery plaque phenotype during the life span will increase the understanding of sex differences in CAD development and may contribute to customise risk stratification in women and men.Figure 1.Total plaque burdenFigure 2.Compositional plaque burden

Sex Differences in Electrophysiology and Calcium Handling in Atrial Health and Fibrillation.

The importance of biological sex on disease etiology and outcomes has long been underinvestigated. While recent focus on characterizing sex differences in cardiac pathophysiology has led to improved inclusion of both sexes in scientific studies and clinical trials, much is still unknown about underlying differences in normal cardiac physiology. This is particularly true for the atria, where the most common arrhythmia, atrial fibrillation (AF), occurs. AF is associated with adverse structural, electrophysiological, and calcium handling remodeling that leads to patient morbidity and mortality. Differences in the onset, prevalence, presentation, and prognosis of AF are known to differ between males and females, yet the sex-specific baseline phenotypes from which AF arises are not well characterized. This review examines what is currently known about sex differences in atrial physiology, the alterations that occur in AF, potential mechanisms underlying sex divergence, and the need for sex-targeted therapeutic strategies.

Sex differences in the relationship between body composition and cardiac structure and function.

The purpose of this study was to characterize sex differences in the relationship between body composition and cardiac structure and function. In secondary analyses, we explored pathophysiologic mediators of these relationships. In a cross-sectional analysis of 25,063 UK Biobank participants (54% female, median age 55 years), the sex-specific associations of visceral adipose tissue volume (VAT), appendicular lean mass (ALM), and muscle fat infiltration (MFI) with cardiac magnetic resonance (CMR) measures of cardiac structure and function were assessed using linear regression models. Using causal mediation analysis, 10 biomarkers were explored as mediators of the relationship between adipose depots and cardiac parameters. VAT was associated with increased left ventricular mass (LVM; βwomen = 0.54, βmen = 0.00, pint = 0.01) and wall thickness (βwomen = 0.12, βmen = 0.08, pint<0.001) in women only. A similar sex-specific pattern was observed for MFI effects on LVM (βwomen = 0.44, βmen = 0.03, pint<0.001). ALM was associated with increased LVM and LV volumes in both women and men. In mediation analyses, insulin resistance as measured by triglycerides/high density lipoprotein ratio was a potential partial mediator of VAT effects on chamber dimensions. In the largest and most rigorous analyses of body composition and cardiac parameters to date, we demonstrated that VAT is associated with increased LVM and wall thickness in women but not in men. MFI association with cardiac parameters was similar to VAT, significant in women but not in men.

Sex Differences in Obstructive Patterns on Drug-Induced Sleep Endoscopy.

To identify and characterize sex differences in collapse patterns on drug-induced sleep endoscopy (DISE) in patients with obstructive sleep apnea (OSA). Retrospective cohort analysis. An outpatient tertiary care academic medical center. A retrospective cohort study at a single tertiary care institution was performed from 2020 to 2023. All adult patients who underwent a DISE were included in this study. Univariate and multivariate analyses were used to compare differences between males and females on DISE. 117 patients who underwent DISE were included in this study, including 30% females (n = 35). The average age was 54.7 years (SD 15.2), mean BMI was 28.6 kg/m2 (SD 4.1), and mean apnea-hypopnea index (AHI) was 32.3 events per hour (SD 21.3). Most patients had severe OSA (48.7%). There was no difference in palatine or lingual tonsil size between sexes. On DISE, a significantly lower proportion of females demonstrated complete oropharyngeal lateral wall collapse (25.7% females vs 51.2% males, P = .008). Multivariate analysis revealed that male sex was independently associated with the presence of complete collapse at the oropharynx (odds ratio [OR] 2.55, 95% confidence interval [CI] [0.005-1.868], P = .048) but not at other levels. Additionally, higher BMI was associated with any collapse (partial or complete) at the oropharynx (OR 1.30, 95% CI [0.131-0.392], P < .001). This study demonstrates that a lower proportion of females have complete oropharyngeal lateral wall collapse even when controlling for BMI and AHI. Additional studies are needed to better understand the differences in OSA physiology between the sexes.

