bims-simsho Biomed News
on Systems immunology and sex hormones
Issue of 2026–02–15
forty-one papers selected by
Chun-Chi Chang, Lunds universitet
  1. Changes in temperature perception in transgender persons undergoing gender-affirming hormone therapy.
  2. Treg-γδ T cell axis determines sexual dimorphism in hepatocarcinogenesis.
  3. Androgen Receptor Signaling Induces CD8⁺ T Cell Dysfunction that is Reversed by Androgen Deprivation Therapy in Male Head and Neck Squamous Cell Carcinoma.
  4. Ovarian Hormones and Obesity Drive Th17-mediated Airway Inflammation through Estrogen Receptor-α Signaling.
  5. Sex differences in disease severity and immune responses in murine and human inflammatory arthritis.
  6. Sex Hormones-Mediated Modulation of Immune Checkpoints in Pregnancy and Recurrent Pregnancy Loss.
  7. Neuroendocrine crosstalk between sex and metabolic hormones: mechanisms and implications across the female reproductive spectrum.
  8. Multi-Omics Analysis Reveals Sex-Specific Signatures for BCG Vaccine Efficacy.
  9. Sex steroid receptors in colorectal cancer: implications for tumor progression, therapeutic opportunities, and sex-specific outcomes.
  10. Unveiling the Role of Sex Hormones and Reproductive Life Factors in Parkinson's Disease.
  11. ZNF711 promotes enzalutamide resistance through transcriptional and epigenetic modification of the androgen receptor signaling pathway.
  12. Correlation between follicular fluid hormonal levels in PCOS women and embryo development in ART cycles.
  13. Ablation of ACSS2 drives alteration to cardiac and hepatic proteomic landscapes in a tissue- and sex-specific manner.
  14. Sex and the Developmental Environment Shape Molecular Networks Underlying Bronchial Responsiveness in Mice.
  15. ADT and activation of HGF and WNT axes in double-null prostate cancer.
  16. Sex differences in human umbilical vein endothelial cells following ox-LDL injury.
  17. Integrated transcriptomic and metabolomic profiling reveals sex-specific regulation of breast muscle development during sexual maturation in Huanglang chicken.
  18. Y chromosome-linked EIF1AY deletion drives sex differences in multiple myeloma.
  19. The Ontogeny of Mouse Salivary Gland Macrophages Is Distinct between Sexes.
  20. Advances in the Role of Endometrial Microbiota Alterations in the Pathogenesis of Endometriosis.
  21. Gynecologic function and dysfunction in transmasculine and gender diverse individuals using testosterone therapy: a systematic review.
  22. Integrated chromatin and transcriptomic profiling reveals sex-specific mechanisms of gene regulation in hepatic nutrient responses.
  23. Mind the "CRP gender gap"! sex differences in CRP evolution over time in neonatal sepsis: a monocentric retrospective cohort study.
  24. Female reproductive microbiome in fertility care.
  25. The microbiome: a determinant of reproductive health and fitness?
  26. Characterization of endometrial immune cells during the window of implantation in infertile women with adenomyosis.
  27. In vitro sex-specific function-structure relationship in neonatal rat cardiac monolayers.
  28. Identification of A p300-SP1-BRD4 Transcriptional Axis as a Key Driver of AR Hyperactivation in Polycystic Ovarian Syndrome.
  29. Gut microbiota composition and systemic immune-inflammatory marker correlations in infertile women with endometriosis: a pilot case-control study.
  30. Re-shaping the immune response to influenza vaccination in a host with immune memory from influenza infection.
  31. Loss of GPR133 Promotes Enzalutamide Resistance in Prostate Cancer by Upregulating HSD3B1 and Intratumoral Androgen Synthesis.
  32. Sex-Specific Genetic Architecture of ALS: Evidence of a Female Protective Effect?
  33. Androgen receptor expression and immune characteristics of HER2-low metastatic triple-negative breast cancer.
  34. Sex Hormone-Dependent Modulation of Nrf2 and Its Association With Apoptosis, Metastasis, and Drug Resistance in Hepatocellular Carcinoma.
  35. Second to Fourth Digit Ratio (2D:4D) in Female Patients With Systemic Sclerosis: Evidence for Prenatal Androgen Exposure.
  36. The progression of sex differences in brain networks across the lifespan.
  37. High-protein diets increase microbiota associated p-cresol production in the colon and reduce gut barrier function in a sex-dependent manner.
  38. Underexplored maternal microbiomes: immune, metabolic, and microbial pathways shaping pregnancy outcomes.
  39. Biologic sex and health differences, diabetes, metabolic syndrome, and cancer.
  40. The Role of Sex Hormone-Binding Globulin (SHBG) as a Marker of Metabolic Dysfunction-Associated Steatotic Liver Disease, with an Extended Analysis in Both Men and Women.
  41. Commensal Microbiota and Reproductive Health in Livestock: Mechanisms, Cross-System Crosstalk, and Precision Strategies.
  1. Commun Med (Lond). 2026 Feb 07.
    Changes in temperature perception in transgender persons undergoing gender-affirming hormone therapy.
    Pauline Zimmermann, Martin Kaar, Theresa Bokeloh, Lotta Moll, Franziska Labinski, Falk Eippert, Matthias Blüher, Michael Stumvoll, Sascha Heinitz, Haiko Schlögl.
       BACKGROUND: There are known sex disparities in temperature perception with lower thermal detection thresholds found in people assigned female at birth compared to people assigned male at birth. However, underlying mechanisms of these differences and the influences of sex hormones are not yet sufficiently understood.
    METHODS: To assess the effects of sex hormones on temperature perception, we measured in a prospective observational cohort study temperature detection and pain thresholds with quantitative sensory testing and subjective temperature sensation in transgender patients undergoing gender-affirming hormone therapy (GAHT). We included 12 trans women (male-to-female transgender) and 17 trans men (female-to-male transgender) before and 3 and 6 months after start of GAHT. As a control group, we measured 13 cis women and 10 cis men without hormone treatment at the same timepoints.
    RESULTS: Here we show that temperature detection thresholds in persons assigned female at birth at baseline are lower than in persons assigned male at birth. Accordingly, in trans women, temperature detection thresholds decrease with GAHT. Pain detection thresholds do not differ between sexes assigned at birth and do not change with time.
