bims-simsho 2026-01-04 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2026–01–04
27 papers selected by
Chun-Chi Chang, Lunds universitet

Hormones, heat, and health: a comprehensive review of sex-based differences in brown and beige fat biology.
The Impact of Biological Sex and Female Sex Hormone Concentration on the Maximal Metabolic Steady State.
The Role of Estrogen Receptors in Lung Diseases.
Sex-specific transcriptome similarity networks elucidate comorbidity relationships.
The importance of sex dimorphism in liver metabolism and progressive liver diseases.
Distinct Effects of GnRH Immunocastration Versus Surgical Castration on Gut Microbiota.
Endometrial immune profile: A predictor of pregnancy success.
Single Nucleus MultiOmics Links Novel Transcription Factor Motifs to Murine Hepatic Sex Differences in Chromatin Accessibility and Metabolic Dysfunction-Associated Steatotic Liver Disease.
Sex hormones, the gut microbiome, and neurodegenerative diseases: Lifespan perspective.
The pioneering gut microbiome acquired via different delivery modes in neonates shapes distinct immune and metabolic environments.
Bioavailable testosterone reduces the risk of lung squamous cell carcinoma: a comprehensive data study.
A transcriptome-wide association study of sex effects identifies sex-specific nasal epithelial gene expression profiles for total IgE.
Uncoupling Insulin Sensitivity From Longevity: A Sex-Dependent Effect of Hepatic Glucagon Signaling.
Human epidermal growth factor receptor 2 and androgen receptor expression in invasive breast carcinoma of no special type with medullary pattern.
Sex differences in bile acid homeostasis and excretion underlie the disparity in liver cancer incidence between males and females.
Sex-Specific Diet-Microbiota Interactions in Ageing: Implications for Healthy Longevity.
Adipose-androgen crosstalk in polycystic ovary syndrome: mechanisms and therapeutic implications.
Estradiol Modulates the Sensitivity to Vancomycin of Lactobacillus paracasei and Staphylococcus aureus Biofilms-Constituents of Human Skin and Vaginal Microbiota.
GnRHa Triggering Versus hCG Triggering in PCOS Patients Who Undergo Fresh or FET Cycles: Is the King Fake or Real?
17β-Estradiol and Its Metabolites Induce Oxidative Damage to Membrane Lipids in Primary Porcine Thyroid Follicular Cells-Comparison Between Sexes.
The Impact of Sex Hormones on Transcranial Magnetic Stimulation Against the Oxidative Stress in the Pathogenesis of Multiple Sclerosis.
Vitexin Reduced the Dihydrotestosterone (DHT)-Induced Fibrosis in KGN Cells by Regulating the NR4A1/NLRP3 Pathway.
Endometrial Microbial Profile in Infertile Women with Chronic Endometritis: Intensified Culturomics and 16S rDNA Gene Sequencing.
The evaluation of the effect of estrogen administration on cutaneous wound healing in Staphylococcus aureus-infected diabetic and nondiabetic mice.
Longitudinal sex differences in cerebrovascular ageing in older adults: results from the brain in motion study.
Sex Differences in the Response to Lung Cancer and Its Relation to Programmed Cell Death Protein-1/Programmed Death-Ligand-1 Checkpoint Therapies.
"Rare but Not Forgotten Five Cases of Swyer Syndrome": Case Series and Literature Review.

Biol Sex Differ. 2025 Dec 31.

Hormones, heat, and health: a comprehensive review of sex-based differences in brown and beige fat biology.

Chikkamagaluru Gopalakrishna Shashank, Raga Mandali, Umesh D Wankhade.

  This review takes a close look at the biology of brown and beige fat, not just as thermogenic tissues, but as active metabolic organs influenced by sex, hormones, age, and even environment. Brown adipose tissue (BAT) and beige adipocytes differ in their origins, gene expression, and regulation. These differences are especially relevant when considering how they behave in males and females. Across both animal and human studies, females show higher BAT volume and more efficient thermogenic activity. Estrogen, acting mainly through estrogen receptor alpha (ERα), increases uncoupling protein 1(UCP1) expression, promotes mitochondrial biogenesis, and supports the formation of beige fat within white adipose tissue. In contrast, testosterone and glucocorticoids tend to reduce thermogenic gene expression and shift fat storage toward visceral depots, which increases metabolic risk, particularly in men. These hormone-driven effects are not limited to adulthood. Puberty, pregnancy, menopause, and andropause all influence thermogenic capacity in sex-specific ways. We also outline the key signaling pathways behind beiging such as PR domain-containing 16 (PRDM16), Peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1α), and β3-adrenergic signaling and how they interact with sex hormones to shape thermogenic responses. Findings from Positron Emission Tomography with Computed Tomography (PET/CT) imaging, genetic models, and molecular profiling show that beige and brown fat are regulated by distinct mechanisms and developmental cues depending on sex. We also review how BAT activity is linked to a lower risk of type 2 diabetes, cardiovascular disease, and inflammation, particularly in women with obesity. Conditions like Polycystic Ovary Syndrome (PCOS), hormone therapy, and exposure to endocrine-disrupting chemicals further influence BAT function in sex dependent ways. Understanding how brown and beige fat respond differently in men and women to internal and external signals, is critical. These differences have clear implications for developing targeted, more effective strategies to treat obesity and metabolic disease.

Keywords:  Beige fat; Brown fat; Menopause; Metabolic health; Obesity; PCOS; Sexual dimorphism; Thermogenic adipocytes; UCP1

DOI:  https://doi.org/10.1186/s13293-025-00787-4
J Appl Physiol (1985). 2025 Dec 29.

The Impact of Biological Sex and Female Sex Hormone Concentration on the Maximal Metabolic Steady State.

Mira I Schoeberlein, Jake H Hudgins, Olivia DeVelasco, Brad W Wilkins.

  PURPOSE: The goal was to explore the impact of fluctuating female sex hormone concentrations on the work rate delineating sustainable from unsustainable work rates at the heavy-severe domain boundary or maximal metabolic steady state (MMSS). METHODS: Thirty endurance trained participants (15 F / 15 M; V̇O2MAX 48.1 ± 5.2 vs 57.3 ± 5.3 ml·min-1·kg-1; P = 0.001) completed four MMSS estimation protocols at distinct sex hormone profiles. Serum sex hormone concentrations, specifically estradiol, progesterone, and testosterone, were determined during each study visit. To identify MMSS at each hormone profile, participants completed a muscle oxygenation (%SmO2) zero-slope prediction cycling protocol once a week for four weeks. The %SmO2 zero-slope protocol consisted of four, 4-min stages (2-min rest) spanning intensity domains. The work rate associated with MMSS was determined using linear regression analysis between workload and %SmO2 signal slope during the final 2 min of each stage. RESULTS: Linear mixed models showed male sex to be a significant predictor of power at MMSS (p < 0.001), but changes in sex hormone concentrations were not associated with changes in MMSS work rate. No sex differences in MMSS were found when normalized to lean body mass (LBM) (P = 0.224) nor across the four visits (P = 0.074). CONCLUSIONS: The LBM normalized work rate at MMSS was similar between men and women. Fluctuations in sex hormone profile in women were not associated with differences in the heavy-severe exercise domain boundary, nor were there any observed sex differences across distinct hormone profiles.