Investigating female versus male differences in white matter neuroplasticity associated with complex visuo-motor learning

Magnetic resonance imaging (MRI) has increasingly been used to characterize structure–function relationships during white matter neuroplasticity. Biological sex differences may be an important factor that affects patterns of neuroplasticity, and therefore impacts learning and rehabilitation. The current study examined a participant cohort before and after visuo-motor training to characterize sex differences in microstructural measures. The participants (N = 27) completed a 10-session (4 week) complex visuo-motor training task with their non-dominant hand. All participants significantly improved movement speed and their movement speed variability over the training period. White matter neuroplasticity in females and males was examined using fractional anisotropy (FA) and myelin water fraction (MWF) along the cortico-spinal tract (CST) and the corpus callosum (CC). FA values showed significant differences in the middle portion of the CST tract (nodes 38–51) across the training period. MWF showed a similar cluster in the inferior portion of the tract (nodes 18–29) but did not reach significance. Additionally, at baseline, males showed significantly higher levels of MWF measures in the middle body of the CC. Combining data from females and males would have resulted in reduced sensitivity, making it harder to detect differences in neuroplasticity. These findings offer initial insights into possible female versus male differences in white matter neuroplasticity during motor learning. This warrants investigations into specific patterns of white matter neuroplasticity for females versus males across the lifespan. Understanding biological sex-specific differences in white matter neuroplasticity may have significant implications for the interpretation of change associated with learning or rehabilitation.

Sex differences in physiological response to increased neuronal excitability in a knockin mouse model of pediatric epilepsy.

Epilepsy is a common neurological disease; however, few if any of the currently marketed antiseizure medications prevent or cure epilepsy. Discovery of pathological processes in the early stages of epileptogenesis has been challenging given the common use of preclinical models that induce seizures in physiologically normal animals. Moreover, despite known sex dimorphism in neurological diseases, females are rarely included in preclinical epilepsy models. We characterized sex differences in mice carrying a pathogenic knockin variant (p.N1768D) in the Scn8a gene that causes spontaneous tonic-clonic seizures (TCs) at ∼3 months of age and found that heterozygous females are more resilient than males in mortality and morbidity. To investigate the cellular mechanisms that underlie female resilience, we utilized blood-brain barrier (BBB) and hippocampal transcriptomic analyses in heterozygous mice before seizure onset (pre-TC) and in mice that experienced ∼20 TCs (post-TC). In the pre-TC latent phase, both sexes exhibited leaky BBB; however, patterns of gene expression were sexually dimorphic. Females exhibited enhanced oxidative phosphorylation and protein biogenesis, while males activated gliosis and CREB signaling. After seizure onset (chronic phase), females exhibited a metabolic switch to lipid metabolism, while males exhibited increased gliosis and BBB dysfunction and a strong activation of neuroinflammatory pathways. The results underscore the central role of oxidative stress and BBB permeability in the early stages of epileptogenesis, as well as sex dimorphism in response to increasing neuronal hyperexcitability. Our results also highlight the need to include both sexes in preclinical studies to effectively translate results of drug efficacy studies.

Differential Effects of Targeted Temperature Management on Sex-Dependent Outcomes After Experimental Asphyxial Cardiac Arrest.

Asphyxial cardiac arrest (ACA) survivors face lasting neurological disability from hypoxic ischemic brain injury. Sex differences in long-term outcomes after cardiac arrest (CA) are grossly understudied and underreported. We used rigorous targeted temperature management (TTM) to understand its influence on survival and lasting sex-specific neurological and neuropathological outcomes in a rodent ACA model. Adult male and female rats underwent either sham or 5-minute no-flow ACA with 18 hours TTM at either ∼37°C (normothermia) or ∼36°C (mild hypothermia). Survival, temperature, and body weight (BW) were recorded over the 14-day study duration. All rats underwent neurological deficit score (NDS) assessment on days 1-3 and day 14. Hippocampal pathology was assessed for cell death, degenerating neurons, and microglia on day 14. Although ACA females were less likely to achieve return of spontaneous circulation (ROSC), post-ROSC physiology and biochemical profiles were similar between sexes. ACA females had significantly greater 14-day survival, NDS, and BW recovery than ACA males at normothermia (56% vs. 29%). TTM at 36°C versus 37°C improved 14-day survival in males, producing similar survival in male (63%) versus female (50%). There were no sex or temperature effects on CA1 histopathology. We conclude that at normothermic conditions, sex differences favoring females were observed after ACA in survival, NDS, and BW recovery. We achieved a clinically relevant ACA model using TTM at 36°C to improve long-term survival. This model can be used to more fully characterize sex differences in long-term outcomes and test novel acute and chronic therapies.