    CONCLUSIONS: We demonstrate that in trans women undergoing GAHT with estradiol and cyproterone acetate sensitivity to temperature changes increases, consistent with the greater temperature sensitivity observed in cis women compared to cis men. Future studies need to assess at which neurobiological processing stages the relevant changes occur and what molecular mechanisms play a role.
    TRIAL REGISTRATION: NCT04838249.
    DOI:  https://doi.org/10.1038/s43856-026-01420-0
  2. Nat Commun. 2026 Feb 11.
    Treg-γδ T cell axis determines sexual dimorphism in hepatocarcinogenesis.
    Qing Liang, Qian Zhang, Wei Zhang, Rui Wang, Yinjiang Ma, Xiaoya Mai, Zhenglang Zhang, Bing Liu, Ping Lu, Huijuan Wan, Kejia Wang.
      Sexual dimorphism in the incidence and mortality of hepatocellular carcinoma (HCC) has been observed worldwide. Sex hormones play an essential role in determining male predominance in hepatocarcinogenesis. Here we reveal significant sexual dimorphism in regulatory T cells (Tregs). Compared with HCC in female mice/patients, tumours in male mice/patients are more enriched in Tregs. The male sex hormone androgen is shown to activate the NFκB pathway and reinforce the binding of NFκB to Ccl2 promoter loci in HCC cells, thereby promoting Ccl2 production, which facilitates the intratumoral recruitment of Tregs via the Ccl2-Ccr2 axis. Additionally, Treg infiltration shapes the HCC microenvironment through the suppression of the antitumorigenic activity of γδ T cells rather than CD8+T cells. Moreover, intratumoral hypoxia induces the secretion of Treg-derived extracellular vesicle (EV)-S100a4, which serves as a transcriptional corepressor to impede γδ T cell activation in an epigenetic manner. Overall, these results demonstrate that sex-specific differences in Tregs from HCC are related to the ability of androgen-dependent Ccl2 secretion to enable immune evasion through the suppression of γδ T cell activity.
    DOI:  https://doi.org/10.1038/s41467-026-69603-w
  3. Cancer Res. 2026 Feb 09.
    Androgen Receptor Signaling Induces CD8⁺ T Cell Dysfunction that is Reversed by Androgen Deprivation Therapy in Male Head and Neck Squamous Cell Carcinoma.
    Qiyue Wang, Zhuo Tan, Chuanming Zheng, Jiajie Xu, Qing Li, Shiqin Hong, Dilong Yu, Xiaoping Hu, Jiafeng Wang, Liehao Jiang, Ping Huang, Yiwen Zhang, Minghua Ge.
      Head and neck squamous cell carcinoma (HNSCC) exhibits a distinct sex disparity in incidence, with a higher incidence in males than females. Recent studies have suggested that this difference persists even after accounting for smoking and alcohol use, highlighting the need to elucidate the underlying biological mechanisms. In this study, we demonstrated that sex differences in HNSCC are androgen-dependent and identified androgen receptor (AR) signaling as a key regulator of the tumor immune microenvironment by modulating CD8⁺ T cell differentiation and function. Mechanically, early growth response 4 (EGR4) functioned as a direct downstream transcriptional effector of AR that induced CD8⁺ T cell dysfunction. Clinically, androgen deprivation therapy (ADT) was an effective therapeutic strategy in HNSCC, suppressing tumor growth in mice while improving intratumoral CD8⁺ T cell function. Moreover, combining ADT with immune checkpoint inhibitors led to improved antitumor efficacy. Together, these findings reveal ADT as a promising therapeutic approach to enhance the antitumor activity of sex-biased CD8⁺ T cells in HNSCC, which could inform the development of sex-biased immunotherapies for treating HNSCC patients.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-2384
  4. Am J Physiol Lung Cell Mol Physiol. 2026 Feb 13.
    Ovarian Hormones and Obesity Drive Th17-mediated Airway Inflammation through Estrogen Receptor-α Signaling.
    Emely Henriquez Pilier, Jacqueline-Yvonne Cephus, Shelby N Kuehnle, Elie Tannous, Alessandra Tomasello, Kaitlin Elizabeth McKernan, R Stokes Peebles, Katherine N Cahill, Jeffrey C Rathmell, Dawn C Newcomb.
      Obesity is a risk factor for increased prevalence and severity of asthma, particularly in females. As adults, females have increased prevalence of asthma compared to males. Yet, the mechanisms remain unclear on how sex hormones and obesity increase airway inflammation. We hypothesize that estrogen signaling through estrogen receptor-alpha (ER-α) in T cells increased airway inflammation in the context of obesity. To test our hypothesis, we utilized a high fat (HFD) on female and male mice that underwent ovariectomy or gonadectomy or in Esr1fl/fl X Cd4Cre+ male and female mice. As controls, mice in similar groups were fed normal chow. After 8-12 weeks on diets, house dust mite (HDM) sensitization and challenge occurred in all mice. Lungs and BAL fluid were harvested 24 hours after the last challenge. Ovarian hormones and ER-α signaling in T cells increased eosinophils, neutrophils, and Th17-mediated airway inflammation in the lungs of obese female mice. Additionally, using PBMCs from a well-characterized obese asthma cohort, we determined that obese women with asthma had increased Th17 cells compared to obese men with asthma. Our results show that ER-α signaling in T cells increases Th17-mediated airway inflammation in obese mice and that Th17 cells circulate at higher frequencies in women with asthma compared to men with asthma. Further research into the interplay between hormonal signaling and immune responses in asthma is essential for developing personalized treatments.
    Keywords:  Allergic Asthma; CD4+ T cells; Estrogen Receptor-alpha; Obesity
    DOI:  https://doi.org/10.1152/ajplung.00400.2025
  5. Biol Sex Differ. 2026 Feb 07.
    Sex differences in disease severity and immune responses in murine and human inflammatory arthritis.
    Mahadevappa Hemshekhar, Liam J O'Neil, Nyambura Kahia, Courtney L Marshall, Tamarah Singh, Mario Navarrete, Hani El-Gabalawy, Neeloffer Mookherjee, Janilyn Arsenio.
