Search Results (92)

Chronic pain is a highly prevalent and disabling condition with a well-documented female predominance in incidence, severity and persistence. These sex differences are driven by sexually dimorphic neuroimmune mechanisms rather than psychosocial factors alone. This systematic review was conducted to comprehensively synthesize human clinical and translational evidence on sex-specific neuroimmune and glial cell pathways underlying chronic pain. Scientific literature was systematically searched from database inception to December 2025 across multiple biomedical databases to identify relevant clinical and translational studies. Across pain conditions, convergent evidence demonstrated that chronic pain mechanisms diverge by sex at cellular and molecular levels. Male-predominant pathways were characterized by microglial activation, particularly P2X4 receptor–mediated signaling and brain-derived neurotrophic factor–dependent neuronal disinhibition, supported by neuroimaging, transcriptomic, and pharmacological data. In contrast, female-predominant mechanisms involved adaptive immune processes, including CD4⁺ and CD8⁺ T cell infiltration, pannexin-1–dependent leptin release, chemokine signaling, and astrocyte-mediated neuroimmune crosstalk. Sex-specific cytokine and chemokine profiles, differential glial activation patterns, and divergent neuroimmune–endocrine interactions further distinguished pain pathways between males and females. Despite consistent mechanistic trends, substantial heterogeneity within each sex, limited sex-stratified power in many studies, and variability in outcome measures constrained quantitative synthesis and generalizability. The findings indicate that chronic pain is not a unitary disorder but rather a collection of mechanistically distinct conditions shaped by biological sex. These results highlight the limitations of sex-neutral therapeutic strategies and support the development of precision medicine approaches incorporating sex-informed neuroimmune biomarkers and mechanism-matched interventions. Future studies should prioritize adequately powered sex-stratified analyses, integration of neuroimmune biomarkers and clinical trial designs capable of detecting sex-by-treatment interactions. Full article

Sexual size dimorphism (SSD) refers to the phenomenon where males and females of the same species exhibit differences in overall or partial body size, and it is widespread among mammals, birds, reptiles, and fish. Notably, this dimorphism is significantly influenced by the sexually dimorphic secretion of growth hormone (gh), a key pituitary-derived growth regulator. Commonly, the secretion of gh is positively regulated by glucagon family members such as growth hormone-releasing hormone (ghrh) and adenylate cyclase-activating polypeptide 1 (adcyap1). To explore the stimulators for pituitary hormones (especially gh) in the teleost, we performed genome-wide identification and functional characterization of the glucagon family on Chinese tongue sole (Cynoglossus semilaevis) that exhibits typical female-biased sexual size dimorphism. Four members of adcyap1/vasoactive intestinal polypeptide(vip)/ghrh family and ten members of their receptor family were identified. Expression pattern analysis revealed high expression of adenylate cyclase-activating polypeptide 1b (adcyap1b) and its receptors in the brain. Moreover, two alternative splice variants for the adcyap1b gene were discovered, resulting from the skipping of exon 4. Following the acquisition of the two eukaryotic recombinant protein splice variants (ADCYAP1b_tv1 and ADCYAP_tv2) from HEK 293T cells, incubation experiments were conducted using C. semilaevis pituitary cell line. The results demonstrated that both variants promoted the expression of gh, pro-opiomelanocortin (pomc), and corticoliberin (crh), but ADCYAP1b_tv1 had a significantly stronger effect and uniquely stimulated prolactin (prl) and somatolactin (sl). This study demonstrates a functional divergence between the two ADCYAP1b splice variants in teleosts, with ADCYAP1b_tv1 acting as a more potent and versatile pituitary hormone stimulator. Further research on their receptor-binding affinity and downstream signaling pathways would be valuable for exploring the mechanism underlying sexual size dimorphism. Full article