Keywords:  Estrogen and Progesterone; cycling; muscle oxygenation; sex differences; sex hormones

DOI:  https://doi.org/10.1152/japplphysiol.00913.2025
Am J Physiol Lung Cell Mol Physiol. 2025 Dec 31.

The Role of Estrogen Receptors in Lung Diseases.

Carolyn Damilola Ekpruke, Patricia Silveyra.

  Lung diseases are major global causes of morbidity and mortality, yet the molecular basis of their observed sex differences remains unclear. Beyond their roles in reproductive biology, estrogens are central regulators of pulmonary homeostasis through three principal receptors: estrogen receptor α (ERα), estrogen receptor β (ERβ), and the G-protein-coupled estrogen receptor (GPER1). These receptors are widely expressed across the airway epithelium, smooth muscle, fibroblasts, lung endothelium, and immune cells, where they integrate slow, genomic transcriptional programs and rapid, membrane-initiated signaling cascades to regulate inflammation, oxidative balance, and tissue remodeling. ERβ, often the dominant pulmonary isoform, tends to preserve extracellular matrix integrity and attenuate maladaptive inflammation, whereas ERα frequently amplifies pro-inflammatory transcriptional programs. GPER1 mediates rapid non-genomic responses that modulate vascular tone, airway smooth-muscle reactivity, and innate immune function, and is both an important regulator of allergic inflammation and a modulator of oncogenic signaling. Together, estrogen receptor subtype balance, subcellular localization, and ligand context determine whether estrogenic signaling is protective or pathogenic. Clinically, this framework helps explain life-course and sex differences, such as post-pubertal female predominance of asthma, menstrual and pregnancy-related exacerbations, and enhanced Chronic Obstructive Pulmonary Disease (COPD) susceptibility in women at lower tobacco exposure. In this review, we synthesize mechanistic and clinical evidence across lung diseases; delineate areas where data remain incomplete or contradictory; and outline opportunities for experimental and translational innovation. These include development of receptor-selective or biased ligands, inhaled or localized delivery, and implementation of sex-aware clinical trial designs to leverage estrogen-receptor biology for precision respiratory therapeutics.

Keywords:  Asthma; COPD; Estrogen receptors; Lung cancer; Sex differences

DOI:  https://doi.org/10.1152/ajplung.00060.2025
Commun Med (Lond). 2025 Dec 30.

Sex-specific transcriptome similarity networks elucidate comorbidity relationships.

Jon Sánchez-Valle, María Flores-Rodero, Felipe Xavier Costa, Jose Carbonell-Caballero, Iker Núñez-Carpintero, Rafael Tabarés-Seisdedos, Luis Mateus Rocha, Davide Cirillo, Alfonso Valencia.

BACKGROUND: Biological differences between women and men lead to variations in the prevalence and progression of many diseases, influencing diagnosis, management, and treatment outcomes. However, the biological mechanisms that contribute to sex differences in disease co-occurrence remain largely unexplored. This study aims to uncover the molecular processes underlying sex-specific patterns of comorbidity.
METHODS: We analyze gene expression data from over 100 diseases, considering the biological sex of each sample (8906 samples, 43.06% women). For each sex, we construct disease similarity networks based on differential gene expression profiles and identify enriched biological processes. We then compare these networks with epidemiological data from population-level comorbidity studies to assess their concordance. Finally, we investigate drugs associated with sex-specific comorbidities to identify potential differences in therapeutic response.
RESULTS: We show that 13-16% of transcriptomically similar disease pairs are sex-specific. These similarities recover 53-60% of known comorbidities that differ between women and men. Diseases can co-occur through the differential alteration of biological processes, with immune and metabolic pathways playing a greater role in women, and extracellular matrix organization and signal transduction pathways in men. We also identify drugs differentially linked to comorbid diseases depending on sex, suggesting possible sex-dependent effects on disease co-occurrence.
CONCLUSIONS: Our findings demonstrate that transcriptomic data can reveal sex-specific molecular links between diseases and suggest that biological sex should be considered in the design of therapeutic strategies and drug administration.

DOI: https://doi.org/10.1038/s43856-025-01329-0
Biol Sex Differ. 2025 Dec 27.

The importance of sex dimorphism in liver metabolism and progressive liver diseases.

Eva Kočar, Kaja Blagotinšek Cokan, Tinkara Kreft, Tadeja Režen, Damjana Rozman.

  The liver is a central metabolic organ with pronounced sex-specific differences shaped by sex hormones, sex chromosome-linked gene expression, ageing, and circadian rhythm. These factors influence disease susceptibility, progression, and treatment response, with notable differences between females and males in the prevalence, severity, and clinical outcomes of metabolic dysfunction-associated steatotic liver disease. This condition represents a growing global health burden that can progress to hepatocellular carcinoma, the second leading cause of cancer-related death worldwide. Despite this impact, sex remains an underexplored variable in liver research, and the molecular mechanisms by which sex influences disease development remain poorly understood. In this review, we examine the key determinants of sex differences in liver pathogenesis. We highlight the protective role of estrogen signaling in female liver metabolism, the increased vulnerability to disease progression after menopause, and the contribution of circadian regulation to sex-specific outcomes. We further discuss how the lack of systematic inclusion of both sexes in preclinical and clinical studies limits the identification of biomarkers and the development of effective therapeutic interventions. Incorporating sex as a biological variable is therefore essential to improve mechanistic understanding, translational relevance, and the personalization of treatment approaches. Particular emphasis is placed on animal models that reflect sex-specific liver physiology and pathophysiology, as these provide valuable frameworks for studying disease progression and testing targeted interventions. In summary, recognizing and integrating sexual dimorphism in liver metabolism is crucial to advancing prevention, diagnosis, and treatment strategies. Addressing sex differences is critical for developing accurate diagnostic tools and personalized therapeutic approaches, ultimately improving outcomes for both women and men with liver disease.

Keywords:  Animal models; Fibrosis; HCC; Liver; MASH; MASLD; Sexual dimorphism

DOI:  https://doi.org/10.1186/s13293-025-00811-7
Animals (Basel). 2025 Dec 05. pii: 3512. [Epub ahead of print]15(24):

Distinct Effects of GnRH Immunocastration Versus Surgical Castration on Gut Microbiota.

Fanli Kong, Ruohan Yang, Xingyu Zhou, Yuanyuan Shen, Wenhao Wei, Xianyin Zeng, Xiaogang Du, Xinfa Han.