       BACKGROUND: Rheumatoid Arthritis (RA), a systemic autoimmune disorder of unknown etiology, disproportionately affects females at a 3:1 ratio compared to males. While biological sex differences in the immune system exist, sex-related differences in inflammatory and immune mediators of RA disease severity are undefined. Our objective was to characterize sex-related differences in immune responses in a murine collagen-induced arthritis (CIA) model and in human RA patients.
    METHODS: In CIA compared to saline control mice, inflammatory disease severity was assessed using standardized clinical scores. Anti-collagen antibodies, neutrophil elastase, calprotectin/ S100A8/A9 heterodimer, CRAMP, MMP3, and MMP9 were quantified by ELISA in the sera and joint tissues. Cytokine/chemokine levels in sera and joints were assessed using a Luminex based-44-Plex Discovery Assay® Array. Immunophenotyping of mouse splenic T cells analysis was performed by flow cytometry. Proteomic profiling of serum samples from an established RA cohort (72 female and 19 male that were at least 84% ACPA+) was performed using an aptamer-based SomaScan platform.
    RESULTS: We identified distinct sex-related differences in disease severity and pro-inflammatory profiles in the sera and joint tissues of CIA mice, with inflammatory responses that were male-skewed in the sera and female-skewed in the joints. Furthermore, we demonstrated heightened neutrophil activation markers and CD4+ T cell-mediated inflammatory responses in female CIA mice. Similar sex-related differences in neutrophil activation and leucocyte migration were identified in RA patients.
    CONCLUSIONS: Our study demonstrates novel sex differences in pro-inflammatory mediators and activities of neutrophils and CD4+ T cells associated with disease severity in CIA mice, and in human RA patients. These findings provide new insights into sex-related differences in immunological pathways associated with inflammatory arthritis, which may contribute to the sex disparity in RA pathogenesis.
    Keywords:  Collagen-induced arthritis; Immune responses; Rheumatoid arthritis; Sex differences
    DOI:  https://doi.org/10.1186/s13293-026-00840-w
  6. Int J Mol Sci. 2026 Jan 27. pii: 1265. [Epub ahead of print]27(3):
    Sex Hormones-Mediated Modulation of Immune Checkpoints in Pregnancy and Recurrent Pregnancy Loss.
    Michał Zych, Aleksander Roszczyk, Marzenna Zakrzewska, Radosław Zagożdżon, Leszek Pączek, Filip Andrzej Dąbrowski, Monika Joanna Kniotek.
      Recurrent pregnancy loss (RPL) is defined as the loss of two or more pregnancies before the 22nd gestational week and affects 10-15% of clinical pregnancies. Despite extensive diagnostics, over 50% of RPL cases remain unexplained, suggesting an important role for immunological mechanisms. Sex hormones (SH) are key regulators of immune responses during pregnancy; however, their influence on immune checkpoint proteins (ICPs) is poorly understood. This study evaluated the effects of progesterone, β-estradiol, and dihydrotestosterone (DHT) on ICP expression on immune cells, including Treg, NK, NKT, TC, Th, and T cells, collected from pregnant women and patients with unexplained RPL (uRPL). Peripheral blood mononuclear cells from 20 pregnant women and 20 uRPL patients were cultured for 48 h with SH. The expression of the first generation of ICPs-PD-1 and TIM-3-and the second-LAG-3, TIGIT, and VISTA-on T, NK, and NKT cells was analyzed by the flow cytometry method. In pregnant women, SH exerted modest effects, with DHT increasing VISTA and LAG-3 expression, while progesterone and estradiol mainly upregulated LAG-3 and TIM-3 on cytotoxic cells. In contrast, uRPL immune cells showed pronounced SH sensitivity, characterized by increased TIM-3 and VISTA expression and reduced TIGIT expression, particularly after DHT stimulation. In conclusion, SH modulates ICP expression in a cell-specific manner, with stronger effects observed in uRPL patients' lymphocytes. These findings highlight a potential role for hormonal and ICP-targeted strategies in RPL management.
    Keywords:  LAG-3; PD-1; TIGIT; TIM-3; VISTA; immune checkpoints; recurrent pregnancy loss; sex hormones
    DOI:  https://doi.org/10.3390/ijms27031265
  7. Discov Endocrinol Metab. 2026 ;2(1): 1
    Neuroendocrine crosstalk between sex and metabolic hormones: mechanisms and implications across the female reproductive spectrum.
    Virginie Goulet, Dali Léveillé, Jimeng Li, Alexandre Fisette.
      Energy metabolism and fertility are intricately linked across the female lifespan, from puberty through pregnancy, lactation, and menopause, ensuring that nutrition aligns with reproductive demands. We review here the nature of the synergistic crosstalk between sex hormones (notably estradiol) and metabolic hormones (including insulin, leptin, adiponectin, GLP‑1, ghrelin) within the brain, across the female reproductive spectrum. Estradiol amplifies metabolic signaling via shared pathways such as PI3K/Akt and JAK/STAT and enhances receptor sensitivity and secretion of multiple metabolic hormones, supporting the regulation of appetite, energy expenditure, and glucose homeostasis. Menopause disrupts this integrated network as estradiol declines, resulting in metabolic imbalances characterized by impaired hormone sensitivity, weight gain, and insulin resistance. In contrast, pregnancy enhances hormonal crosstalk through placental hormones, triggering metabolic realignments necessary for fetal energy demands. However, excessive or dysregulated adaptations may contribute to disorders like gestational diabetes. Understanding these synergies, and how estrogen receptor-associated co‑transcription factors can modulate them, represents a promising therapeutic direction to restore metabolic and reproductive health during hormonal transitions such as menopause and pregnancy.
    Keywords:  Adiponectin; Diabetes; Estradiol; GLP-1; Ghrelin; Hormones; Insulin; Leptin; Menopause; Neuroendocrinology; Obesity; Reproduction
    DOI:  https://doi.org/10.1007/s44417-026-00014-7
  8. Eur J Immunol. 2026 Feb;56(2): e70144
    Multi-Omics Analysis Reveals Sex-Specific Signatures for BCG Vaccine Efficacy.