Serotonin reuptake inhibitors (SSRIs) are commonly prescribed to pregnant women experiencing depression. Such drugs, however, might adversely affect placenta and fetal brain development. Parietal trophoblast giant cells (pTGCs) in the mouse placenta are postulated to internalize maternal serotonin (5-HT) via transport through SERT, encoded by Slc6a4, and to provide the initial source of 5-HT to the emerging brain via the placental–brain axis. Genetic deletion of Slc6a4 in pTGCs has been hypothesized to impact placental and fetal brain development. A transgenic mouse line with high-affinity SERT, encoded by Slc6a4, was selectively deleted by pairing mice with Cre recombinase linked to Prl2c2, with LoxP sites flanking the Slc6a4 gene. PRL2C2 is solely expressed by pTGCs and other giant cells of the placenta. To compare placental and fetal brain development in selective Slc6a4 KO and WT mice, 5-HT content in the placenta and fetal brains of conceptuses was measured. No significant differences in 5-HT content were evident between knockout (KO) and wild-type (WT) placentas or fetal brains. However, there were significantly fewer pTGCs in KO placentas compared to WT (p ≤ 0.05). Sexually dimorphic differences in gene expression were evident in the placenta and fetal brain between KO and WT counterparts, with female conceptuses showing the most dramatic responses, including decrease in Prl7a2, Prl5a1, Prl3a1, Slc28a3, and Ceacam 15 in female placental samples. These findings suggest that ablation of Slc6a4 in pTGC disrupts the placenta–brain axis in a sex-dependent manner. The results might have important clinical ramifications for pregnant women being treated with SSRIs. Full article

The global obesity pandemic has unveiled adipose tissue as a pivotal, active modulator of neurological health, intricately linking metabolic dysfunction to chronic pain and cognitive decline. This review synthesizes current evidence to propose a unified “neuro-metabo-inflammatory” model of the adipose-central nervous system (CNS) axis. We articulate a framework where, in pathological states such as obesity, dysfunctional adipose tissue releases a milieu of factors—including adipokines, lipids, and extracellular vesicles—that propagate peripheral and central neuroinflammation, disrupt blood–brain barrier integrity, and impair synaptic plasticity. These processes converge to drive pain sensitization and cognitive deficits. Critically, we evaluate the clinical evidence linking visceral adiposity to multisite chronic pain and accelerated cognitive impairment, while highlighting sexually dimorphic pathways. The review moves beyond cataloging findings to prioritize the most robust mechanisms, assess evidence quality, and identify key translational gaps. We conclude by discussing emerging therapeutic strategies targeting this axis and proposing precise directions for future research to disentangle the complex temporal and spatial dynamics of adipose–CNS communication. Full article

Background/Objectives: The external occipital protuberance (EOP) is an anatomical landmark with radiological and anthropological implications. Although the morphology and prevalence of EOP have been studied in many populations, data remain lacking for Northeastern Thais. Population-specific characterization of EOP variation may improve diagnostic and forensic accuracy applications. Materials and Methods: This study has investigated the prevalence and morphometry of EOPs using two primary sources: CT brain scans from 750 adult patients (375 males, 375 females) and anatomical investigations of 1060 dry skulls. EOPs were classified as Type I (flat), Type II (crest), or Type III (spur). Measurements for Type II (crest-shaped) EOPs were performed using standardized linear and angular parameters. Data differences were analyzed by sex and age group; intra- and inter-observer reliability was calculated for imaging measurements. Results: The study showed that Type II EOP was most common in both CT (56.1%) and dry skull (64.6%) samples. Type I was significantly more frequent in females (CT: 37.0%; dry skull: 32.8%), while Type III prevalence was higher in males (CT: 28.5%; dry skull: 18.4%). After age 60, the incidence of Type III declined in both datasets. Type II EOPs were significantly larger in males (mean crest length in CT: males 7.1 ± 0.1 mm, females 5.6 ± 0.1 mm; p < 0.001), with notable sex- and age-associated variation in associated angular dimensions. Conclusions: These findings established the first region-specific morphometric reference database for EOP in Northeastern Thais. The demonstrated sexual dimorphism in Type II EOP measurements provided the foundational data that may support future applications in clinical assessment, radiological interpretation, and forensic sex estimation in this population. Full article

Traumatic brain injury (TBI) is a leading cause of death and disability, with broad heterogeneity in recovery outcomes particularly noted in pediatric patients. Children post-TBI are vulnerable to aberrant neurodevelopment, specifically in structural and functional neural networks as they correlate with cognitive, behavioral, and motor function outcomes. Consideration for sex as a biological variable which innately influences neuroanatomy, neurodevelopment, and functional organization may elucidate risk factors for negative outcomes in pediatric TBI. For example, TBI damage in sexually dimorphic neural structures and networks may explain deficits in social cognition, working memory, as well as internalizing and externalizing behaviors, which differentially impact the quality of life in male versus female TBI patients. However, characterization of sex in conjunction with developmental patterns in normal and injured pediatric populations is limited due to small sample sizes, the low representation of females, a lack of longitudinal data, and the utilization of analyses that are not sensitive enough to detect subtle differences in TBI pathologies and recovery between the sexes. This review aims to analyze and synthesize the existing evidence regarding the influence of sex on the developmental trajectories of neuroanatomical structures, white and gray matter compartments, and the network disruptions that align with sex-specific functional recovery outcomes following pediatric TBI. The delineation of these sex influences will facilitate better precision-based medicine approaches to improve patient outcomes. Full article

