Baseline Sex Differences Research Articles

Sex differences in arterial identity correlate with neointimal hyperplasia after balloon injury

BackgroundEndovascular treatment of atherosclerotic arterial disease exhibits sex differences in clinical outcomes including restenosis. However, sex-specific differences in arterial identity during arterial remodeling have not been described. We hypothesized that sex differences in expression of the arterial determinant erythropoietin-producing hepatocellular receptor interacting protein (Ephrin)-B2 occur during neointimal proliferation and arterial remodeling.Methods and resultsCarotid balloon injury was performed in female and male Sprague–Dawley rats without or 14 days after gonadectomy; the left common carotid artery was injured and the right carotid artery in the same animal was used as an uninjured control. Arterial hemodynamics were evaluated in vivo using ultrasonography pre-procedure and post-procedure at 7 and 14 days and wall composition examined using histology, immunofluorescence and Western blot at 14 days after balloon injury. There were no significant baseline sex differences. 14 days after balloon injury, there was decreased neointimal thickness in female rats with decreased smooth muscle cell proliferation and decreased type I and III collagen deposition, as well as decreased TNFα- or iNOS-positive CD68+ cells and increased CD206− or TGM2-positive CD68+ cells. Female rats also showed less immunoreactivity of VEGF-A, NRP1, phosphorylated EphrinB2, and increased Notch1, as well as decreased phosphorylated Akt1, p38 and ERK1/2. These differences were not present in rats pretreated with gonadectomy.ConclusionsDecreased neointimal thickness in female rats after carotid balloon injury is associated with altered arterial identity that is dependent on intact sex hormones. Alteration of arterial identity may be a mechanism of sex differences in neointimal proliferation after arterial injury.

Assessing Sex-Specific Circadian, Metabolic, and Cognitive Phenotypes in the AβPP/PS1 and APPNL-F/NL-F Models of Alzheimer's Disease.

Circadian disruption has long been recognized as a symptom of Alzheimer's disease (AD); however, emerging data suggests that circadian dysfunction occurs early on in disease development, potentially preceding any noticeable cognitive deficits. This study compares the onset of AD in male and female wild type (C57BL6/J), transgenic (AβPP/PS1), and knock-in (APPNL-F/NL-F) AD mouse models from the period of plaque initiation (6 months) through 12 months. Rhythmic daily activity patterns, glucose sensitivity, cognitive function (Morris water maze, MWM), and AD pathology (plaques formation) were assessed. A comparison was made across sexes. Sex-dependent hyperactivity in AβPP/PS1 mice was observed. In comparison to C57BL/6J animals, 6-month-old male AβPP/PS1 demonstrated nighttime hyperactivity, as did 12-month-old females. Female AβPP/PS1 animals performed significantly worse on a MWM task than AβPP/PS1 males at 12 months and trended toward increased plaque pathology. APPNL-F/NL-F 12-month-old males performed significantly worse on the MWM task compared to 12-month-old females. Significantly greater plaque pathology occurred in AβPP/PS1 animals as compared to APPNL-F/NL-F animals. Female AβPP/PS1 animals performed significantly worse than APPNL-F/NL-F animals in spatial learning and memory tasks, though this was reversed in males. Taken together, this study provides novel insights into baseline sex differences, as well as characterizes baseline diurnal activity variations, in the AβPP/PS1 and APPNL-F/NL-F AD mouse models.

Sex differences in the rodent hippocampal opioid system following stress and oxycodone associated learning processes

Over the past two decades, opioid abuse has risen especially among women. In both sexes hippocampal neural circuits involved in associative memory formation and encoding of motivational incentives are critically important in the transition from initial drug use to drug abuse/dependence. Opioid circuits, particularly the mossy fiber pathway, are crucial for associative memory processes important for addiction. Our anatomical studies, especially those utilizing electron microscopic immunocytochemistry, have provided unique insight into sex differences in the distribution of opioid peptides and receptors in specific hippocampal circuits and how these distributions are altered following stress and oxycodone-associative learning processes. Here we review the hippocampal opioid system in rodents with respect to ovarian hormones effects and baseline sex differences then sex differences following acute and chronic stress. Next, we review sex differences in the hippocampal opioid system in unstressed and chronically stressed rats following oxycodone conditioned place preference. We show that opioid peptides and receptors are distributed within hippocampal circuits in females with elevated estrogen states in a manner that would enhance sensitivity to endogenous and exogenous opioids. Moreover, chronic stress primes the opioid system in females in a manner that would promote opioid-associative learning processes. In contrast, chronic stress has limited effects on the opioid system in males and reduces its capacity to support opioid-mediated learning processes. Interestingly, acute stress appears to prime males for opioid associative learning. On a broader scale the findings highlighted in this review have important implications in understanding sex differences in opioid drug use and abuse.