  Surgical castration, a common practice in animal husbandry, raises animal welfare concerns and adversely affects growth performance. Active immunization against gonadotropin-releasing hormone (GnRH) provides a non-surgical alternative. Both methods ultimately suppress sex hormone production, but their comparative effects on the gut microbiota, a crucial regulator of host health and metabolism, remain unclear. Here, 60 Sprague Dawley (SD) rats were randomly allocated into three groups-control (n = 20; 10 female and 10 male), surgical castration (n = 20; 10 female and 10 male), and GnRH immunocastration groups (n = 20; 10 female and 10 male)-at 4-5 weeks of age to comparatively investigate the impacts of surgical versus GnRH immunocastration on the gut microbiota. Our study demonstrated GnRH immunocastration significantly reduced gonadal weight, effectively suppressing gonadal development to a level comparable to surgical castration. However, the two methods induced distinct, sex-dependent shifts in the gut microbiota. Surgical castration reduced the gut microbial community diversity, whereas the community structure of GnRH immunocastrated rats more closely resembled that of the control group, indicating a milder impact on the microbial diversity and composition. Notably, GnRH immunocastration resulted in higher microbial alpha diversity than surgical castration in both female and male SD rats. Specific bacterial genera, such as Clostridia_UCG014, Lactobacillus, and Lachnospiraceae_UCG006, were similarly altered in both surgical castration and GnRH immunocastration female SD rats, while Intestinimonas and Erysipelatoclostridiaceae_UCG004 were concurrently changed in male SD rats. Conversely, Eubacterium_nodatum_group exhibited opposite responses, increasing with GnRH immunocastration but decreasing with surgical castration in male SD rats. Functional prediction revealed fundamental sex differences in microbial metabolic pathways. In females, nitrogen metabolism, glyoxylate/dicarboxylate metabolism, and mismatch repair were changed, while the pathways involved in siderophore biosynthesis, the citrate cycle (TCA cycle), genetic information processing, and amino acid metabolism were changed in male SD rats. In conclusion, GnRH immunocastration appears to be a less disruptive intervention, better preserving microbial diversity and inducing a unique functional profile. These findings highlighted the importance of considering the castration method's impact on the gut microbial ecosystem in animal production and provided insights for developing humane and effective approaches to animal population control.

Keywords:  GnRH immunocastration; SD rats; gut microbiota; sexual dimorphism; surgical castration

DOI:  https://doi.org/10.3390/ani15243512
Reprod Biol. 2025 Dec 31. pii: S1642-431X(25)00190-1. [Epub ahead of print]26(1): 101174

Endometrial immune profile: A predictor of pregnancy success.

Sina Baharaghdam, Shima Karimi, Mohammad Esfini Farahani, Leili Aghebati-Maleki, Mehdi Yousefi.

  The likelihood of a successful pregnancy is influenced by a set of variables that influence endometrial receptivity, including hormonal, genetic, metabolic, age, lifestyle, and immunological factors. Among these, the endometrial immune profile has received particular attention as a critical actor of implantation and embryo tolerance. Dynamic fluctuations in immune cell populations-such as macrophages, dendritic cells, uterine natural killer cells, and regulatory T cells-across the menstrual cycle might significantly affect the endometrium's capacity to support successful implantation. Recent evidence highlights that disruptions in the quantity, phenotype, or function of these immune cells contribute to impaired endometrial receptivity in infertility-related disorders, including recurrent implantation failure, recurrent pregnancy loss, endometriosis, and polycystic ovary syndrome. This review provides a comprehensive assessment of immune cell composition and function in the healthy endometrium compared to pathological conditions, emphasizing how immune dysregulation may impair pregnancy. Furthermore, we evaluate both current and emerging diagnostic modalities-from immunohistochemistry and flow cytometry to high-resolution single-cell transcriptomics-and endometrial microbiome impact on immune profiling that enables more precise characterization of immune profile dysregulation, alongside established and investigational therapies, with particular attention to their efficacy and mechanistic rationale. By integrating these insights, a clinically oriented framework can be provided to guide the development of personalized diagnostic algorithms and targeted immune-based therapies that, ultimately, could lead to improved implantation rates and live birth outcomes in individuals facing infertility disorders with immunological causes.

Keywords:  Endometrial receptivity; Immune profile; Implantation failure; Infertility

DOI:  https://doi.org/10.1016/j.repbio.2025.101174
bioRxiv. 2025 Oct 31. pii: 2025.10.31.685903. [Epub ahead of print]

Single Nucleus MultiOmics Links Novel Transcription Factor Motifs to Murine Hepatic Sex Differences in Chromatin Accessibility and Metabolic Dysfunction-Associated Steatotic Liver Disease.

Kritika Karri, Ting-Ya Chang, Maxim Pyatkov, Shashi Gandhi, Trevor Siggers, David J Waxman.

The liver exhibits striking sexual dimorphism in gene expression that impacts drug and lipid metabolism and disease susceptibility, with males showing substantially higher predisposition to metabolic dysfunction-associated steatotic liver disease (MASLD) and its complications including hepatocellular carcinoma. These sex differences are primarily controlled by sexually dimorphic pituitary growth hormone (GH) secretion patterns; however, the underlying transcriptional and epigenetic regulatory networks remain only partially understood. Here, we generated paired single-nucleus chromatin accessibility (snATAC-seq) and gene expression (snRNA-seq) profiles from 46,188 liver nuclei isolated from male, female and continuous GH-infused male mice to comprehensively map the epigenetic basis of hepatic sexual dimorphism. We identified 127,957 accessible chromatin regions genome-wide, including thousands of novel regions enriched specifically in non-parenchymal cells. Sex-biased differentially accessible chromatin regions (DARs) were almost exclusively hepatocyte-localized, and continuous GH infusion feminized their accessibility, demonstrating that plasma GH patterns alone are sufficient to reprogram sex-biased hepatocyte chromatin landscapes. Correlation-based peak-to-gene linkage analysis mapped these DARs to sex-biased gene targets and revealed that regulatory interactions are constrained by topologically associated domain boundaries. Motif enrichment analysis identified both established regulators (STAT5, CUX2, BCL6) and novel transcription factors (TFs) at sex-biased DARs. ATAC-seq footprinting revealed novel TF motifs predicted to be occupied at DARs linked to sex-biased genes implicated in MASLD, providing mechanistic insights into the male bias in fatty liver disease. Further, motif co-occurrence analysis revealed TF clusters likely cooperating to regulate sex-dependent gene expression programs. We also identified stringently cell type-specific regulatory regions with cell type-specific TF motifs that define the regulatory architecture underlying hepatocyte and non-parenchymal cell identities. This comprehensive multiOmic atlas elucidates TF networks controlling sex-dependent liver gene expression and serves as a foundational resource for understanding molecular mechanisms underlying sex disparities in MASLD and other liver diseases.

DOI: https://doi.org/10.1101/2025.10.31.685903
Neural Regen Res. 2025 Dec 30.

Sex hormones, the gut microbiome, and neurodegenerative diseases: Lifespan perspective.

Sarah Stahlke, Carsten Theiss.

  The gut-brain axis represents a highly integrated communication network, connecting the gastrointestinal tract and the central nervous system via neural, immune, endocrine, and metabolic pathways. Steroid hormones, such as estrogens, androgens, and glucocorticoids, play a pivotal role in modulating these interactions across the lifespan. These hormones influence the composition of microbiota, intestinal permeability, and neuroimmune responses, thereby shaping brain function and behavior. Emerging evidence suggests a correlation between disruptions in the gut-brain axis and the onset and progression of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and multiple sclerosis. The diseases exhibit distinct sex-specific patterns in terms of prevalence, symptomatology, and progression. These patterns are often the consequence of differences in steroid hormone levels, receptor distribution, and immune responses. Despite these differences, the role of sex as a biological variable remains underrepresented in experimental and clinical research. This review synthesizes current evidence on how steroid hormones modulate gut-brain axis interactions and how these mechanisms contribute to neurodegeneration in a sex-specific manner. We highlight recent findings on hormonal regulation of the gut microbiome and its impact on neuroinflammation and neuronal vulnerability. This overview focuses not only on Parkinson's disease, in which genetic variations in the gene for brain-derived neurotrophic factor have been observed among others as triggers for dopaminergic neurodegeneration. In addition, Alzheimer's disease and multiple sclerosis are also considered, in which the prevalence of intestinal dysbiosis and impaired intestinal barrier function have been identified as significant influencing factors. This review provides a comprehensive framework for understanding the gender-specific neurobiology of gut-brain axis by integrating perspectives from the fields of endocrinology, neuroimmunology, and microbiome research. It is argued that a targeted investigation of the interactions between hormones and gut-brain axis is essential for the development of sex-specific therapeutic strategies for neurodegenerative diseases.