Heterotopic ossification (HO) is a disease characterized by ectopic bone formation, which can occur following severe traumatic brain injury (TBI). However, the underlying mechanisms remain poorly understood. In this study, we established a stem cell model using adipose-derived stem cells (ADSCs) and skeletal stem cells (SSCs) to examine osteogenic factors present in the sera of TBI patients. Incubation of ADSCs and SSCs with osteoinductive medium supplemented with TBI serum significantly enhanced osteogenic differentiation, particularly in male ADSCs and both female and male SSCs, with male SSCs exhibiting the highest osteogenic potential. Furthermore, we identified TGF-β1 as an important factor involved in these osteogenic processes. Elevated levels of TGF-β1 were detected in the serum of male TBI patients 14 days post-injury. Cellular assays revealed a sexual dimorphism in response to TGF-β1 neutralization: osteogenic differentiation in male SSCs was significantly reduced, while no effect was detectable in female SSCs. These findings, together with the rarity of HO in female patients, suggest that TGF-β1 plays a central role in the development of HO in males. Furthermore, this study highlights the importance of considering sex-specific mechanisms in traumatic HO for the development of sex-specific therapy options. Full article

Microtus ochrogaster, monogamous prairie voles, serve as translational animal models for studying monogamy and pair bonding. Microglia, the resident immune cells of the brain, are one of several cell types still poorly understood in non-classical animal models including prairie voles. Microglia are known to play mechanistic roles in mediating social behaviors using inflammatory signaling, but the relationship between microglia reactivity and pair bonding has not yet been investigated. The present study first developed a robust protocol for quantitative histological visualization of microglia in Microtus ochrogaster. Second, it investigated differences in microglia morphology, a reliable index of microglia reactivity and function, in pair-bonded vs. unpaired voles. Sections containing prefrontal cortex (PFC) and anterior cingulate cortex (ACC) were stained for ionized calcium-binding adaptor molecule I (Iba1) using immunohistochemistry (IHC). IHC results provided evidence for the successful use of murine histological protocols in prairie voles. Quantification results revealed a sexually dimorphic effect of pair bonding on microglia: somas were significantly larger in pair-bonded vs. unpaired females, and somas were significantly smaller in pair-bonded vs. unpaired males. Additionally, somas were significantly larger in unpaired males than females, with larger somas indicating higher microglia reactivity. While conclusions are limited due to the small sample size, results provide novel characterization of microglia morphology in the frontal cortex and elucidate how pair bonding may influence microglia function in a sexually dimorphic manner. Full article

Prolactin is a hormone with demonstrated roles in the brain, including neurogenesis, neuroprotection, learning, stress response or memory consolidation. To determine the prolactin expression in the rat hippocampus during aging and to resolve some controversies related to the presence of prolactin in the hippocampus, the aim of this study was to analyze whether changes occur in the expression of prolactin during different stages of life. To determine this, we designed an experimental study in which we analyzed the expression and location of prolactin in the rat hippocampus, Ammon’s horn and Dentate Gyrus, during different stages of life (prepubertal, postpubertal, young adult, adult and old) and checked if there are differences related to sex. Overall, the results obtained show that prolactin is present in the rat hippocampus and that prolactin is synthesized, as deduced from the findings obtained via ELISA, immunohistochemistry, qPCR and in situ hybridization. After analyzing the correlation between serum and hippocampal prolactin levels and comparing the amounts of Prl mRNA and the hormone, the results obtained suggest that hippocampal prolactin has a dual origin: local synthesis of the hormone and its passage from the blood. On the other hand, the amounts of prolactin and its mRNA in the hippocampus vary with sex and age, suggesting the existence of age-related sexual dimorphism. The results obtained suggest that hippocampal aging is related to a decrease in the hippocampal prolactin system, which helps to better understand brain aging. Full article