Longitudinal effects of sex on pathology accumulation, neurodegeneration and cognitive decline in Presenilin‐1 E280A mutation carriers: preliminary findings from the Colombia‐Boston (COLBOS) biomarker study

AbstractBackgroundPrevious work showed that females at risk for autosomal dominant Alzheimer’s disease (AD) due to a single mutation (E280A) in the Presenilin‐1 gene (PSEN1) may have greater cognitive resilience to AD‐pathology and neurodegeneration than males. However, more research is needed to clarify the effect of sex on AD risk and progression. We investigated the effects of sex on rates of amyloid and tau accumulation, neurodegeneration, and memory decline in PSEN1 mutation carriers with and without cognitive impairment, who are genetically determined to develop early‐onset dementia.MethodA total of 66 cognitively unimpaired mutation carriers (mean age of 34.41 +/‐ 4.86 years; 38 females), and 23 cognitively impaired mutation carriers (mean age of 44.91 +/‐ 2.83 years; 17 females) from the Colombia‐Boston Biomarker (COLBOS) study completed baseline cognitive assessments. A subset of 52 participants also completed florbetapir‐ and flortaucipir‐PET, and structural MRI. Cognitive and neuroimaging follow‐up visits were completed at 2‐ (n = 29) and 4‐year (n = 13) intervals. We used linear mixed‐effects models, with random intercepts, to predict rate of change in MMSE scores, CERAD word list delayed recall, cortical amyloid burden, tau in the entorhinal, inferior temporal, and precuneus cortices, and hippocampal volume by sex, controlling for education.ResultOver time, carriers exhibited greater cortical amyloid burden (p&lt;.001), inferior temporal tau (p = .019), precuneus tau (p = .003), lower hippocampal volume (p = .005), and showed a trend towards lower MMSE scores (p = .059) and word list delayed recall (p&lt;.080); entorhinal tau did not significantly increase (p = .137). Female carriers showed a steeper decline in word list delayed recall than male carriers (p = .021). There were no sex differences in the rate of accumulation of mean cortical amyloid or regional tau, hippocampal atrophy, or change in MMSE scores (all ps&gt;.05).ConclusionPreliminary findings of this ongoing study suggest that despite similar rates of pathology accumulation or atrophy between female and male PSEN1 E280A carriers, female mutation carriers may have faster memory decline. Future analyses with additional participants and follow‐up intervals are needed to characterize sex differences in ADAD risk and resilience, as well as inform development of treatments and interventions.

Identifying sex differences in EEG-based emotion recognition using graph convolutional network with attention mechanism

Objective. Sex differences in emotions have been widely perceived via self-reports, peripheral physiological signals and brain imaging techniques. However, how sex differences are reflected in the electroencephalography (EEG) neural patterns of emotions remains unresolved. In this paper, we detect sex differences in emotional EEG patterns, investigate the consistency of such differences in various emotion datasets across cultures, and study how sex as a factor affects the performance of EEG-based emotion recognition models. Approach. We thoroughly assess sex differences in emotional EEG patterns on five public datasets, including SEED, SEED-IV, SEED-V, DEAP and DREAMER, systematically examine the sex-specific EEG patterns for happy, sad, fearful, disgusted and neutral emotions, and implement deep learning models for sex-specific emotion recognition. Main results. (1) Sex differences exist in various emotion types and both Western and Eastern cultures; (2) The emotion patterns of females are more stable than those of males, and the patterns of happiness from females are in sharp contrast with the patterns of sadness, fear and disgust, while the energy levels are more balanced for males; (3) The key features for emotion recognition are mainly located at the frontal and temporal sites for females and distributed more evenly over the whole brain for males, and (4) the same-sex emotion recognition models outperform the corresponding cross-sex models. Significance. These findings extend efforts to characterize sex differences in emotional brain activation, provide new physiological evidence for sex-specific emotion processing, and reinforce the message that sex differences should be carefully considered in affective research and precision medicine.