Keywords:  enteric nervous system; gut-brain axis; lifespan; neurodegenerative diseases; progesterone; steroid hormones

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00932
medRxiv. 2025 Oct 02. pii: 2025.09.30.25337005. [Epub ahead of print]

The pioneering gut microbiome acquired via different delivery modes in neonates shapes distinct immune and metabolic environments.

Sivaranjani Namasivayam, Hector N Romero-Soto, Mickayla Bacorn, P Juliana Perez-Chaparro, Andrew S Burns, Shreni Mistry, Nathan Brandes, Audrey Chong, Gwendolyn Cooper, Ian S LaCroix, Phoebe LaPoint, Keona Banks, Qing Chen, Anal Patel, Noel T Mueller, Maria Gloria Dominguez-Bello, George L Maxwell, Shira Levy, Benjamin Schwarz, Yasmine Belkaid, Suchitra K Hourigan.

BACKGROUND: Cesarean section (CS) delivery is associated with an increased risk of inflammatory diseases, hypothesized to be driven by differences in the microbiome acquired at birth compared to vaginally delivered (VD) infants. How delivery mode associated differences in initial colonizers directly modulate early life immune education and metabolic development is poorly understood.
OBJECTIVE: First, to investigate how differences in pioneering colonizers associated with delivery mode directly modulate early life immune education and metabolic programming. Second, to examine the effect of vaginal seeding, an intervention aimed to restore the microbiome of CS infants to a VD state.
DESIGN: Germ-free mice were colonized with transitional stool from VD, CS or CS-delivered and vaginally seeded neonates. Immune cell populations, serum immunoglobulin levels, and fecal microbiome and metabolome profiles were analyzed.
RESULTS: Mice colonized with stool from VD neonates displayed increased numbers of myeloid cells at barrier tissues, whereas CS microbiome colonized mice exhibited decreased Th1/Th2 ratios and increased serum IgE levels. Key amino-acid pathways including tryptophan metabolism, riboflavin co-enzymes and carbohydrate metabolites were significantly enriched in the murine VD fecal metabolome and correlate with the increased abundance of Escherichia typically observed in the VD microbiome. Mice colonized with stool from CS neonates who received vaginal seeding, resulted in increased regulatory T cells and serum IgA in mice, suggesting potential benefits of vaginal seeding.
CONCLUSION: Collectively, our studies demonstrate the ability of pioneering colonizers to set the immune and metabolic tone that could have long-lasting effects and provide avenues for microbiome-mediated interventions.

DOI: https://doi.org/10.1101/2025.09.30.25337005
J Transl Med. 2025 Dec 29.

Bioavailable testosterone reduces the risk of lung squamous cell carcinoma: a comprehensive data study.

Jihang Luo, Puyu Liu, Jian Song, Yin Li, Meng Xu.

   BACKGROUND: The association between testosterone and lung cancer remains unclear. This study investigates the relationship between testosterone levels and lung cancer risk, focusing on bioavailable testosterone levels (BTLs), total testosterone levels (TTLs), and sex hormone-binding globulin (SHBG) in relation to lung cancer subtypes.
METHODS: We utilized bidirectional and multivariable Mendelian randomization (MR) analyses based on genome-wide association studies (GWAS) to assess causal links. To validate the findings clinically, immunohistochemical (IHC) staining for androgen receptor (AR) expression and survival analyses were conducted on a cohort of 90 patients with lung squamous cell carcinoma (LUSC).
RESULTS: MR analysis demonstrated that higher BTLs were significantly associated with a reduced risk of LUSC (OR = 0.365, P = 0.001), while no significant associations were observed for TTLs or SHBG. Reverse MR analysis found no causal effect of lung cancer on testosterone levels. Multivariable MR confirmed BTLs as an independent protective factor. In the clinical cohort, AR expression was significantly associated with better prognosis, showing improved median progression-free survival (12.3 vs. 9.0 months, P = 0.01) and median overall survival (35.3 vs. 29.4 months, P < 0.01). Cox regression identified AR expression as an independent protective factor for patient outcomes. However, study limitations include potential residual confounding, ethnic heterogeneity between European GWAS data and Asian clinical cohorts, and the lack of direct experimental validation.
CONCLUSIONS: Our findings suggest that higher BTLs may play a protective role against LUSC. BTLs and AR expression show potential as valuable biomarkers for the diagnosis and prognostic assessment of LUSC.

Keywords:  Androgen receptor (AR); Bioavailable testosterone levels (BTLs); Lung squamous cell carcinoma (LUSC); Mendelian randomization (MR); Total testosterone levels (TTLs)

DOI:  https://doi.org/10.1186/s12967-025-07639-0
J Allergy Clin Immunol. 2025 Dec 31. pii: S0091-6749(25)02233-X. [Epub ahead of print]

A transcriptome-wide association study of sex effects identifies sex-specific nasal epithelial gene expression profiles for total IgE.

Molin Yue, Yidan Sun, Yueh Ying Han, Glorisa Canino, Erick Forno, Judith M Vonk, Elin T G Kersten, Wei Chen, Gerard H Koppelman, Juan C Celedón.

   BACKGROUND: Asthma is the most common chronic respiratory disease in children, with known sex differences in prevalence and severity that shift after puberty. Total IgE, a marker of T2-high asthma, also differs by sex and age and may contribute to these disparities.
METHODS: We tested whether nasal epithelial gene expression differs by sex and interacts with total IgE in ways that may inform asthma pathogenesis in a transcriptome-wide association study in nasal epithelial samples from participants in two cohorts: EVA-PR (including 398 Puerto Rican youths aged 12-20 years) and PIAMA (including 303 Dutch adolescents aged 16 years).
RESULTS: Differential expression analysis by sex identified 406 genes at FDR-P < 0.05, with 225 upregulated and 181 downregulated in females compared with males. Top differentially expressed genes included hormone- and immune-related genes such as THRB, IL17REL, and CD207. Among these, six genes (MNDA, IFIT1, IFIT2, SLC22A17, JAG2, and MT3) showed significant sex-by-total IgE interaction effects on expression. Pathway enrichment analyses revealed that females had activation of eukaryotic translation pathways (e.g., EIF2 signaling), while males showed activation of immune-related pathways (e.g., interferon signaling). Additionally, 19 pathways were enriched in the sex-by-IgE interaction model, including TREM1 and cytokine storm signaling.
CONCLUSIONS: Our findings provide new insights into sex-specific regulation of gene expression in airway epithelium and its interaction with total IgE, helping to explain observed sex differences in asthma. This underscores the need to consider sex as a biological variable in asthma research and points to potential targets for precision medicine approaches.

Keywords:  EVA-PR; PIAMA; TWAS; sex; total IgE

DOI:  https://doi.org/10.1016/j.jaci.2025.12.1003
Aging Cell. 2026 Jan;25(1): e70349

Uncoupling Insulin Sensitivity From Longevity: A Sex-Dependent Effect of Hepatic Glucagon Signaling.

Alexander Tate Lasher, Ben Heckman, Parth Sarker, Kaimao Liu, Liou Y Sun.