GluN2B‐containing NMDA Receptors on Sst‐interneurons act as Initial Cellular Trigger for Antidepressant Actions of Ketamine

A single subanesthetic dose of ketamine exerts rapid antidepressant-like effects via rapid glutamate efflux, activation of mTORC1 signaling, and enhanced synaptic transmission in the medial prefrontal cortex (mPFC); however, the initial cellular trigger for these synaptic and behavioral actions of ketamine still remains unclear. Here, we used electrophysiology, biochemistry, molecular biology and behavioral approaches to determine the baseline sex differences in behavior after GluN2B conditional deletion from Sst-interneurons, and effect of ketamine on chronic unpredictable stress (CUS)-induced behavioral deficits, activation of mTOR signaling cascade and changes in synaptic transmission in male and female GluN2Bfl/fl (WT) and Sst-creGluN2Bfl/fl mice (KO) mice. Acute treatment of ketamine reduces NMDA-induced burst firing of Sst-interneurons ex vivo in mPFC. Deletion of GluN2B from Sst-GABAergic interneurons in the KO produced sexually dimorphic changes in synaptic transmission and behavior. Consistent with the disinhibition hypothesis, ketamine reduces inhibitory, but enhances excitatory transmission of layer V pyramidal neurons of mPFC and reverses CUS-induced behavioral deficits only in WT, but not KO, mice. Preliminary data demonstrate that deletion of GluN2B from Sst-interneurons blocks ketamine-induced activation of mTOR signaling cascade. Our results demonstrate that Sst-interneurons are an initial cellular trigger for synaptic and behavioral actions of ketamine. Consistent with the disinhibition hypothesis, ketamine actions are mediated by GluN2B-NMDARs on Sst-interneurons via disinhibition of pyramidal neurons, activation of mTOR signaling, and enhanced synaptic function in mPFC.

Sex Differences in The Regulation of Neuron Excitability within Layer VI of The Mouse Entorhinal Cortex

The entorhinal cortex (EC) comprises part of the hippocampal formation and plays an important role to facilitate cognitive processes including learning and memory. The EC may be divided into six cellular layers that have unique neuron populations and communication targets. In particular, the sixth EC layer (ECVI) receives afferent signals from the hippocampus and contains glutamatergic pyramidal neurons that transmit efferent signals to other regions of the brain. Although several studies have characterized basic electrophysiological properties of neurons within the more superficial layers of the EC, detailed characteristics of pyramidal neurons within ECVI are not well understood. We recently identified a profound sex difference in the excitability of ECVI neurons during early postnatal life, in that neurons from female mice are more excitable than neurons from male mice. While this sex difference correlates with a smaller afterhyperpolarization of medium duration (mAHP) in female ECVI neurons, the precise mechanisms have not been determined. This study aims to determine the contribution of small-conductance calcium-activated potassium (SK) channels toward sex differences in ECVI neuron excitability in young postnatal (P5-10) and adult (P80-120) mice. Contrary to our previous finding in young postnatal mice, we observed no baseline sex differences in adult mice for passive electrophysiological properties such as resting membrane potential and membrane resistance, or for active electrophysiological properties such as input-output responses or mAHP magnitude. The SK channel blocker apamin increased input resistance and decreased rheobase in both sexes. However, the ability of apamin to decrease mAHP magnitude and increase input-output excitability responses was far greater in male than in females. Ongoing experiments aim to determine the effect of SK channel blockade on neuronal excitability in young postnatal mice. These novel findings demonstrate that SK channels play a greater role in regulating ECVI neuron excitability in male mice than in female mice. This knowledge advances our understanding of neuron function within the hippocampal formation and mechanisms underlying potential sex differences in hippocampal-dependent cognitive functions.