    Qiuyao Zhan, Liang Zhou, Jianbo Fu, Xun Jiang, Xuan Liu, Wenchao Li, Simone J C F M Moorlag, Valerie A C M Koeken, L Charlotte J de Bree, Vera P Mourits, Leo A B Joosten, Yang Li, Mihai G Netea, Cheng-Jian Xu.
      Vaccines are a cornerstone of global public health, but their efficacy can vary significantly among individuals. Bacille Calmette-Guérin (BCG) vaccine against tuberculosis is one of the most used vaccines, and its efficacy is influenced by numerous factors, including sex, age, and geographical location. Systematic investigations using large-scale multi-omics analyses to dissect sex-specific determinants of vaccine efficacy remain limited. To better understand this variability and improve vaccine efficacy, we analyzed multi-omics data from a cohort of 321 healthy individuals vaccinated with BCG, integrating immune cell frequencies, single-cell RNA sequencing, plasma proteins, metabolites, and DNA methylation profiles. Our findings revealed significant sex-specific differences in immune pathways that contribute to BCG efficacy. In males, pre-vaccination signatures were associated with a stronger pro-inflammatory response, highlighting the importance of an innate-driven immune response, while females exhibited enhanced antigen presentation pathways and adaptive immune responses. This study underscores the need for understanding individual baseline immune status in relation to biological sex, an approach that could represent a promising path to optimizing vaccine effectiveness.
    Keywords:  BCG vaccine efficacy; baseline immune status; multi‐omics; sex‐specific; systems immunology
    DOI:  https://doi.org/10.1002/eji.70144
  9. Ann Med Surg (Lond). 2026 Feb;88(2): 1427-1436
    Sex steroid receptors in colorectal cancer: implications for tumor progression, therapeutic opportunities, and sex-specific outcomes.
    Shreya Singh Beniwal, Yash Janu, Kareema Cummings, Saif Syed, Rafael Everton Assunção Ribeiro da Costa, Prashasti Dahiya, Yujin Jeong, Alyanna Cabe Cacas, Chimuka Mwaanga, Jana Kotaich.
      Colorectal cancer (CRC) is a common malignancy with high incidence and mortality. Hormone signaling pathways, including estrogen, progesterone (P4), and androgen receptors (ARs), influence tumor development and progression and offer potential therapeutic opportunities. This study investigates the role of sex steroid receptors in CRC, explores therapeutic strategies, and considers sex-specific implications. Multiple cohort studies were analyzed based on gender, age, clinical stage, and tumor location. A structured literature search was conducted across PubMed, Web of Science, and Google Scholar, selecting studies with relevant sex-specific data and study designs. ERβ exhibits antitumor effects, with lower levels linked to tumors in females, while ERα and AR promote growth, particularly in postmenopausal women. Progesterone receptors (PGRs) are associated with poorer prognosis, though P4 treatment inhibits CRC cell proliferation. Malignant tissues show increased ERα and AR but decreased ERβ and PGR. ER isoforms' mRNA is lower in malignant females, and AR expression is higher in males. Women more often develop proximal colon tumors (reduced ERβ) and men develop distal tumors, reflecting nuanced gene transcription modulation by ERα, ERβ, and G-protein coupled estrogen receptor (GPER). The mechanism of P4's protective effect remains unclear. Variability in cell lines, hormone concentrations, receptor expression, and hormone replacement therapy outcomes complicates interpretation, as do interactions between cytokines and estrogen signaling in the tumor microenvironment. Future strategies include combined ERβ and PGR activation, sequential estrogen-P4 therapy for early stage CRC, and simultaneous therapy for advanced cases. Research should clarify sex hormone roles, advance prognostic markers, explore selective estrogen receptor modulators, target ERβ pharmacologically, and investigate gut microbiome influences for tailored interventions.
    Keywords:  androgen receptor; colorectal cancer; estrogen receptor beta; estrogen-progesterone therapy; progesterone receptor; sex steroid receptors; tumor progression
    DOI:  https://doi.org/10.1097/MS9.0000000000004261
  10. Mov Disord Clin Pract. 2026 Feb 11.
    Unveiling the Role of Sex Hormones and Reproductive Life Factors in Parkinson's Disease.
    Roberta Bovenzi, Clara Simonetta, Maria Mancini, Veronica Buttarazzi, Alessandro Stefani, Tommaso Schirinzi.
      Biological sex shapes the risk, presentation, and progression of Parkinson's disease (PD). Nevertheless, the pathophysiological bases remain poorly understood, and sex-specific and hormonal factors are still insufficiently explored in both research and clinical practice. In the first part of this narrative review, we synthesize the most relevant evidence on sex-specific aspects of PD, including epidemiology, genetic bases, motor and non-motor features, and disease progression. We then explore sex-specific biological underpinnings revealed by translational, neuroimaging, and neurophysiological studies. In the second part, we summarize the roles of sex hormones in PD and of reproductive life factors, from menarche to pregnancy, focusing particularly on women with PD. With this review, we aim to highlight a still underexplored dimension of PD and the importance of systematically considering sex, reproductive life, and sex hormones, from experimental research to clinical care. Recognizing and integrating these factors is essential for achieving more individualized and equitable care.
    Keywords:  Parkinson's disease; gender; reproductive life factors; sex; sex hormones
    DOI:  https://doi.org/10.1002/mdc3.70543
  11. Cell Mol Life Sci. 2026 Feb 09. 83(1): 103
    ZNF711 promotes enzalutamide resistance through transcriptional and epigenetic modification of the androgen receptor signaling pathway.
    Ping Liu, Baozhen Wang, Hui Liu, Long Liu, Feifei Sun, Pinpin Sui, Jing Hu, Lin Gao, Bo Han.