Glucagon, a key hormone in maintaining euglycemia during fasting, also exerts broad metabolic effects, including regulation of lipid oxidation, adiposity, insulin sensitivity, and metabolic rate. However, its role in aging and longevity remains largely unexplored, a significant omission given the extensive research on dietary restriction and insulin signaling in lifespan modulation. Here, we investigated the impact of hepatic glucagon receptor (GCGR) signaling on lifespan using a liver-specific GCGR knockout (LKO) mouse model. While male LKO mice exhibited normal lifespan, female LKO mice displayed a significant reduction in survival. Strikingly, and in contrast to prevailing expectations based on metabolic improvements, this shortened lifespan in females occurred despite marked enhancements in metabolic health, including reduced body weight and adiposity, preferential glucose oxidation, elevated metabolic rate, and enhanced glucose tolerance and insulin sensitivity throughout adulthood. Underpinning this detrimental outcome, transcriptomic and biochemical analyses revealed a striking, female-specific activation of pro-inflammatory pathways, notably NF-κB and cGAS-STING signaling, in the liver and kidney of aged LKO mice as well as reduced expression of hepatic xenobiotic metabolism genes. These findings identify a novel, sexually dimorphic role for the hepatic glucagon receptor in regulating lifespan, linking its interruption in females to late-life inflammation and reduced longevity despite an otherwise beneficial metabolic phenotype.

DOI: https://doi.org/10.1111/acel.70349
J Cancer Res Ther. 2025 Dec 01. 21(6): 1110-1114

Human epidermal growth factor receptor 2 and androgen receptor expression in invasive breast carcinoma of no special type with medullary pattern.

Manxiu Li, Liting Jin, Jun Shao, Tiejun Wang, Yaojun Feng.

   BACKGROUND: Invasive breast carcinoma of no special type with medullary pattern (BCNST-MP) is a rare subtype of breast cancer. Previous studies have reported the high prevalence of the triple-negative phenotype in BCNST-MP. This study aimed to investigate the prevalence of human epidermal growth factor receptor 2 (HER2)-low and androgen receptor (AR) expression in this distinct breast cancer subtype.
METHODS: We conducted a retrospective analysis of breast cancer patients diagnosed at our center between 2019 and 2024. Medical records and pathology reports were reviewed to assess the clinicopathological characteristics of BCNST-MP.
RESULTS: A total of 45 patients with BCNST-MP met the inclusion criteria. The median age at diagnosis was 51 years. Most tumors (93.3%) measured ≤5 cm, and axillary lymph node metastasis was observed in 26.7% of cases. Eighty percent of the patients were estrogen receptor (ER)-negative, 84% were progesterone receptor (PR)-negative, and 75.6% were AR-negative. Regarding the HER2 status, 15.6% were HER2-positive, 33.3% exhibited HER2-low expression, and 51.1% had HER2-zero expression. With a median follow-up duration of 26 months, only one patient-a 30-year-old with triple-negative breast cancer-developed distant metastasis. An 82-year-old died of a cerebrovascular accident.
CONCLUSIONS: Our findings suggest that BCNST-MP tumors are rarely larger than 5 cm and are frequently lymph node-negative. Most patients were negative for ER, PR, AR, and HER2. Notably, HER2-low expression was observed in approximately 30% of cases, suggesting therapeutic implications.

Keywords:  Androgen receptor; HER2-low; invasive breast carcinoma; medullary pattern

DOI:  https://doi.org/10.4103/jcrt.jcrt_455_25
Elife. 2025 Dec 29. pii: RP96783. [Epub ahead of print]13

Sex differences in bile acid homeostasis and excretion underlie the disparity in liver cancer incidence between males and females.

Megan E Patton, Sherwin Kelekar, Lauren J Taylor, Angela E Dean, Qianying Zuo, Rhishikesh N Thakare, Sung Hwan Lee, Emily C Gentry, Morgan Panitchpakdi, Pieter Dorrestein, Yazen Alnouti, Zeynep Madak-Erdogan, Ju-Seog Lee, Milton J Finegold, Sayeepriyadarshini Anakk.

  Hepatocellular carcinoma (HCC), the common liver cancer, exhibits higher incidence in males. Here, we report that mice lacking bile acid (BA) regulators, Farnesoid X Receptor (FXR also termed NR1H4) and Small Heterodimer Partner (SHP also termed NR0B2), recapitulate the sex difference in liver cancer risk. Since few therapeutic options are available, we focused on understanding the intrinsic protection afforded to female livers. Transcriptomic analysis in control and NR1H4 and NR0B2 double knockout livers identified female-specific changes in metabolism, including amino acids, lipids, and steroids. To assess translational relevance, we examined if transcriptomic signatures obtained from this murine HCC model correlate with survival outcomes for HCC patients. Gene signatures unique to the knockout females correspond with low-grade tumors and better survival. Ovariectomy blunts the metabolic changes and promotes liver tumorigenesis in females that, intriguingly, coincides with increased serum bile acid (BA) levels. Despite similar genetics, knockout male mice displayed higher serum BA concentrations, while female knockouts excreted more BAs. Decreasing enterohepatic BA recirculation using cholestyramine, an FDA-approved resin, dramatically reduced the liver cancer burden in male mice. Overall, we reveal that sex-specific BA metabolism leading to lower circulating BA concentration protects female livers from developing cancer. Thus, targeting BA excretion may be a promising therapeutic strategy against HCC.

Keywords:  bile acid metabolism; cancer biology; liver cancer; mouse; sex differences

DOI:  https://doi.org/10.7554/eLife.96783
Nutrients. 2025 Dec 08. pii: 3833. [Epub ahead of print]17(24):

Sex-Specific Diet-Microbiota Interactions in Ageing: Implications for Healthy Longevity.

Julieta Herndez-Acosta, Armando R Tovar, Nimbe Torres.

  Background/Objectives: Diet-microbiota interactions shape ageing; however, their sex-specific dimensions remain poorly defined. Human studies rarely stratify analyses by sex, while most evidence of sex-dependent microbial and metabolic responses comes from preclinical models. This review synthesizes current findings on the sex-specific pathways linking diet, microbiota, and healthy ageing. Methods: A narrative review was conducted by integrating human observational studies, randomized controlled trials, and mechanistic animal research. Evidence was organized into four domains: (1) age-related changes in gut microbial composition; (2) microbiota-derived metabolites; (3) dietary patterns and functional nutrients; and (4) sex-specific endocrine and immunometabolism interactions influenced by the gut microbiota. Results: Ageing is characterized by dysbiosis, loss of short-chain fatty acid (SCFA)-producing taxa, expansion of Proteobacteria, and reduced production of key metabolites including butyrate, indoles, and polyamines. Dietary fiber, polyphenols, omega-3 fatty acids, and plant-based proteins help restore these pathways and mitigate inflammaging. Sex differences persist into later life: women show reduced estrobolome activity and SCFA decline after menopause, whereas men display higher levels of pro-atherogenic metabolites such as trimethylamine N-oxide (TMAO). Nutritional interventions, probiotics, and microbial metabolites exhibit sex-dependent responses in both human and animal studies. Conclusions: Diet-microbiota interactions shape ageing outcomes through sex-specific metabolic, hormonal, and immunological pathways. Incorporating sex as a biological variable is essential for developing personalized, nutrition-based strategies to support healthy ageing.