Serotonin Pretreatment Abolishes Sex-specific NMDA-induced Seizure Behavior in Developing Rats

Neuronal excitability and susceptibility to excitotoxic damage can be sex-specific, with neurons from males usually being more ‘easily excitable’ compared to neurons from females, especially during development. Increased excitability at an individual neuronal level can lead to the formation of hyperexcitable neuronal networks, which, consequently can make the brain more seizure prone. Both animal and clinical data suggest that males experience more frequent and severe seizures than do females. Serotonin (5-hydroxytryptamine; 5-HT) can mediate neuronal excitability and seizure behavior, often serving as an anticonvulsant. Importantly, 5-HT signaling during parts of the perinatal period is sexually dimorphic. Sex differences during development have been reported in both serotonin levels and receptor type (excitatory vs. inhibitory) expression in a manner that may leave the male brain more vulnerable to over-excitation. Thus, we aimed to determine if the anticonvulsant effects of 5-HT were sex- and/or age-dependent in juvenile animals. We report a baseline sex difference in N-methyl-d-aspartate (NMDA)-induced seizure behavior and hippocampal neuronal loss, with postnatal day (PND) 14 males exhibiting more severe seizure behavior compared to females. Pretreatment with the general 5-HT receptor agonist 5-methoxytryptamine (5-MT) abolishes baseline sex differences, providing an anticonvulsant effect for males only. These sex differences appear to be at least in part organized by testosterone, as females given neonatal androgen exhibit a seizure behavior profile in between that of males and females.

The Role of Parvalbumin Interneuron GIRK Signaling in the Regulation of Affect and Cognition in Male and Female Mice.

Pathological impairments in the regulation of affect (i.e., emotion) and flexible decision-making are commonly observed across numerous neuropsychiatric disorders and are thought to reflect dysfunction of cortical and subcortical circuits that arise in part from imbalances in excitation and inhibition within these structures. Disruptions in GABA transmission, in particular, that from parvalbumin-expressing interneurons (PVI), has been highlighted as a likely mechanism by which this imbalance arises, as they regulate excitation and synchronization of principle output neurons. G protein-gated inwardly rectifying potassium ion (GIRK/Kir3) channels are known to modulate excitability and output of pyramidal neurons in areas like the medial prefrontal cortex and hippocampus; however, the role GIRK plays in PVI excitability and behavior is unknown. Male and female mice lacking GIRK1 in PVI (Girk1flox/flox:PVcre) and expressing td-tomato in PVI (Girk1flox/flox:PVCre:PVtdtom) exhibited increased open arm time in the elevated plus-maze, while males showed an increase in immobile episodes during the forced swim test (FST). Loss of GIRK1 did not alter motivated behavior for an appetitive reward or impair overall performance in an operant-based attention set-shifting model of cognitive flexibility; however it did alter types of errors committed during the visual cue test. Unexpectedly, baseline sex differences were also identified in these tasks, with females exhibiting overall poorer performance compared to males and distinct types of errors, highlighting potential differences in task-related problem-solving. Interestingly, reductions in PVI GIRK signaling did not correspond to changes in membrane excitability but did increase action potential (AP) firing at higher current injections in PVI of males, but not females. This is the first investigation on the role that PVI GIRK-signaling has on membrane excitability, AP firing, and their role on affect and cognition together increasing the understanding of PVI cellular mechanisms and function.

Chronic stress differentially altersmRNAexpression of opioid peptides and receptors in the dorsal hippocampus of female and male rats

Chronic immobilization stress (CIS) results in sex-dependent changes in opioid peptide levels and receptor subcellular distributions within the rat dorsal hippocampus, which are paralleled with an inability for males to acquire conditioned place preference (CPP) to oxycodone. Here, RNAScope in situ hybridization was used to determine the expression of hippocampal opioid peptides and receptors in unstressed (US) and CIS estrus female and male adult (∼2.5 months old ) Sprague Dawley rats. In all groups, dentate granule cells expressed PENK and PDYN; additionally, numerous interneurons expressed PENK. OPRD1 and OPRM1 were primarily expressed in interneurons, and to a lesser extent, in pyramidal and granule cells. OPRK1-was expressed in sparsely distributed interneurons. There were few baseline sex differences: US females compared to US males had more PENK-expressing and fewer OPRD1-expressing granule cells and more OPRM1-expressing CA3b interneurons. Several expression differences emerged after CIS. Both CIS females and males compared to their US counterparts had elevated: (1) PENK-expressing dentate granule cells and interneurons in CA1 and CA2/3a; (2) OPRD1 probe number and cell expression in CA1, CA2/3a and CA3b and the dentate gyrus; and (3) OPRK1-expressing interneurons in the dentate hilus. Also, CIS males compared to US males had elevated: (1) PDYN expression in granule cells; (2) OPRD1 probe and interneuron expression in CA2/3a; (3) OPRM1 in granule cells; and (4) OPRK1 interneuron expression in CA2/3a. The sex-specific changes in hippocampal opioid gene expression may impact network properties and synaptic plasticity processes that may contribute to the attenuation of oxycodone CPP in CIS males.