      Although androgen receptor (AR) inhibitors such as enzalutamide are initially effective in castration resistant prostate cancer through suppression of AR signaling pathway, acquired resistance invariably develops, presenting a significant therapeutic challenge. Understanding the mechanisms of enzalutamide resistance (ENZR) is essential for developing improved therapeutic strategies. Here, we demonstrated that ZNF711 was significantly overexpressed in ENZR, and high ZNF711 levels correlated with poor clinical outcomes. Functionally, ZNF711 promoted ENZR progression both in vitro and in vivo. Mechanistically, ZNF711 directly bound to the AR promoter, transcriptionally upregulating AR expression. ZNF711 knockdown markedly reduced AR chromatin occupancy at target loci. Additionally, ZNF711 formed a complex with BMI1 and AR, enhancing AR signaling pathway by suppressing CpG methylation at the promoter of AR and its downstream target genes (e.g., KLK3, TMPRSS2), thereby potentiating AR transcriptional activity. Notably, targeting ZNF711 with antagonistic chimeric siRNA restored enzalutamide sensitivity in vivo. Collectively, our findings establish ZNF711 as a critical regulator of ENZR that promotes resistance by dually modulating the AR signaling pathway via transcriptional activation and epigenetic demethylation. Targeting the ZNF711-AR axis represents a novel therapeutic strategy to overcome ENZR in prostate cancer.
    Keywords:  AR; BMI1; Enzalutamide resistance prostate cancer; Transcriptional regulation; ZNF711
    DOI:  https://doi.org/10.1007/s00018-026-06092-6
  12. PLoS One. 2026 ;21(2): e0342463
    Correlation between follicular fluid hormonal levels in PCOS women and embryo development in ART cycles.
    Sunatchana Kongsomnuan, Pornsri Niransuk, Artitaya Singwongsa, Chonthicha Satirapod.
      Polycystic ovarian syndrome (PCOS) is a common endocrine disorder characterized by ovulatory dysfunction. Fertility outcomes in PCOS patients are often suboptimal, potentially owing to alterations in the follicular fluid (FF) microenvironment. However, the differences in FF hormone levels between PCOS and non-PCOS patients, as well as their correlation with assisted reproductive technology (ART) outcomes, remain unclear. This prospective study included 18 PCOS patients and 18 infertile women without PCOS (control group) undergoing intracytoplasmic sperm injection at the Division of Reproductive Medicine, Ramathibodi Hospital. The primary objective was to compare ART outcomes between the groups. Furthermore, FF testosterone, dehydroepiandrosterone sulfate, and luteinizing hormone levels were evaluated to assess their correlation with these outcomes. The number of retrieved oocytes was significantly higher in the PCOS group; however, the rates of metaphase II oocyte formation, fertilization, blastocyst formation, and high-quality blastocyst formation were comparable between the groups. Although FF testosterone and FF luteinizing hormone levels were higher in the PCOS group than in the control group, the differences were not statistically significant. Spearman correlation analysis showed that FF testosterone levels were negatively correlated with fertilization rate (r = -0.3496, p = 0.0366). These findings suggest that increased FF testosterone levels may negatively correlation with fertilization rates, which may reflect one of the contributing factors to the suboptimal ART outcomes observed in PCOS patients.
    DOI:  https://doi.org/10.1371/journal.pone.0342463
  13. J Proteomics. 2026 Feb 10. pii: S1874-3919(26)00026-6. [Epub ahead of print]327 105623
    Ablation of ACSS2 drives alteration to cardiac and hepatic proteomic landscapes in a tissue- and sex-specific manner.
    Alexis M Winters, Jessica Wohlfahrt, Tiara Wolf, Ankita Sarkar, Suraj J Patel, Jennifer Guergues, Brant R Burkhardt, Stanley M Stevens.
      ACSS2 catalyzes the conversion of acetate into acetyl-CoA, linking nutrient availability to cellular processes such as lipid biosynthesis, energy production, and epigenetic regulation. Although ACSS2 has been studied under metabolically stressful conditions, its basal sex- and tissue-specific functions remain poorly defined. Here, we employed comprehensive proteomic characterization of the impact of global ACSS2 ablation in the liver and heart of adult male and female mice. Over 6000 proteins were identified per tissue, providing deep proteomic coverage. Despite the liver exhibiting greater baseline abundance of ACSS2, the most extensive remodeling occurred in the heart. Both tissues displayed marked sex differences, with males showing greater overall proteomic shifts, and minimal overlap in differentially abundant proteins occurring between males and females. Shared alterations across tissues converged on metabolic and immune regulation, whereas sex-specific changes implicated distinct structural and signaling pathways. Comparatively modest hepatic changes may reflect compensatory processes in the liver, in contrast to the strong inhibitory remodeling observed in the heart. These findings reveal a previously unrecognized degree of tissue- and sex-specificity in regulation by ACSS2, while also highlighting the importance of including female mice in proteomic studies, as male only approaches may overlook key sex-dependent adaptations.
    Keywords:  ACSS2; Fibrosis; Heart; Lipid metabolism; Liver; Mitochondrial dysfunction; Proteomics; Sex-specific; Tissue-specific
    DOI:  https://doi.org/10.1016/j.jprot.2026.105623
  14. FASEB J. 2026 Feb 28. 40(4): e71535
    Sex and the Developmental Environment Shape Molecular Networks Underlying Bronchial Responsiveness in Mice.
    Razia Zakarya, Baoming Wang, Yik Lung Chan, Dikaia Xenaki, Kin Fai Ho, Hai Guo, Hui Chen, Brian G Oliver, Christopher O'Neill.
      Epidemiological evidence supports sex-specific prevalence patterns of respiratory disease, yet the molecular basis of these dimorphic patterns under normal physiological conditions remains poorly understood. Using an isogenic murine model, we assessed bronchial responsiveness to methacholine in male and female adult offspring, with and without maternal exposure to air pollution particulates. We confirmed that males exhibit significantly greater bronchial responsiveness than females, independent of maternal exposure. RNA sequencing of lung tissue, coupled with gene co-expression analysis, revealed differentially expressed genes and sex-specific gene network modules associated with this physiological dimorphism. Interestingly, although maternal exposure did not alter the physiological response, it did interact with sex to affect which gene modules are associated with bronchial responsiveness. These findings provide new insight into the molecular architecture of sex-based differences in lung function and highlight the importance of incorporating both sex and developmental context in respiratory research.
    DOI:  https://doi.org/10.1096/fj.202503280R
  15. Nat Rev Urol. 2026 Feb 09.
    ADT and activation of HGF and WNT axes in double-null prostate cancer.