Keywords:  dietary patterns; gut microbiota; healthy ageing; inflammageing; microbial metabolites; precision nutrition; sex differences

DOI:  https://doi.org/10.3390/nu17243833
Front Endocrinol (Lausanne). 2025 ;16 1731179

Adipose-androgen crosstalk in polycystic ovary syndrome: mechanisms and therapeutic implications.

Muchu Ni, Hongyan Lei, Tao Ye, Yongzhou Wang.

  Polycystic ovary syndrome (PCOS) is the most common endocrine-metabolic disorder in reproductive-age women, characterized by hyperandrogenism (HA) and insulin resistance (IR). Despite its high prevalence, the underlying pathophysiology remains incompletely understood. In recent years, bidirectional interactions between androgens and adipose tissue (AT) have been recognized as a key driver of the vicious cycle in PCOS. This review systematically examines this core interaction mechanism: on one hand, dysfunctional AT (particularly visceral fat) exacerbates ovarian androgen overproduction by intensifying IR, inducing chronic low-grade inflammation (e.g., elevated TNF-α and IL-6), and reducing adiponectin levels. Conversely, HÀ exacerbates AT dysfunction and systemic IR by altering body fat distribution (central obesity), suppressing lipogenesis, impairing lipolysis, and disrupting adipokine secretion (e.g., reduced adiponectin, elevated leptin). This bidirectional positive feedback loop within the fat-androgen axis perpetuates the worsening metabolic and reproductive abnormalities in PCOS. Based on this mechanism, existing therapeutic strategies-including lifestyle interventions, insulin sensitizers (e.g., metformin), GLP-1 receptor agonists, and anti-androgens-partially exert their effects by improving AT function and antagonizing androgenic effects. Emerging therapies such as SGLT-2 inhibitors, BAT transplantation, anti-TNF-α therapies, and gut microbiota targeting offer promising new avenues for directly intervening in this axis and breaking the vicious cycle of PCOS. A deeper understanding of fat-androgen interactions is crucial for developing precision treatments for PCOS.

Keywords:  adipose tissue; hyperandrogenism; insulin resistance; ovulatory dysfunction; polycystic ovary syndrome

DOI:  https://doi.org/10.3389/fendo.2025.1731179
Microorganisms. 2025 Dec 05. pii: 2777. [Epub ahead of print]13(12):

Estradiol Modulates the Sensitivity to Vancomycin of Lactobacillus paracasei and Staphylococcus aureus Biofilms-Constituents of Human Skin and Vaginal Microbiota.

Anna M Mosolova, Nadezhda A Loginova, Ecaterina V Diuvenji, Artem G Chebotarevskii, Marina V Sukhacheva, Sergey V Tsibulnikov, Polina Y Bikmulina, Vera M Tereshina, Elena A Ianutsevich, Olga A Danilova, Aleksandra S Novikova, Vladimir K Plakunov, Sergey V Martyanov, Alexander I Netrusov, Andrei V Gannesen.

  We investigated the effects of vancomycin, estradiol, ethanol, and their combinations on the growth of mono- and binary-species biofilms of Lactobacillus paracasei and Staphylococcus aureus. It was found that vancomycin at a subinhibitory concentration of 0.001 µg/mL, estradiol, and ethanol acted antagonistically in all cases. This effect was observed across all strains studied. Furthermore, the effects of the active compounds were evident at population, cellular and molecular levels, and were reflected in changes to the count of colony-forming units (CFUs), gene expression, and the physiological and biochemical characteristics of cells (e.g., lipid composition of membranes and the extracellular matrix). Therefore, at subinhibitory concentrations of vancomycin in the medium, estradiol can modulate the antibiotic's effect on biofilms, thereby regulating deeply microbial communities.

Keywords:  Lactobacillus; Staphylococcus aureus; antibiotic resistance; antibiotics; biofilms; estradiol; hormones; microbial endocrinology; vancomycin

DOI:  https://doi.org/10.3390/microorganisms13122777
Medicina (Kaunas). 2025 Dec 11. pii: 2195. [Epub ahead of print]61(12):

GnRHa Triggering Versus hCG Triggering in PCOS Patients Who Undergo Fresh or FET Cycles: Is the King Fake or Real?

Muserref Banu Yilmaz, Reyyan Gokcen Iscan, Sevdenur Banu Yigit, Esra Tustas Haberal, Belgin Devranoglu, Ayse Nur Aksoy, Ali Irfan Guzel, Pinar Kumru.

  Background and Objectives: To evaluate the impact of gonadotropin-releasing hormone agonist (GnRHa) triggering compared to human chorionic gonadotropin (hCG) triggering on frozen-thawed and fresh embryo transfer outcomes in patients with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF). Materials and Methods: This retrospective cohort study analyzed 267 IVF cycles of 261 PCOS patients treated with GnRH antagonist protocols. Patients were divided into three groups: GnRHa-triggered frozen-thawed embryo transfer (ET) (n = 126), hCG-triggered frozen-thawed ET (n = 68), and hCG-triggered fresh ET (n = 73). Baseline characteristics, stimulation parameters, and cycle outcomes were compared between groups. A binary logistic regression analysis was established to identify independent predictors of clinical pregnancy. Results: The GnRHa-triggered group had significantly higher numbers of retrieved oocytes, mature (MII) oocytes, and fertilized oocytes compared to both hCG-triggered groups (p < 0.001). The number of obtained embryos and frozen embryos (good-quality embryos) was highest in the GnRHa group (p < 0.001). However, clinical pregnancy rates were comparable between the groups with a similar number and grade of transferred embryos (32.53%, 38.23%, and 32.87%, respectively). Multivariate regression analysis revealed that the grade of the transferred embryo was a significant predictor of clinical pregnancy (p = 0.034). Conclusions: This study provides insights into different triggering strategies for final oocyte maturation in PCOS patients. GnRH-agonist-triggered frozen-thawed cycles showed comparable clinical pregnancy outcomes to those of hCG-triggered cycles, with a potentially lower OHSS risk. The findings suggest that individualized triggering approaches based on patient characteristics and OHSS risk may be beneficial for PCOS patients undergoing IVF.

Keywords:  GnRHa triggering; IVF; PCOS; cycle outcome; hCG triggering; infertility

DOI:  https://doi.org/10.3390/medicina61122195
Int J Mol Sci. 2025 Dec 06. pii: 11807. [Epub ahead of print]26(24):

17β-Estradiol and Its Metabolites Induce Oxidative Damage to Membrane Lipids in Primary Porcine Thyroid Follicular Cells-Comparison Between Sexes.

Jan Stępniak, Małgorzata Karbownik-Lewińska.