Since the initial report indicating that LPA₁ signaling plays a key role in initiating nerve injury-induced neuropathic pain (NeuP), subsequent studies using knockout mice and LPA_1/3 antagonists have demonstrated that LPA₁ and LPA₃ signaling impact NeuP and fibromyalgia (FM) models. In the present study, we identified hyperalgesia sexual dimorphism involving LPA_1/3 signaling in the intermittent psychological stress induced-related FM-like model called intermittent psychological stress (IPS)-induced generalized pain (IPGP) model where the hyperalgesia in IPGP mice was abolished in LPA₁- and LPA₃-knock-out mice. Pharmacological intervention by intraperitoneal (i.p.) treatments with the LPA_1/3 antagonist Ki16425 consistently prevented hyperalgesia. However, intracerebroventricular treatments with Ki16425 abolished hyperalgesia in male, but not female, mice. Notably, intrathecal treatments of Ki16425 did not prevent hyperalgesia. Further studies revealed that splenocytes derived from female IPGP mice could initiate hyperalgesia via adoptive transfer in naïve mice, and this effect was abolished when donor mice were pre-treated with Ki16425 (i.p.). Thus, these studies identify male-specific LPA_1/3-mediated mechanisms in the brain underlying IPGP, as well as distinct LPA-LPA_1/3-mediated peripheral immune mechanisms. Full article

Malaria, the deadliest parasitic disease in the world, is sexually dimorphic, inflammatory, and oxidative. Males experience more severe symptoms and mortality than females do; therefore, the roles of 17β-estradiol and testosterone in this phenomenon have been studied. Both hormones affect oxidative stress, the primary mechanism of Plasmodium elimination. Estradiol has antioxidant activity, but the role of testosterone is controversial. Testosterone increases oxidative stress by reducing superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) activities, which increase lipoperoxidation in the testis. However, the antioxidant properties of testosterone in prostate and nervous tissue have also been reported. The discrepancies are probably because when testosterone levels increase, the aromatase enzyme transforms testosterone into estrogens that possess antioxidant activity, which masks the results. Therefore, it is unknown whether testosterone is involved in the sexual dimorphism that occurs in oxidative stress in malaria. In this work, we administered testosterone and simultaneously inhibited aromatase with letrozole to evaluate the role of testosterone in the sexually dimorphic pattern of oxidative stress that occurs in the blood, spleen, and brain of male and female CBA/Ca mice infected with Plasmodium berghei ANKA (P. berghei ANKA). Testosterone triggers parasitemia in males, who also display more oxidative stress than females in the absence of infection, leading to sexually dimorphic patterns. Interestingly, increasing testosterone levels in infected mice reduced oxidative stress in males and increased oxidative stress in females, reversing or eliminating the dimorphic patterns observed. Oxidative stress varies in each tissue; the brain was the most protected, while the blood was the greatest damaged. Our findings highlight the role of testosterone as a regulator of oxidative stress in a tissue and sex-specific manner; therefore, understanding the role of testosterone in malaria may contribute to the development of sex-specific personalized antimalarial therapies. Full article

Sleepy cod (Oxyeleotris lineolata) is native to Australia and is now an economically valuable fish cultured in China and Southern Asian countries. Its growth rate exhibits as sexually dimorphic, with males generally growing more rapidly and attaining a larger body size compared to females. Thus, the effective development of sex control breeding can significantly contribute to increased yields and output value. Nevertheless, due to the lack of genomic and transcriptomic data, the molecular mechanisms underlying sex determination and gonadal differentiation in sleepy cod remain poorly understood. In this study, long-read PacBio isoform sequencing (Iso-Seq) was performed to obtain a full-length transcriptome from a pooled sample of eight tissues (kidney, brain, liver, muscle, heart, spleen, ovary and testis). A total of 30.41 G subread bases were generated and 49,113 non-redundant full-length transcripts with an average length of 2948 bp were produced. Using the full-length transcriptome as a reference, short-read Illumina sequencing was performed to investigate the differences in gene expression at the transcriptome level between ovaries and testes from 12-month-old individuals. A total of 19,102 differentially expressed transcripts (DETs) were identified, of which 8510 (44.55%) were up-regulated in the ovary and 10,592 (55.45%) were up-regulated in the testis. The DETs were mainly clustered into 241 KEGG pathways, in which oocyte meiosis and arachidonic acid metabolism were the most relevant pathways involved in gonadal differentiation. To verify the validity of the transcriptomic data, 20 DETs were selected to investigate the gonad expression profiles based on qPCR. The expression levels of all 20 screened genes were consistent with the transcriptome sequencing results. The present study provides new genetic resources—including full-length transcriptome sequences and annotation information—as a coding genomic-level reference for sleepy cod—yielding valuable insights into the genetic mechanisms of sex determination and gonadal differentiation in this economically important species. Full article