Selective deletion of endothelial mineralocorticoid receptor protects from vascular dysfunction in sodium-restricted female mice

BackgroundRecent evidence by our laboratory demonstrates that women and female mice endogenously express higher endothelial mineralocorticoid receptor (ECMR) than males. Mounting clinical evidence also indicates that aldosterone production is higher in pathological conditions in females compared to males. However, the role for increased activation of ECMR by aldosterone in the absence of a comorbid condition is yet to be explored. The current study hypothesized that increased ECMR activation induced by elevated aldosterone production predisposes healthy female mice to endothelial dysfunction.MethodVascular reactivity was assessed in aortic rings from wild-type (WT) and ECMR KO (KO) mice fed either a normal salt (NSD, 0.4% NaCl) or sodium-restricted diet (SRD, 0.05% NaCl) for 28 days.ResultsSRD elevated plasma aldosterone levels as well as adrenal CYP11B2 and angiotensin II type 1 receptor (AT1R) expressions in female, but not male, WT mice. In baseline conditions (NSD), endothelial function, assessed by vascular relaxation to acetylcholine, was higher while vascular contractility to phenylephrine, serotonin, and KCl lower in female than male WT mice. SRD impaired endothelial function and increased vascular contractility in female, but not male, WT mice effectively ablating the baseline sex differences. NOS inhibition with LNAME ablated endothelial relaxation to a higher extent in male than female mice on NSD and ablated differences in acetylcholine relaxation responses between NSD- and SRD-fed females, indicating a role for NO in SRD-mediated endothelial function. In association, SRD significantly reduced vascular NOX4 expression in female, but not male, mice. Lastly, selective deletion of ECMR protected female mice from SRD-mediated endothelial dysfunction and increased vascular contractility.ConclusionCollectively, these data indicate that female mice develop aldosterone-induced endothelial dysfunction via endothelial MR-mediated reductions in NO bioavailability. In addition, these data support a role for ECMR to promote vascular contractility in female mice in response to sodium restriction.

Sex Disparities in Cardiovascular Outcome Trials of Populations With Diabetes: A Systematic Review and Meta-analysis.

Sex differences have been described in diabetes cardiovascular outcome trials (CVOTs). We systematically reviewed for baseline sex differences in cardiovascular (CV) risk factors and CV protection therapy in diabetes CVOTs. Randomized placebo-controlled trials examining the effect of diabetes medications on major adverse cardiovascular events in people ≥18 years of age with type 2 diabetes. Included trials reported baseline sex-specific CV risks and use of CV protection therapy. Two reviewers independently abstracted study data. We included five CVOTs with 46,606 participants. We summarized sex-specific data using mean differences (MDs) and relative risks (RRs) and pooled estimates using random effects meta-analysis. There were fewer women than men in included trials (28.5-35.8% women). Women more often had stroke (RR 1.28; 95% CI 1.09, 1.50), heart failure (RR 1.30; 95% CI 1.21,1.40), and chronic kidney disease (RR 1.33; 95% CI 1.17; 1.51). They less often used statins (RR 0.90; 95% CI 0.86, 0.93), aspirin (RR 0.82; 95% CI 0.71, 0.95), and β-blockers (RR 0.93; 95% CI 0.88, 0.97) and had a higher systolic blood pressure (MD 1.66 mmHg; 95% CI 0.90, 2.41), LDL cholesterol (MD 0.34 mmol/L; 95% CI 0.29, 0.39), and hemoglobin A1c (MD 0.11%; 95% CI 0.09, 0.14 [1.2 mmol/mol; 1.0, 1.5]) than men. We could not carry out subgroup analyses due to the small number of studies. Our study is not generalizable to low CV risk groups nor to patients in routine care. There were baseline sex disparities in diabetes CVOTs. We suggest efforts to recruit women into trials and promote CV management across the sexes.

Acute peripheral inflammation and post-traumatic sleep differ between sexes after experimental diffuse brain injury.