    Dexter Hoi Long Leung, Yao Mawulikplimi Adzavon, Gaeul Chu, Tae Ju Park, Kristoffer Nikias, Cheong-Wun Kim, Chenmiao Liu, Zijie Sun.
      Prostate cancer remains the most frequently diagnosed malignancy in men worldwide. Most primary prostate cancer cells express the androgen receptor (AR) and rely on androgens for oncogenic growth and progression. Thus, androgen deprivation therapy (ADT) that directly targets AR-expressing prostate cancer cells has been the frontline treatment for advanced prostate cancer. However, ADT inevitably fails in most patients, resulting in castration-resistant prostate cancer development. To inhibit reactivation of AR-promoted tumour progression via residual androgens and altered AR activation, next-generation AR antagonists and inhibitors of androgen biosynthesis were developed to improve clinical outcomes. However, these therapeutic advances also induce heterogeneous resistance phenotypes. Among them, double-null prostate cancer, featuring AR-null and neuroendocrine-null cell properties, occurs in patients treated with abiraterone and enzalutamide. Emerging clinical and experimental evidence demonstrates that current ADT induces HGF and canonical WNT signalling activation, which further elevates nuclear exporting and ribosomal biogenesis to foster tumour lineage plasticity and promote diverse castration-resistant prostate cancer phenotypes and double-null prostate cancer development. These mechanistic insights remain under active investigation, but they provide therapeutic prospects for co-targeting nuclear exporting, ribosomal biosynthesis and other oncogenic pathways in combination with current ADT to forestall the lethal disease.
    DOI:  https://doi.org/10.1038/s41585-026-01129-8
  16. Biol Sex Differ. 2026 Feb 07.
    Sex differences in human umbilical vein endothelial cells following ox-LDL injury.
    Camilla Cittadini, Elisabetta Straface, Ilaria Campesi, Lucrezia Gambardella, Giampiero Capobianco, Letizia Barbieri, Laura Doro, Flavia Franconi, Giulio Testone, Rosa Vona.
       BACKGROUND: Numerous sex differences has been described in aterosclerosis including in endothelial dysfunction. Oxidized low-density lipoproteins (ox-LDL) contribute to the formation of atherosclerotic plaque by binding to a membrane glycoprotein expressed by endothelial cells. Ox-LDL also play a key role in mediating endothelial dysfunction during pregnancy. Elevated maternal ox-LDL levels can lead to oxidative stress, inflammation and apoptosis in placental and fetal endothelial cells. The aim of this study was to investigate sex-related differences in the response to ox-LDL-induced damage in human umbilical vein endothelial cells (HUVECs) isolated from male and female newborns.
    METHODS: In our study, the effects of 100 µg/ml ox-LDL on HUVECs, obtained from umbilical cords of healthy newborns of both sexes, were analyzed. By flow cytometry, fluorescence microscopy, and Western blotting techniques, mitochondrial function, cell survival, and autophagy were studied.
    RESULTS: Sex differences in cell motility and fate have been detected after ox-LDL treatment. Indeed, following ox-LDL treatment, male HUVECs (MHUVECs) exhibited reduced motility and a significant increase in adhesion molecules ICAM-1 and VCAM-1, in contrast to female HUVECs (FHUVECs). Furthermore, MHUVECs exhibited higher levels of fission proteins (DRP1 and Fis1), superoxide anion (O₂⁻), and earlier mitochondrial membrane (MM) hyperpolarization, while FHUVECs showed higher levels of fusion proteins (OPA1 and MFN2), hydrogen peroxide (H₂O₂), and delayed MM changes. These findings were consistent with a greater propensity for apoptosis in MHUVECs. In contrast, FHUVECs exhibited higher levels of Survivin, making them less susceptible to apoptosis and more susceptible to the autophagy process.
    CONCLUSIONS: Our findings reveal significant sex-related variations in endothelial responses to oxidative stress. The enhanced survival and repair capacity of FHUVECs suggests that female cells are more resilient to ox-LDL-induced damage.
    Keywords:  Atherosclerosis; Cardiovascular diseases; Endothelial dysfunction; Female human umbilical vein endothelial cells (FHUVECs); Male human umbilical vein endothelial cells (MHUVECs); Oxidized low-density lipoproteins (ox-LDL); Sex differences
    DOI:  https://doi.org/10.1186/s13293-026-00845-5
  17. Food Chem (Oxf). 2026 Jun;12 100366
    Integrated transcriptomic and metabolomic profiling reveals sex-specific regulation of breast muscle development during sexual maturation in Huanglang chicken.
    Qingyuan Ouyang, Yuanbo Song, Jing Li, Jian Xiao, Zehe Song, Haihan Zhang, Xi He.
      To better understand the regulatory mechanisms of breast muscle growth in small-sized local breeds, this study aimed to investigate metabolic and transcriptional networks during the initiation of sexual maturation in Huanglang chickens. We hypothesized that sex-specific metabolic and gene expression patterns regulate muscle growth and fat deposition in these chickens. To test this hypothesis, multi-omics approaches were used to analyze chickens at 80 and 120 days post-hatch (dph). Both male and female chickens showed a significant increase in intramuscular fat (IMF) at 120 dph, but with sex-specific changes: females exhibited a significantly higher liver index, while males had a significantly greater breast muscle index. We identified 2627 differentially expressed genes (DEGs) in males and 2991 in females, along with 473 and 232 differentially abundant metabolites (DAMs), respectively. The sex-shared ABC transporter pathway supports muscle growth via substrate transport, while the Steroid biosynthesis pathway is female-specific, and the Glycerophospholipid metabolism pathway is male-specific. These results demonstrate that sex-specific regulatory networks shape muscle growth and fat deposition during early sexual maturation, and they provide potential molecular targets for improving intramuscular fat content and meat quality in local chicken breeding programs.
    Keywords:  Intramuscular fat deposition; Lipid metabolism; Local chicken breeds; Metabolism; Sex differences
    DOI:  https://doi.org/10.1016/j.fochms.2026.100366
  18. NPJ Precis Oncol. 2026 Feb 14.
    Y chromosome-linked EIF1AY deletion drives sex differences in multiple myeloma.