Sex differences in binge alcohol drinking and the behavioral consequences of protracted abstinence in C57BL/6J mice.

Binge alcohol drinking is a risk factor linked to numerous disease states including alcohol use disorder (AUD). While men binge drink more alcohol than women, this demographic gap is quickly shrinking, and preclinical studies demonstrate that females consistently consume more alcohol than males. Further, women are at increased risk for the co-expression of AUD with neuropsychiatric diseases such as anxiety and mood disorders. However, little is understood about chronic voluntary alcohol drinking and its long-term effects on behavior. Here, we sought to characterize sex differences in chronic binge drinking and the effects of protracted alcohol abstinence on anxiety- and affective-related behaviors in males and females. We assessed binge alcohol drinking patterns in male and female C57BL/6J mice using a modified Drinking in the Dark (DID) paradigm in which mice received home cage access to one bottle of 10% or 20% alcohol (EtOH) or water for 2h per day on Days 1-3 and to two bottles (EtOH/H2O + H2O) for 24h on Day 4 for 8 weekly cycles. Mice were then tested for the effects of protracted abstinence on avoidance, affective, and compulsive behaviors. Female mice consumed more alcohol than males consistently across cycles of DID and at 2, 4, and 24-h timepoints within the day, with a more robust sex difference for 20% than 10% EtOH. Females also consumed more water than males, an effect that emerged at the later time points; this water consumption bias diminished when alcohol was available. Further, while increased alcohol consumption was correlated with decreased water consumption in males, there was no relationship between these two measures in females. Alcohol preference was higher in 10% vs. 20% EtOH for both sexes. During protracted abstinence following chronic binge drinking, mice displayed decreased avoidance behavior (elevated plus maze, open field, novelty suppressed feeding) and increased compulsive behavior (marble burying) that was especially robust in females. There was no effect of alcohol history on stress coping and negative affective behaviors (sucrose preference, forced swim test, tail suspension) in either sex. Female mice engaged in higher volume binge drinking than their male counterparts. Although females also consumed more water than males, their higher alcohol consumption was not driven by increased total fluid intake. Further, the effects of protracted abstinence following chronic binge drinking was driven by behavioral disinhibition that was more pronounced in females. Given the reciprocal relationship between risk-taking and alcohol use in neuropsychiatric disease states, these results have implications for sex-dependent alcohol drinking patterns and their long-term negative neuropsychiatric/physiological health outcomes in humans.

Sex differences in infective endocarditis: a Danish nationwide study.

Sex differences in infective endocarditis (IE) are reported, but patient characteristics are sparse and conflicting findings on the association between sex and short-term outcomes demand further research. We aimed to characterize sex differences in IE in terms of patient characteristics, frailty, microbiology, socioeconomic status, management and outcome on a nationwide scale. Between 2010 and 2020, we used Danish national registries to characterize patients with IE according to sex using ICD codes and microbiological lab reports. Frailty was assessed with the Hospital Frailty Risk Score. Mortality was reported with Kaplan-Meier estimates. Logistic regression and Cox regression were used for adjusted analyses. We included 6259 patients with IE with 2047 (32.7%) female patients and 4212 (67.3%) male patients. Female patients were older (median age 75.0years (64.3-82.2) vs. 71.7 (61.7-78.9)) and more frail (Intermediate frailty: 36.5% vs. 33.1%, High frailty: 11.4% vs. 9.2%). Staphylococcus aureus-IE were most common in both sexes (34.6% vs. 28.8%), but fewer female patients had Enterococcus-IE (10.5% vs. 18.1%). Female patients were less surgically treated (14.0% vs. 21.2%). Female sex was associated with increased in-hospital mortality (adj. OR 1.33, 95% CI 1.16-1.52), but no statistically significant difference in associated 1- and 5-year mortality from hospital discharge were identified (adj. HR 1.09, 95% CI 0.95-1.24 and 1.02, 95% CI 0.92-1.12, respectively). Female sex is associated with increased in-hospital mortality, but not in long-term mortality as compared with male patients. Female patients have a lower prevalence of Enterococcus-IE and rates of surgery. Further research is needed to understand these differences.