Identifying differential responses between sexes following traumatic brain injury (TBI) can elucidate the mechanisms behind disease pathology. Peripheral and central inflammation in the pathophysiology of TBI can increase sleep in male rodents, but this remains untested in females. We hypothesized that diffuse TBI would increase inflammation and sleep in males more so than in females. Diffuse TBI was induced in C57BL/6J mice and serial blood samples were collected (baseline, 1, 5, 7days post-injury [DPI]) to quantify peripheral immune cell populations and sleep regulatory cytokines. Brains and spleens were harvested at 7DPI to quantify central and peripheral immune cells, respectively. Mixed-effects regression models were used for data analysis. Female TBI mice had 77%-124% higher IL-6 levels than male TBI mice at 1 and 5DPI, whereas IL-1β and TNF-α levels were similar between sexes at all timepoints. Despite baseline sex differences in blood-measured Ly6Chigh monocytes (females had 40% more than males), TBI reduced monocytes by 67% in TBI mice at 1DPI. Male TBI mice had 31%-33% more blood-measured and 31% more spleen-measured Ly6G+ neutrophils than female TBI mice at 1 and 5DPI, and 7DPI, respectively. Compared with sham, TBI increased sleep in both sexes during the first light and dark cycles. Male TBI mice slept 11%-17% more than female TBI mice, depending on the cycle. Thus, sex and TBI interactions may alter the peripheral inflammation profile and sleep patterns, which might explain discrepancies in disease progression based on sex.

GENE-21. ROLE OF POT1 MUTATION IN GLIOMA PROLIFERATION AND SEXUAL DIVERGENCE OF SURVIVAL

Abstract Germline POT1 mutations are associated with risk of several cancers including glioma. In The Cancer Genome Atlas, we found that the level of POT1 gene expression in tumors is associated with overall survival in IDH wild-type glioma independent of age and tumor grade (P=0.036). To assess if POT1 expression in a native mouse model of IDH wild-type glioma (referred to as C3 tumors) affects survival, we targeted both mouse POT1 orthologs (Pot1a/Pot1b) in C3 tumors using CRISPR/Cas9, generating C5 tumors. Interestingly, we noted a sexual divergence of survival, with female C5 mice dying faster than males (P=0.0034), whereas C3 mice show no sexual divergence in survival. To assess the genes and pathways underlying this divergence, we performed RNAseq profiling on C3 and C5 tumors and normalized the sex differences in the C5 profile for baseline sex differences in the C3 profile. Compared to males, female C5 tumors had lower enrichment of numerous gene sets related to immune surveillance. To specifically assess the effects of glioma-associated human POT1 variants, we expressed these variants in a mouse tumor sphere culture. We noted that expression of POT1-G95C variant increased the rate of sphere formation in vitro. In vivo expression of this variant in embryonic mouse brain during the gliogenic period increased the proliferative rate as assessed by BrdU uptake (P=0.008). These findings suggest a potential role for human POT1 variants in growth and proliferation of glial progenitor cells as well as glioma tumor cells. Additionally, the sexual divergence of survival in C5 tumors points to a differential interaction between POT1 loss and sex in regulation of immune response to these tumors.

Impact of sex, androgens, and prostate size on C57BL/6J mouse urinary physiology: functional assessment.

Laboratory mice are used to identify causes of urinary dysfunction including prostate-related mechanisms of lower urinary tract symptoms. Effective use of mice for this purpose requires a clear understanding of molecular, cellular, anatomic, and endocrine contributions to voiding function. Whether the prostate influences baseline voiding function has not been specifically evaluated, in part because most methods that alter prostate mass also change circulating testosterone concentrations. We performed void spot assay and cystometry to establish a multiparameter "baseline" of voiding function in intact male and female 9-wk-old (adult) C57BL/6J mice. We then compared voiding function in intact male mice to that of castrated male mice, male (and female) mice treated with the steroid 5α-reductase inhibitor finasteride, or male mice harboring alleles (Pbsn4cre/+; R26RDta/+) that significantly reduce prostate lobe mass by depleting prostatic luminal epithelial cells. We evaluated aging-related changes in male urinary voiding. We also treated intact male, castrate male, and female mice with exogenous testosterone to determine the influence of androgen on voiding function. The three methods used to reduce prostate mass (castration, finasteride, and Pbsn4cre/+; R26RDta/+) changed voiding function from baseline but in a nonuniform manner. Castration feminized some aspects of male urinary physiology (making them more like intact female mice) while exogenous testosterone masculinized some aspects of female urinary physiology (making them more like intact male mice). Our results provide evidence that circulating testosterone is responsible in part for baseline sex differences in C57BL/6J mouse voiding function while prostate lobe mass in young, healthy adult mice has a lesser influence.