    Zuxi Feng, Jun Bai, Yanhong Li, Lijuan Li, Liansheng Zhang.
      Sex differences in cancer susceptibility and prognosis are partially driven by sex chromosomes and sex hormones. However, the molecular mechanisms underlying the higher incidence and mortality of multiple myeloma (MM) in males remain poorly defined. In this study, we identify the Y-linked gene EIF1AY as a tumor-suppressive regulator in male MM. Clinical analysis reveals that partial deletions of EIF1AY in male MM patients are significantly associated with disease progression, reduced treatment responsiveness, and shorter overall survival. Functionally, loss of EIF1AY promotes M2 macrophage polarization and recruitment, thereby enhancing MM cell proliferation. Mechanistically, EIF1AY forms a protein complex with RPS4Y1 that directly binds to and stabilizes CD134 mRNA, thereby promoting CD134 expression in MM cells. The RPS4Y1-EIF1AY-CD134 axis suppresses IL-4 and IL-13 secretion from MM cells, which in turn downregulates the membrane receptor DDR1 on co-cultured macrophages, thereby inhibiting M2 macrophage polarization and recruitment, and ultimately restraining MM cell proliferation. These findings uncover a feed-forward loop in which the RPS4Y1-EIF1AY-CD134 axis suppresses IL-4/IL-13-DDR1 signaling, thereby suppressing M2 macrophage polarization and recruitment, and sustaining tumor growth through reciprocal crosstalk between tumor cells and macrophages. Collectively, our study elucidates a novel immune regulatory pathway driving sex differences in MM and highlights EIF1AY as a promising target for precision immunotherapy in male patients.
    DOI:  https://doi.org/10.1038/s41698-026-01317-0
  19. J Dent Res. 2026 Feb 11. 220345251411907
    The Ontogeny of Mouse Salivary Gland Macrophages Is Distinct between Sexes.
    Q Zhao, S Pan, J Jaiswal, L Zhang, L-T Wang, E Chang, A Shahsavari, Y Zhang, V Yu, R Zheng, T Chen, F Liu.
      Sexual dimorphism is found in gene expression and polarization of macrophages in mammals but remains unclear in the ontogeny of tissue-resident macrophages. Remarkable sex differences are present in salivary glands and risks for a related autoimmune disease, Sjögren'sdisease. Macrophages are the most abundant immune cells in healthy mouse salivary glands and essential for the maintenance of immune quiescence and tissue repair after radiation or inflammatory damages. Therefore, we compared the origins of macrophages in salivary glands between male and female mice using conditional Cx3cr1 and Ccr2 lineage-tracing approaches. We found that among salivary gland macrophages in adult mice, most are locally maintained and derived from yolk sac progenitors or perinatal monocytes in males, but much more are short-lived and continuously replenished by monocytes in females. In wild type C57BL/6 mice, female adult submandibular glands (SMGs) consistently contain more leukocytes, including classical monocytes expressing Ccr2, Ly6c, or Csf2rb and macrophages carrying these monocyte markers, as compared with male SMGs. Single-cell RNA sequencing and flow cytometry indicated that female SMG macrophages are more polarized and express several proinflammatory genes at higher levels. Meanwhile, female SMGs contain more innate lymphoid cells and T/NKT cells expressing Csf2 and other proinflammatory cytokines. The potential contributions of these sexual differences warrant further studies as they relate to Sjögren's disease, the most female-dominant autoimmune disease, characterized by chronic inflammation in salivary and lacrimal glands. Also, these differences need be considered in developing macrophage-targeting therapies of dry mouth caused by autoimmunity or radiation.
    Keywords:  lineage tracing; monocytes; origin of macrophages; salivary glands; sex differences; tissue-resident macrophages
    DOI:  https://doi.org/10.1177/00220345251411907
  20. Reprod Sci. 2026 Feb 09.
    Advances in the Role of Endometrial Microbiota Alterations in the Pathogenesis of Endometriosis.
    Ziying Xu, Weina Guo, Yi Shen.
      The uterine cavity was formerly considered sterile; however, over recent years, researchers have identified the presence of endometrial microbiota. An imbalance in the endometrial microbiota, or dysbiosis, has been shown to be associated with a variety of gynecological diseases. Endometriosis (EM) is a chronic and inflammatory gynecological disease that affects 6-10% of all women of reproductive-age. Previous studies suggested that endometrial dysbiosis can participate in the development of EM by generating an inflammatory state, leading to disorders of immune homeostasis and thus creating an intrauterine environment conducive to endometrial stromal cell migration and adhesion. In this review, we investigate differences in the endometrial microbiota of patients with EM compared with that of healthy women and discuss the possible pathogenic mechanisms responsible for endometrial dysbiosis. Critically, we identified that an increase of lipopolysaccharides resulting from microbiological disorders may generate chronic inflammation, leading to increased adhesion and angiogenesis, and the development of EM. The findings of our review may identify new therapeutic strategies and potential therapeutic targets for EM.
    Keywords:  Endometrial microbiota; Endometriosis; Immune dysregulation; Inflammation; Lipopolysaccharides
    DOI:  https://doi.org/10.1007/s43032-026-02050-6
  21. Am J Obstet Gynecol. 2026 Feb 05. pii: S0002-9378(26)00067-0. [Epub ahead of print]
    Gynecologic function and dysfunction in transmasculine and gender diverse individuals using testosterone therapy: a systematic review.
    Wouter L J van Vugt, Emmy van den Boogaard, Karin van der Tuuk, Laura Spinnewijn, Baudewijntje P C Kreukels, Stephanie Both, Judith A F Huirne, Norah M van Mello.
       OBJECTIVE: To systematically review the current literature on gynecologic function and dysfunction in transmasculine and gender diverse individuals in the context of testosterone therapy, with a focus on menstrual suppression, contraceptive needs, pelvic pain, vulvovaginal changes, and sexual health.
    DATA SOURCES: PubMed, Embase and Web of Science databases were searched through September 2025 using search terms related to transmasculine individuals, assigned female at birth, reproductive organs, and testosterone and gender-affirming hormone therapy. No restrictions on publication year were applied.