  Sexual dimorphism significantly influences the epidemiology of thyroid disorders, with females exhibiting higher incidence of thyroid diseases. Estrogens and their hydroxylated metabolites are key regulators of cellular redox balance and may contribute to sex-specific susceptibility through pro-oxidative mechanisms. However, the impact of individual estrogen metabolites on oxidative stress in thyroid follicular cells remains poorly defined. Here, we investigated the pro-oxidative effects of 17β-estradiol (E2) and its hydroxylated metabolites-2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2), and 16α-hydroxyestrone (16α-OHE1)-in primary porcine thyroid cell cultures from males and females. Primary follicular thyroid cells were isolated from six male and six female pigs. Cells were exposed to E2 (100 nM) or its metabolites (1 μM), with or without Fenton reaction substrates (Fe2+ and H2O2), for 24 h. Lipid peroxidation (an index of oxidative damage to lipids) was quantified using BODIPY® 581/591 C11 fluorescence via flow cytometry. Basal lipid peroxidation did not differ between sexes. 2-OHE2 increased lipid peroxidation in both male and female thyroid cells, with a more pronounced effect observed in males. In contrast, 4-OHE2 selectively enhanced lipid peroxidation only in female cells. 16α-OHE1 elevated lipid peroxidation in both sexes. E2 significantly increased lipid peroxidation in both male and female cells. Among all compounds tested, E2 exhibited the most potent pro-oxidative activity, particularly in female-derived cells. These findings provide novel insights into the redox-modulating effects of estrogen metabolism in the thyroid and suggest a potential molecular basis for sex-related susceptibility to thyroid dysfunction. While based on an in vitro porcine model, the study increases our understanding of the mechanisms by which estrogenic compounds may influence thyroid pathophysiology, possibly including early events in thyroid disease development or oncogenesis.

Keywords:  17β-estradiol; estradiol metabolites; lipid peroxidation; oxidative damage; sexual dimorphism; thyroid

DOI:  https://doi.org/10.3390/ijms262411807
Biomolecules. 2025 Dec 10. pii: 1714. [Epub ahead of print]15(12):

The Impact of Sex Hormones on Transcranial Magnetic Stimulation Against the Oxidative Stress in the Pathogenesis of Multiple Sclerosis.

Begoña M Escribano, Manuel E Valdevira, Ana Muñoz-Jurado, Montse Feijóo, Eduardo Agüera, Javier Caballero-Villarraso, Manuel LaTorre, Ana I Giraldo, Abel Santamaría, Isaac Túnez.

   BACKGROUND: Multiple sclerosis (MS) is an autoimmune neurodegenerative disease with a higher prevalence in women. While puberty appears to act as a trigger for MS, menopause has no clear effects on disease progression. Many studies have shown that transcranial magnetic stimulation (TMS) is a potential antioxidant treatment for MS, but the sexual hormones have been identified as a potential factor affecting TMS response by affecting cortical excitability and possibly clinical outcomes.
METHODS: The aim of this study was to test the effect of estrogen, progesterone, and testosterone hormonal supplementation as adjuvants to TMS treatment of experimental autoimmune encephalomyelitis (EAE), an experimental model of MS. The effects of the three hormones were also tested as replacement therapy in ovariectomized rats treated with TMS. Clinical signs of the disease, as well as disease-induced oxidative stress and antioxidant defenses of the glutathione system, were evaluated.
RESULTS: TMS alone, without supplements or replacement therapies, is effective against oxidative stress caused by EAE. Estrogen and progesterone replacement therapy is useful to enhance the role of TMS in ovariectomized rats, activating antioxidant defenses and improving clinical signs of the disease.
CONCLUSIONS: TMS is effective in the treatment of MS, but its role could be enhanced, using hormone replacement therapy with estrogens and/or progesterone.

Keywords:  estrogens; experimental autoimmune encephalomyelitis; hormone replacement therapies; ovariectomy; progesterone

DOI:  https://doi.org/10.3390/biom15121714
J Steroid Biochem Mol Biol. 2025 Dec 31. pii: S0960-0760(25)00255-9. [Epub ahead of print] 106927

Vitexin Reduced the Dihydrotestosterone (DHT)-Induced Fibrosis in KGN Cells by Regulating the NR4A1/NLRP3 Pathway.

Jie-Jing Xu, Chuan-Zhi Yan, Zhi-Qiang Liu, Hao-Ran Sun, Ming-Yu Zhang, Qiu-Ping Huang, Chen-Xi Tong, Cheng-Xue Pan, Jia-Le Song, Yan-Yuan Zhou.

  Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder in women of reproductive age, markedly impairing their health and reducing overall quality of life. Vitexin is a natural flavonoid compound that has demonstrated diverse pharmacological properties, including anti-inflammatory and antioxidant effects. The aim of this study was to investigate the effects of vitexin on dihydrotestosterone (DHT)-induced fibrosis in KGN cells, as well as its regulatory role in the NR4A1/NLRP3 signaling pathway. Experimental findings suggested that DHT treatment resulted in decreased cell viability, disrupted sex hormone balance, increased oxidative stress, and elevated levels of inflammation and fibrosis in KGN cells. However, vitexin intervention significantly reversed these pathological changes. Transcriptomics sequencing analysis and molecular docking further indicated that NR4A1 is a pivotal target of vitexin in modulating the inflammatory response. Vitexin significantly inhibited NLRP3 inflammasome-mediated inflammation by activating NR4A1, conversely NR4A1 knockdown partially attenuated the protective effects of vitexin (P < 0.01). Therefore, vitexin was found to effectively ameliorate DHT-induced alterations in cell viability, sex hormone levels, oxidative stress, inflammation and fibrosis in KGN cells. These protective effects appear to be closely related to the regulation of the NR4A1/NLRP3 signaling pathway.

Keywords:  NR4A1/NLRP3 signaling pathway; Polycystic ovary syndrome; fibrosis; inflammation; vitexin

DOI:  https://doi.org/10.1016/j.jsbmb.2025.106927
Genes (Basel). 2025 Dec 01. pii: 1432. [Epub ahead of print]16(12):

Endometrial Microbial Profile in Infertile Women with Chronic Endometritis: Intensified Culturomics and 16S rDNA Gene Sequencing.

Bárbara Lara-Del-Río, Rocío Sánchez-Ruiz, Mónica Bernal-Sánchez, Francisco Ruiz-Cabello-Osuna, José María Navarro-Marí, José Gutiérrez-Fernández.

   BACKGROUND/OBJECTIVES: Chronic endometritis (CE) has been linked to implantation failure, recurrent pregnancy loss, and endometrial dysbiosis with low Lactobacillus abundance. We assessed the endometrial microbiota in infertile women with CE and the added value of combining intensified culturomics with 16S rDNA NGS.
METHODS: Cross-sectional study with descriptive results of 15 endometrial biopsies analyzed in parallel by intensified culture and 16S rDNA (V3-V6) sequencing (RA threshold ≥ 5%).
RESULTS: Culture yielded growth in 13/15 samples (86.7%), whereas NGS reported findings in 15/15 (100%). NGS provided additional taxa beyond culture in 14/15 (93.3%), while culture identified taxa missed by NGS in 10/15 (66.7%). In both culture-negative cases, NGS detected ≥1 taxon. Lactobacillus spp. appeared exclusively by NGS in 26.7% of samples; Fannyhessea vaginae showed the highest mean RA by NGS and did not grow in culture, underscoring complementarity.
CONCLUSIONS: 16S NGS complements intensified culturomics for characterizing the endometrial microbiota in CE, enhancing detection-especially when culture is negative-and supports a combined, clinically contextualized interpretation. Larger, controlled cohorts are warranted to validate diagnostic and prognostic utility.

Keywords:  Gardnerella; Lactobacillus; chronic endometritis; culturomics; endometrial microbiota; infertility; next-generation sequencing

DOI:  https://doi.org/10.3390/genes16121432
PLoS One. 2025 ;20(12): e0339341

The evaluation of the effect of estrogen administration on cutaneous wound healing in Staphylococcus aureus-infected diabetic and nondiabetic mice.

Kanae Mukai, Kohei Ogura, Yukari Nakajima, Toshio Nakatani.