Sex-related differences in vision are heterogeneous

Despite well-established sex differences for cognition, audition, and somatosensation, few studies have investigated whether there are also sex differences in visual perception. We report the results of fifteen perceptual measures (such as visual acuity, visual backward masking, contrast detection threshold or motion detection) for a cohort of over 800 participants. On six of the fifteen tests, males significantly outperformed females. On no test did females significantly outperform males. Given this heterogeneity of the sex effects, it is unlikely that the sex differences are due to any single mechanism. A practical consequence of the results is that it is important to control for sex in vision research, and that findings of sex differences for cognitive measures using visually based tasks should confirm that their results cannot be explained by baseline sex differences in visual perception.

Sex differences in mitochondrial respiratory function in human skeletal muscle.

Mitochondrial bioenergetic contributions to sex differences in human skeletal muscle metabolism remain poorly defined. The primary aim of this study was to determine whether mitochondrial respiratory kinetics differed between healthy young men and women in permeabilized skeletal muscle fibers. While men and women displayed similar ( P > 0.05) maximal respiration rates and abundance of mitochondrial/adenosine diphosphate (ADP) transport proteins, women had lower ( P < 0.05) mitochondrial ADP sensitivity (+30% apparent Km) and absolute respiration rates at a physiologically relevant ADP concentration (100 μM). Moreover, although men and women exhibited similar carnitine palmitoyl transferase-I protein content- and palmitoyl-CoA-supported respiration, women displayed greater sensitivity to malonyl-CoA-mediated respiratory inhibition. These data establish baseline sex differences in mitochondrial bioenergetics and provide the foundation for studying mitochondrial function within the context of metabolic perturbations and diseases that affect men and women differently.

EXAMINING DIFFERENCES IN RECOVERY OUTCOMES BETWEEN MALE AND FEMALE HIP FRACTURE PATIENTS: DESIGN AND BASELINE RESULTS OF A PROSPECTIVE COHORT STUDY FROM THE BALTIMORE HIP STUDIES

Incidence of hip fractures in men is expected to increase, yet little is known about consequences of hip fracture in men compared to women. It is important to investigate differences at time of fracture using the newest technologies and methodology regarding metabolic, physiologic, neuromuscular, functional, and clinical outcomes, with attention to design issues for recruiting frail older adults across numerous settings. To determine whether at least moderately-sized sex differences exist across several key outcomes after a hip fracture. This prospective cohort study (Baltimore Hip Studies 7th cohort [BHS-7]) was designed to include equal numbers of male and female hip fracture patients to assess sex differences across various outcomes post-hip fracture. Participants were recruited from eight hospitals in the Baltimore metropolitan area within 15 days of admission and were assessed at baseline, 2, 6 and 12 months post-admission. Assessments included questionnaire, functional performance evaluation, cognitive testing, measures of body composition, and phlebotomy. Of 1709 hip fracture patients screened from May 2006 through June 2011, 917 (54%) were eligible and 39% (n=362) provided informed consent. The final analytic sample was 339 (168 men and 171 women). At time of fracture, men were sicker (mean Charlson score= 2.4 vs. 1.6; p<0.001) and had worse cognition (3MS score= 82.3 vs. 86.2; p<0.05), and prior to fracture were less likely to be on bisphosphonates (8% vs. 39%; p<0.001) and less physically active (2426 kilocalories/week vs. 3625; p<0.001). This paper provides the study design and methodology for recruiting and assessing hip fracture patients and evidence of baseline and pre-injury sex differences which may affect eventual recovery one year later.

Sex differences in the drinking response to angiotensin II (AngII): Effect of body weight

Sex differences in fluid intake stimulated by angiotensin II (AngII) have been reported, but the direction of the differences is inconsistent. To resolve these discrepancies, we measured water intake by male and female rats given AngII. Males drank more than females, but when intake was normalized to body weight, the sex difference was reversed. Weight-matched males and females, however, had no difference in intake. Using a linear mixed model analysis, we found that intake was influenced by weight, sex, and AngII dose. We used linear regression to disentangle these effects further. Comparison of regression coefficients revealed sex and weight differences at high doses of AngII. Specifically, after 100ng AngII, weight was a predictor of intake in males, but not in females. Next, we tested for differences in AngII-induced intake in male and females allowed to drink both water and saline. Again, males drank more water than females, but females showed a stronger preference for saline. Drinking microstructure analysis suggested that these differences were mediated by postingestive signals and more bottle switches by the females. Finally, we probed for differences in the expression of components of the renin-angiotensin system in the brains of males and females and found sex differences in several genes in discrete brain regions. These results provide new information to help understand key sex differences in ingestive behaviors, and highlight the need for additional research to understand baseline sex differences, particularly in light of the new NIH initiative to balance sex in biomedical research.