Characterizing Sex Differences in Mitochondrial Dysfunction After Severe Traumatic Brain Injury in Mice.

Traumatic brain injury (TBI) is caused by an impact or penetrating injury to the head resulting in abnormal brain function. Mitochondrial dysfunction is an important hallmark of TBI and has been thoroughly studied in male rodent models of brain injury, but relatively little is known about these outcomes in females. These studies were designed to examine sex as a biological variable for mitochondria-related outcomes after the severe controlled cortical impact (CCI) mouse model of TBI. Synaptic and non-synaptic mitochondria were isolated from the sham- or CCI-injured cortex as well as the hippocampus ipsilateral to the craniotomy 3, 12, 24, or 48 h post-surgery, and then bioenergetics were measured. Subtle variations were observed in the timeline of mitochondrial dysfunction between sexes. Non-synaptic cortical mitochondria from injured females showed early impairment at 12 h post-CCI compared to mitochondria from injured males at 24 h post-CCI. Contrastingly, in the synaptic fraction, mitochondria from injured males showed early impairment at 12 h post-CCI, whereas mitochondria from injured females showed impairment at 24 h post-CCI. Based on bioenergetic impairments at 24 h post-CCI, synaptic and non-synaptic mitochondrial calcium loading was also measured at this time point. Consistent with bioenergetic data at 24 h, non-synaptic mitochondria from injured males had increased calcium loading compared to uninjured control, but this effect was not observed in females. Finally, histological assessment of cortical tissue sparing in each sex was measured at 7 days post-injury. There was a lack of sex-based differences in cortical tissue sparing after severe CCI. Overall, there were some subtle sex differences in mitochondrial outcomes after CCI, but these findings were not statistically significant. This study highlights the importance of utilizing both sexes when measuring mitochondrial function after severe CCI.

Sex-related differences in PROMs prior to the outcome: comparison of preoperative PROMIS physical function scores in female vs. male patients undergoing shoulder arthroplasty

Patient-reported outcome measures (PROMs) are increasingly used to evaluate outcomes in patients undergoing shoulder arthroplasty. The Patient-Reported Outcome Measures Information System (PROMIS) is popular due to low cost and question burden. Females have been reported to have lower postoperative PROMIS scores after shoulder surgery, but studies have not focused on a dedicated cohort of shoulder arthroplasty patients or examined upstream differences in preoperative scores. This study aimed to characterize sex differences in baseline PROMIS scores among anatomic total shoulder arthroplasty (TSA) and reverse total shoulder arthroplasty (rTSA) patients. Data were collected over a 9-month period. Demographics, Charlson Comorbidity Index (CCI), smoking status, BMI, American Shoulder and Elbow Surgeons (ASES) scores, PROMIS Pain, Physical Function (PF), Upper Extremity, Depression, and Anxiety scores, as well as Single Assessment Numeric Evaluation (SANE) scores were collected. Student t-tests were performed to determine correlation with baseline PROMs. A minimal clinically important difference (MCID) of 4 was used to determine if a PROMIS score difference between groups was clinically important. Significance was set as P<.05. A total of 88 females (34 TSAs 54 rTSA) and 99 males (35 TSA, 64 rTSA) were enrolled. Only sex showed a correlation with preoperative PROMIS score. In rTSA patients, females had significantly lower preoperative PROMIS PF scores (P<.05). Among females undergoing TSA vs. rTSA, lower preoperative PROMIS PF scores were found in rTSA (P<.05). These differences exceeded the MCID of 4. The same difference was not found in men undergoing TSA vs. rTSA. Preoperative sex-based differences in PROMIS scores are underappreciated in the shoulder arthroplasty literature. This is the largest study to date focusing on sex-based differences among a dedicated cohort of TSA and rTSA patients, showing a difference in baseline PROMIS scores between males and females above the MCID. These findings suggest that PROMIS scores are affected by sex-based baseline differences in rTSA patients. Further study should investigate sex-based differences in baseline scores to determine their effects on ultimate outcome.