Prenatal alcohol exposure (PAE) affects around 40,000 newborns every year and poses a significant health risk. Although much is already known about the neurotoxic mechanisms of PAE, new findings continue to emerge. Studies with mouse models show that PAE leads to overexpression of proinflammatory cytokines and chemokines in the brain, which disrupts important neurodevelopmental processes such as cell migration, survival and proliferation of neurons. The chemokine CXCL16 is overexpressed in the brain following various impairments, including PAE. This study shows that CXCL16 expression varies by developmental stage and sex, consistent with known sexual dimorphism in immune responses. In females, CXCL16 expression may be influenced by estrogen-related mechanisms, possibly related to the alcohol-mediated rebound effect described here. In contrast, the male hippocampus shows greater resilience to PAE-induced CXCL16 changes. Furthermore, the presence of CXCL16 in neuronal nuclei suggests a role in gene regulation, similar to other chemokines such as CCL5 and CXCL4. These findings shed light on the role of chemokines in hippocampal neuroplasticity and may pave the way for better treatment of fetal alcohol spectrum disorder (FASD). Full article

The Chinese tongue sole (Cynoglossus semilaevis) is a marine flatfish of significant economic value, characterized by pronounced female-biased sexual size dimorphism (SSD). Sexual differences of cell number and gene expression within the PIT-1 lineage of the pituitary gland may be crucial for interpreting the female-biased SSD of C. semilaevis. Among hormones secreted by PIT-1 cell lineage, growth hormone (gh), prolactin (prl), prolactin 2 (prl2), and somatolactin (sl) comprise a gene family within the extensive superfamily of class-1 helical cytokines. To better understand the function of the gh/prl/sl in teleost SSD, we firstly identified five genes of the gh/prl/sl family (gh, sl, prl, prl2a, and prl2b) and their receptors (ghra, ghrb, prlra, prlrb, and prlr-like) from C. semilaevis at the genome-wide level. Phylogenetic analyses revealed that the gh/prl/sl family and their receptors were each clustered into five distinct groups. More microsatellites were revealed in the intron 2 of gh gene of female rather than the male and pseudo-male individuals, which is positively correlated with its sexual expression pattern. Interaction network prediction indicated that gh, prl, and sl may collectively contribute to individual growth and development. A FRET experiment showed that ghra can act as a receptor for sl. Additionally, the transcripts of the gh/prl/sl family and their receptors exhibited varying abundances in the pituitary, brain, gonad, and liver of both female and male C. semilaevis, with most ligands showing the highest abundance in the female pituitary. Furthermore, gh and sl were found to be maternally expressed. The knock-down of gh, prl, and sl in the pituitary cells could lead to the expression change of igf1, c-fos, and sos2. This study provided a foundation for further functional characterization of the gh/prl/sl gene family, contributing to a deeper understanding of the growth and reproductive mechanisms in C. semilaevis. Full article

Sex differences in the neurobiology of responses to chronic stress have been widely discussed but remain poorly understood. We found that chronic unpredictable mild stress (CUMS) experienced during adolescence induced different behavioral patterns in adult males and females. Immunohistochemical analysis of the CA1 field of the dorsal and ventral hippocampus revealed no quantitative or morphological changes in astrocytes in the long term after CUMS. Real-time PCR analysis showed no increase in the expression level of SigmaR1 after CUMS relative to individual housekeeping genes. Analysis of mouse cerebral cortex homogenates showed that IL-1β levels only decreased after CUMS in males. However, the SigmaR1 levels were significantly higher in the CUMS groups than in the control groups in both sexes. It can be concluded that biological sex and age influence the response to CUMS, although not in all cases. Further studies are needed to understand the effects of chronic stress on males and females. This is important because men and women have different risks for stress and mental disorders. Full article