Diabetes-related infection has become a difficult and significant global public health issue. Estrogen has specific hormones that promote cutaneous wounds in diabetic mice. However, the impact of estrogen on skin-colonized pathogenic bacteria is unknown. The purpose of this study was to look into how estrogen affects wounds infected with Staphylococcus aureus. Nondiabetic db/ + mice and diabetic db/db mice were both injured, and bacterial suspension was applied to each wound site. Estrogen or vehicles were injected intraperitoneally every 3-4 days after wounding. S. aureus infection impaired diabetic wounds and reduced collagen deposition. Immunostaining revealed that S. aureus infection reduced the number of blood and lymphatic vessels while increasing the number of neutrophils in nondiabetic wounds, regardless of estrogen treatment. Conversely, estrogen administration reduced the number of macrophages in S. aureus-infected nondiabetic wounds compared to vehicle-treated wounds. The number of lymphatic vessels was roughly double that of estrogen administration in S. aureus-infected nondiabetic wounds. Our findings showed that S. aureus infection in diabetic wounds delayed cutaneous wound healing due to excessive inflammation, inhibited collagen deposition, and impaired angiogenesis or lymphangiogenesis, although estrogen administration did not reverse these effects. Our findings also revealed that estrogen administration effectively treated S. aureus-infected nondiabetic wounds by regulating the immune response and increasing the synthesis of lymphatic vessels.

DOI: https://doi.org/10.1371/journal.pone.0339341
J Physiol. 2026 Jan 02.

Longitudinal sex differences in cerebrovascular ageing in older adults: results from the brain in motion study.

Connor Snow, Alison M H Donald, Kian M Pelechaty, Jordan Gibson, Michael D Hill, Jean M Rawling, Jayna Holroyd-Leduc, Kara Nerenberg, Jessalyn K Holodinsky, R Stewart Longman, Marc J Poulin.

  Older females are at an increased risk of dementia, cardiovascular disease and stroke. However sex differences in cardiovascular and cerebrovascular ageing remain poorly understood. We examined longitudinal changes in vascular function in 82 adults (mean age: 65.4 ± 5.1 years; range: 55-75; 39 females) at two timepoints (T1 and T2) 6.1 ± 1.4 years apart. We measured middle cerebral artery velocity (MCAv) and pulsatility (PI) using transcranial Doppler ultrasound, mean arterial blood pressure (MAP) with finger photoplethysmography and cerebrovascular conductance and resistance (CVCi, CVRi) at rest, with euoxic hypercapnia, and during submaximal exercise. At T1, males had higher resting PI but lower MCAv and CVCi compared to females. By T2, these sex differences were no longer evident, except for PI. Females experienced a greater increase in resting MAP and a decline in CVCi than males between T1 and T2. No sex-time interactions were observed for MCAv or PI. In females testosterone and log-transformed oestradiol were positively associated with MCAv at T1 and with the change in MCAv reactivity from T1 to T2, respectively. In males changes in oestradiol were positively associated with changes in cerebrovascular outcomes from baseline to follow-up. The faster rate of cerebrovascular ageing in females over the follow-up period may contribute to shifting sex differences in cerebrovascular function and their increased risk for dementia, cardiovascular disease and stroke. Sex hormones and menopause may play a key role in these sex-specific ageing trajectories, highlighting the need for sex-specific research to better understand cerebrovascular ageing. KEY POINTS: At baseline, females exhibited higher middle cerebral artery velocity and cerebrovascular conductance than males. By the follow-up, these differences were no longer present. Females experienced greater increases in mean arterial blood pressure and declines in cerebrovascular conductance than males. Higher baseline oestradiol in females was linked to more favourable changes in middle cerebral artery reactivity over time. Testosterone in females was associated with a greater middle cerebral artery velocity at baseline. In males, the change in oestradiol was positively associated with the change in cerebrovascular outcomes from baseline to follow-up. Baseline data had limited ability to predict vascular function at follow-up. Sex did not modify cerebrovascular ageing at the follow-up, suggesting sex- and age-dependent cerebrovascular ageing trajectories. Accelerated cerebrovascular ageing in older females may help explain their increased risk for disease. Sex-specific research is needed to elucidate the mechanistic links between menopause, sex-hormones and vascular ageing.

Keywords:  ageing; cerebrovascular function; sex differences

DOI:  https://doi.org/10.1113/JP289708
Cancers (Basel). 2025 Dec 11. pii: 3953. [Epub ahead of print]17(24):

Sex Differences in the Response to Lung Cancer and Its Relation to Programmed Cell Death Protein-1/Programmed Death-Ligand-1 Checkpoint Therapies.

Morgan Puglisi, Lauren May, Thusna Gardiyehewa, Joseph W Landry.

  Background/Objectives: Tumor cells exploit a variety of mechanisms to inhibit the immune response to lung cancer. The programmed cell death protein-1/programmed death-ligand-1 (PD-1/PD-L1) axis is frequently dysregulated in lung cancers with significant impacts on tumor growth. A sex difference has been observed in lung cancer progression and the response to PD-1/PD-L1 therapy, with the extent of benefits differing between men and women. The mechanism underlying these differences has not been fully established. Methods: In an attempt to better understand the nature of these differences, we searched the available literature for reports connecting sex specific bioactive molecules-including estrogens, progesterone, testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, leptin, and activin/inhibin-to sex differences in lung cancer and the response to PD-1/PDL-1 therapies. We then condensed this information to help generate testable hypotheses to explain the observed sex differences in lung cancer and its immunotherapies. Conclusions: From these efforts, we discovered potential roles for sex steroids, FSH, LH, prolactin, leptin, and activin/inhibin in both immune cell activity and cancer cell survival and in the response to PD-1/PD-L1 therapies.

Keywords:  NK cell; PD-1; PD-L1; T-cell anergy; lung cancer; sex hormones; sex-differences

DOI:  https://doi.org/10.3390/cancers17243953
J Obstet Gynaecol India. 2025 Dec;75(6): 472-476

"Rare but Not Forgotten Five Cases of Swyer Syndrome": Case Series and Literature Review.

Pushplata Kumari, Minakshi Kumari, Madhurima Barik, Lilly Varghese.

   Introduction: Swyer syndrome is a rare condition of complete gonadal dysgenesis due to mutations in the Y chromosome SRY gene, leading to testicular underdevelopment. In this condition individuals present with a female phenotype despite having a male karyotype (46, XY).
Method and Materials: This retrospective review of five cases of Swyer Syndrome at our centre since 2013.
Results: All five patients, raised as girls, presented at 18-31 years with primary amenorrhea; one had hyposmia. Breast development ranged from Tanner stage 1-4 with varying axillary hair. Internal exams showed an infantile uterus and cervix. Imaging revealed small to normal uterus and streak gonads. Elevated serum FSH and low testosterone confirmed the diagnosis (46, XY karyotype). Three patients underwent laparoscopic gonadectomy due to gonadoblastona risk; two were lost to follow-up. All received Estrogens and Progesterone replacement therapy development of secondary sexual characters.
Conclusions: Swyer syndrome requires high clinical suspicion for diagnosis. Early identification allows timely hormone therapy and consideration of gonadectomy to prevent gonadoblastona.

Keywords:  AIS (Androgen Insensitivity syndrome); DSD (Disorder of sex Development); Gonadal dysgenesis; HRT (Hormone Replacement Therapy); SRY-gene

DOI:  https://doi.org/10.1007/s13224-025-02183-9