Sex differences in dominance relationships in Syrian hamsters

Dominance relationships are identified by changes in agonistic behavior toward specific individuals. While there are considerable individual and species differences in dominance relationships, sex differences are poorly understood in rodent models because aggression among female rodents is rare. The aim of this study was to characterize sex differences in the formation and maintenance of dominance relationships in same-sex pairs of male and female Syrian hamsters. We pooled data from multiple projects in our lab to evaluate dominance interactions in 68 male dyads and 88 female dyads. In each project, animals were matched with a partner similar in age, sex, and estrous cycle and we exposed animals to daily social encounters for two weeks in a resident-intruder format. We found that female hamsters were quicker to attack and attacked at higher rates compared to males regardless of dominance status. In addition, resident female hamsters were quicker to attack and attacked at higher rates than intruder females, but aggression in males did not depend on residency status. Female subordinates were quicker to submit and fled at higher rates from their dominant counterparts compared to male subordinates. Intruder subordinate females were quicker to submit and fled at higher rates than resident subordinate females. Females were also more resistant than males to becoming subordinate in that they fought back more consistently and were more likely to reverse their dominance status. These findings indicate that dominance relationships are less stable in females compared to males and that residency status has a larger impact on agonistic behavior in females than males. Overall, differences in how males and females display territorial aggression can lead to sex differences in the establishment and maintenance of dominance relationships.

Treatment outcomes of Veteran men in a comprehensive dialectical behavior therapy program: Characterizing sex differences in symptom trajectories

Dialectical Behavior Therapy (DBT) is one of the primary psychosocial treatments for reducing suicidal behaviors and improving psychosocial outcomes among patients with borderline personality disorder (BPD) and has been shown to reduce BPD symptoms when delivered in a Veteran Affairs medical center setting. Despite evidence of similar rates of BPD in both men and women, the vast majority of treatment outcome research in BPD has focused on women. We sought to characterize sex differences in symptom trajectories among Veterans participating in a comprehensive DBT program. We found that Veteran men and women who entered the DBT program were diagnostically and demographically similar. Participants exhibited reductions in BPD symptoms and improvements in emotion regulation over the course of treatment. Moreover, Veteran men reported BPD symptom reductions that were not statistically inferior to those of Veteran women and exhibited a sharper reduction in these symptoms. This research provides support for the use of DBT as a psychosocial treatment for Veteran men with BPD symptoms.

Neural response to stress differs by sex in young adulthood

Increase in stress-related disorders in women begins post-puberty and persists throughout the lifespan. To characterize sex differences in stress response in early adulthood, we used functional magnetic resonance imaging while participants underwent a stress task in conjunction with serum cortisol levels and questionnaires assessing anxiety and mood. Forty-two healthy subjects aged 18–25 years participated (21M, 21F). Interaction of stress and sex in brain activation and connectivity were examined. Results demonstrated significant sex differences in brain activity with women exhibiting increased activation in regions that inhibit arousal compared to men during the stress paradigm. Women had increased connectivity among stress circuitry regions and default mode network, whereas men had increased connectivity between stress and cognitive control regions. In a subset of subjects (13F, 17M), we obtained gamma-aminobutyric acid (GABA) magnetic resonance spectroscopy in rostral anterior cingulate cortex (rostral ACC) and dorsolateral prefrotal cortex (dlPFC) and conducted exploratory analyses to relate GABA measurements with sex differences in brain activation and connectivity. Prefrontal GABA levels were negatively associated with inferior temporal gyrus activation in men and women and with ventromedial prefrontal cortex activation in men. Despite sex differences in neural response, we found similar subjective ratings of anxiety and mood, cortisol levels, and GABA levels between sexes, suggesting sex differences in brain activity result in similar behavioral responses among the sexes. These results help establish sex differences in healthy brain activity from which we can better understand sex differences underlying stress-associated illnesses.