Sex differences in microglial phagocytosis in the neonatal hippocampus

Microglia regulate brain development through many processes, such as promoting neurogenesis, supporting cell survival, and phagocytizing progenitor, newly-born, and dying cells. Many of these same developmental processes show robust sex differences, yet very few studies have assessed sex differences in microglia function during development. Hormonally-induced sexual differentiation of the brain occurs during the perinatal period, thus we examined sex differences in microglial morphology, phagocytosis, and proliferation in the hippocampus during the early postnatal period. We found that the neonatal female hippocampus had significantly more microglia with phagocytic cups than the male hippocampus. We subsequently found that female microglia phagocytized more neural progenitor cells and healthy cells compared to males, but there were no sex differences in the number of newly-born or dying cells targeted by microglial phagocytosis. We found that the number of phagocytic microglia in females was reduced to male-typical levels by treatment with estradiol, the hormone responsible for masculinizing the rodent brain. Females also had higher expression of several phagocytic pathway genes in the hippocampus compared to males. In contrast to robust sex differences in phagocytic microglia, we found no sex differences in the number of microglia with amoeboid, transitioning, or ramified morphologies or differences in three-dimensional reconstructions of microglial morphology. While we did not find a baseline sex difference in microglial proliferation during or following the prenatal gonadal hormone surge in males, we found that estradiol treatment increased microglia proliferation in females. Overall, these data show that there are important sex differences in microglia function in the hippocampus during the early neonatal period.

Sex differences in the course of schizophrenia across diverse regions of the world.

This study explores sex differences in the outcomes of patients with schizophrenia (clinical/functional remission and recovery) across diverse regions of the world (Northern Europe, Southern Europe, Central and Eastern Europe, Latin America, East Asia, and North Africa and the Middle East). Data (n=16,380 for this post hoc analysis) were taken from the World-Schizophrenia Health Outcomes Study. In most regions, females had a later age at first service contact for schizophrenia, a lower level of overall/negative symptom severity, lower rates of alcohol/substance abuse and paid employment, and higher percentages of having a spouse/partner and independent living. Overall, females had slightly higher rates of clinical remission (58.0% vs 51.8%), functional remission (22.8% vs 16.0%), and recovery (16.5% vs 16.0%) at 36 months (P<0.001 for all). This pattern was consistently observed in Southern Europe and Northern Europe even after controlling for baseline sex differences, but not in other regions. In Central and Eastern Europe, rates of clinical remission were higher in females at 36 months, but those of functional remission and recovery were similar between males and females. The opposite was observed for Latin America. In East Asia, sex differences were rarely observed for these outcomes. Finally, in North Africa and the Middle East, sex differences in these outcomes were pronounced only in regression analyses. These regional variations shed light on the importance of psychosocial and cultural factors and their effects on sex in the prognosis of schizophrenia.

Systematic Analysis of Adverse Event Reports for Sex Differences in Adverse Drug Events.

Increasing evidence has shown that sex differences exist in Adverse Drug Events (ADEs). Identifying those sex differences in ADEs could reduce the experience of ADEs for patients and could be conducive to the development of personalized medicine. In this study, we analyzed a normalized US Food and Drug Administration Adverse Event Reporting System (FAERS). Chi-squared test was conducted to discover which treatment regimens or drugs had sex differences in adverse events. Moreover, reporting odds ratio (ROR) and P value were calculated to quantify the signals of sex differences for specific drug-event combinations. Logistic regression was applied to remove the confounding effect from the baseline sex difference of the events. We detected among 668 drugs of the most frequent 20 treatment regimens in the United States, 307 drugs have sex differences in ADEs. In addition, we identified 736 unique drug-event combinations with significant sex differences. After removing the confounding effect from the baseline sex difference of the events, there are 266 combinations remained. Drug labels or previous studies verified some of them while others warrant further investigation.