A deep transcriptome meta-analysis reveals sex differences in multiple sclerosis

BackgroundMultiple sclerosis (MS), a chronic auto-immune, inflammatory, and degenerative disease of the central nervous system, affects both males and females; however, females suffer from a higher risk of developing MS (2–3:1 ratio relative to males). The precise sex-based factors influencing risk of MS are currently unknown. Here, we explore the role of sex in MS to identify molecular mechanisms underlying observed MS sex differences that may guide novel therapeutic approaches tailored for males or females. MethodsWe performed a rigorous and systematic review of genome-wide transcriptome studies of MS that included patient sex data in the Gene Expression Omnibus and ArrayExpress databases following PRISMA statement guidelines. For each selected study, we analyzed differential gene expression to explore the impact of the disease in females (IDF), in males (IDM) and our main goal: the sex differential impact of the disease (SDID). Then, for each scenario (IDF, IDM and SDID) we performed 2 meta-analyses in the main tissues involved in the disease (brain and blood). Finally, we performed a gene set analysis in brain tissue, in which a higher number of genes were dysregulated, to characterize sex differences in biological pathways. ResultsAfter screening 122 publications, the systematic review provided a selection of 9 studies (5 in blood and 4 in brain tissue) with a total of 474 samples (189 females with MS and 109 control females; 82 males with MS and 94 control males). Blood and brain tissue meta-analyses identified, respectively, 1 (KIR2DL3) and 13 (ARL17B, CECR7, CEP78, IFFO2, LOC401127, NUDT18, RNF10, SLC17A5, STMP1, TRAF3IP2-AS1, UBXN2B, ZNF117, ZNF488) MS-associated genes that differed between males and females (SDID comparison). Functional analyses in the brain revealed different altered immune patterns in females and males (IDF and IDM comparisons). The pro-inflammatory environment and innate immune responses related to myeloid lineage appear to be more affected in females, while adaptive responses associated with the lymphocyte lineage in males. Additionally, females with MS displayed alterations in mitochondrial respiratory chain complexes, purine, and glutamate metabolism, while MS males displayed alterations in stress response to metal ion, amine, and amino acid transport. ConclusionWe found transcriptomic and functional differences between MS males and MS females (especially in the immune system), which may support the development of new sex-based research of this disease. Our study highlights the importance of understanding the role of biological sex in MS to guide a more personalized medicine.

Sex differences in islet stress responses support female β cell resilience

ObjectivePancreatic β cells play a key role in maintaining glucose homeostasis; dysfunction of this critical cell type causes type 2 diabetes (T2D). Emerging evidence points to sex differences in β cells, but few studies have examined male-female differences in β cell stress responses and resilience across multiple contexts, including diabetes. Here, we address the need for high-quality information on sex differences in β cell and islet gene expression and function using both human and rodent samples. MethodsIn humans, we compared β cell gene expression and insulin secretion in donors with T2D to non-diabetic donors in both males and females. In mice, we generated a well-powered islet RNAseq dataset from 20-week-old male and female siblings with similar insulin sensitivity. Our unbiased gene expression analysis pointed to a sex difference in the endoplasmic reticulum (ER) stress response. Based on this analysis, we hypothesized female islets would be more resilient to ER stress than male islets. To test this, we subjected islets isolated from age-matched male and female mice to thapsigargin treatment and monitored protein synthesis, cell death, and β cell insulin production and secretion. Transcriptomic and proteomic analyses were used to characterize sex differences in islet responses to ER stress. ResultsOur single-cell analysis of human β cells revealed sex-specific changes to gene expression and function in T2D, correlating with more robust insulin secretion in human islets isolated from female donors with T2D compared to male donors with T2D. In mice, RNA sequencing revealed differential enrichment of unfolded protein response pathway-associated genes, where female islets showed higher expression of genes linked with protein synthesis, folding, and processing. This differential expression was physiologically significant, as islets isolated from female mice were more resilient to ER stress induction with thapsigargin. Specifically, female islets showed a greater ability to maintain glucose-stimulated insulin production and secretion during ER stress compared with males. ConclusionsOur data demonstrate sex differences in β cell gene expression in both humans and mice, and that female β cells show a greater ability to maintain glucose-stimulated insulin secretion across multiple physiological and pathological contexts.

Maternal Dexamethasone Exposure Induces Sex-Specific Changes in Histomorphology and Redox Homeostasis of Rat Placenta.

As the mediator between the mother and fetus, the placenta allows the most appropriate environment and optimal fetal growth. The placenta of one sex sometimes has a greater ability over the other to respond to and protect against possible maternal insults. Here, we characterized sex differences in the placenta’s morphological features and antioxidant status following dexamethasone (Dx) exposure. Pregnant rats were exposed to Dx or saline. The placenta was histologically and stereologically analyzed. The activity of the antioxidant enzymes, lipid peroxides (TBARS), superoxide anion and nitric oxide (NO) was measured. The decrease in placental zone volumes was more pronounced (p < 0.05) in female placentas. The volume density of PCNA-immunopositive nuclei was reduced (p < 0.05) in both sexes. The reduced (p < 0.05) antioxidant enzyme activities, enhanced TBARS and NO concentration indicate that Dx exposure triggered oxidative stress in the placenta of both fetal sexes, albeit stronger in the placenta of female fetuses. In conclusion, maternal Dx treatment reduced the size and volume of placental zones, altered placental histomorphology, decreased cell proliferation and triggered oxidative stress; however, the placentas of female fetuses exerted more significant responses to the treatment effects. The reduced placental size most probably reduced the transport of nutrients and oxygen, thus resulting in the reduced weight of fetuses, similar in both sexes. The lesser ability of the male placenta to detect and react to maternal exposure to environmental challenges may lead to long-standing health effects.

Sex differences in early and term placenta are conserved in adult tissues

BackgroundPregnancy complications vary based on the fetus’s genetic sex, which may, in part, be modulated by the placenta. Furthermore, developmental differences early in life can have lifelong health outcomes. Yet, sex differences in gene expression within the placenta at different timepoints throughout pregnancy and comparisons to adult tissues remains poorly characterized.MethodsHere, we collect and characterize sex differences in gene expression in term placentas (≥ 36.6 weeks; 23 male XY and 27 female XX). These are compared with sex differences in previously collected first trimester placenta samples and 42 non-reproductive adult tissues from GTEx.ResultsWe identify 268 and 53 sex-differentially expressed genes in the uncomplicated late first trimester and term placentas, respectively. Of the 53 sex-differentially expressed genes observed in the term placentas, 31 are also sex-differentially expressed genes in the late first trimester placentas. Furthermore, sex differences in gene expression in term placentas are highly correlated with sex differences in the late first trimester placentas. We found that sex-differential gene expression in the term placenta is significantly correlated with sex differences in gene expression in 42 non-reproductive adult tissues (correlation coefficient ranged from 0.892 to 0.957), with the highest correlation in brain tissues. Sex differences in gene expression were largely driven by gene expression on the sex chromosomes. We further show that some gametologous genes (genes with functional copies on X and Y) will have different inferred sex differences if the X-linked gene expression in females is compared to the sum of the X-linked and Y-linked gene expression in males.ConclusionsWe find that sex differences in gene expression are conserved in late first trimester and term placentas and that these sex differences are conserved in adult tissues. We demonstrate that there are sex differences associated with innate immune response in late first trimester placentas but there is no significant difference in gene expression of innate immune genes between sexes in healthy full-term placentas. Finally, sex differences are predominantly driven by expression from sex-linked genes.