    STUDY ELIGIBILITY CRITERIA: Studies were included if they reported on the impact of exogenous testosterone on gynecologic or sexual (dys)function, as well as contraceptive use and choices, in transmasculine and gender diverse individuals. Only original human research studies were eligible. Studies focusing on fertility, reproductive outcomes, malignancy, histology, animal models, or individuals with differences of sex development were excluded.
    STUDY APPRAISAL AND SYNTHESIS METHODS: All included studies were critically appraised using Joanna Briggs Institute (JBI) quality assessment tools, and findings were synthesized narratively.
    RESULTS: Fifty-seven studies were included. Testosterone was generally effective in achieving menstrual suppression, though breakthrough bleeding and ovulatory activity occurred in a substantial proportion of individuals. Contraceptive needs were frequently unmet, partly due to misinformation and provider-related barriers. Pelvic pain was commonly reported, with varied etiologies. While testosterone often increased sexual desire, dyspareunia and genital discomfort were frequently described. Vaginal microbiome alterations and epithelial changes were observed, though their clinical implications remain unclear.
    CONCLUSION: Testosterone-based gender-affirming hormone therapy has diverse effects on gynecologic function in transmasculine and gender diverse individuals, including both physiologically expected as well as underexplored effects. Clinicians should adopt an individualized and affirming approach to care, while further research is needed to understand long-term outcomes, improve assessment tools, and close gaps in inclusive gynecologic healthcare.
    Keywords:  gender-affirming hormone therapy; gynecologic health; menstrual suppression; pelvic pain; sexual function; testosterone; transgender
    DOI:  https://doi.org/10.1016/j.ajog.2026.01.036
  22. PLoS Biol. 2026 Feb;24(2): e3003601
    Integrated chromatin and transcriptomic profiling reveals sex-specific mechanisms of gene regulation in hepatic nutrient responses.
    Zhengyi Zhang, Vivien Su, Carrie B Wiese, Lijing Cheng, Dan Wang, Ya Cui, Aneesh Kallapur, Jason Kim, Xiaohui Wu, Peter H Tran, Zhenqi Zhou, David Casero, Wei Li, Andrea L Hevener, Karen Reue, Tamer Sallam.
      Little is known about how sex and diet interact at the level of chromatin organization. A comprehensive analysis of diet-induced chromatin dynamics can reveal how the liver mounts a rapid adaptive response to environmental cues and uncover mechanisms underlying sex differences. Here, we employed an integrative strategy to construct a nucleosome accessibility atlas of the mouse liver under different dietary conditions. Stringent analysis revealed a largely preserved hepatic chromatin landscape across feeding states, with sex being the critical factor driving changes in chromatin accessibility. Notably, lipid-rich diet preferentially enriched CCAAT-binding motifs in females, while nutrient-sensing nuclear receptor motifs were more strongly enriched in males. Furthermore, using the Four Core Genotypes model (XX ovaries / XY testes / XX testes / XY ovaries), we disentangled the effects of gonadal and chromosomal sex on diet-induced gene regulation. By leveraging this framework with multiple mouse models and molecular approaches, we identified a suppressive role of testosterone in regulating the sex-dimorphic GWAS gene PNPLA3. Overall, we establish an unbiased transcriptomic resource that revealed chromatin dynamics and identified gene clusters associated with distinct sex-related factors.
    DOI:  https://doi.org/10.1371/journal.pbio.3003601
  23. Biol Sex Differ. 2026 Feb 13.
    Mind the "CRP gender gap"! sex differences in CRP evolution over time in neonatal sepsis: a monocentric retrospective cohort study.
    Andrea Nebbioso, Isaline Eggermont, Alfredo Vicinanza, Phu-Quoc Lê, Nancy Vitali, Gwenaëlle Augé, Nicolas Lefèvre.
       BACKGROUND: C-reactive protein (CRP) is a readily available test widely used to assess neonatal sepsis (NS). In children with sepsis or other infectious conditions, CRP is more likely to be higher in females than males, however, evidence is lacking on sex differences in CRP in the neonatal population. This study aims to describe sex differences of CRP evolution in the ascending and decreasing phase after its peak in neonates with likely NS.
    METHODS: This is a monocentric retrospective cohort study conducted at Etterbeek-Ixelles Hospital in Brussels. We included all neonates born in the facility between January 2017 and December 2022 who received antibiotics in the first 72 hours of life. Patients whose CRP concentrations remained under 10 mg/L were excluded. To describe the ascending kinetics of CRP and its logarithm for male and female neonates, we fitted a piecewise linear mixed-effects regression model with birth considered as time zero and one knot at 12 hours of life. We used a linear mixed-effects regression model with CRP peak considered as time zero to describe CRP's descending kinetics and its logarithm for male and female neonates.
    RESULTS: We included 506 neonates (60.1% male and 39.9% female). CRP concentration in the first 12 hours of life doubled every 3.2 and 2.8 hours, respectively, in males and females, with female neonates having a statistically significant faster rise of base 2 logarithm of CRP (+0.04 log2 mg/L/hour 95% CI= +0.01 +0.07). After 12 hours of life, CRP doubled every 6.5 and 8.6 hours, respectively, in males and females, with female neonates having a statistically significant slower rise of base 2 logarithm of CRP (-0.039 log2 mg/L/hour 95% CI= -0.02 -0.06). After its peak, CRP decreased by half every 31.1 and 30.9 hours, respectively, for males and females. No statistically significant sex differences were found in CRP peak or decline.
    CONCLUSION: In neonates of both sexes with likely but unconfirmed NS, CRP seems to increase, reach a peak, and then decrease, following a logarithmic pattern. Before antibiotic treatment, female neonates in our population showed an earlier increase in CRP levels, with no difference in peak CRP levels.
    Keywords:  CRP; Inflammation; Neonatal infection; Neonatal inflammation; Neonatal sepsis; Sex differences; Sexual dimorphism
    DOI:  https://doi.org/10.1186/s13293-026-00841-9
  24. Fertil Steril. 2026 Feb 10. pii: S0015-0282(26)00105-6. [Epub ahead of print]
    Female reproductive microbiome in fertility care.
    Samiya Dash, Dong Zhao, Ina Schuppe-Koistinen, Juan Du.
      The microbiome has emerged as a critical determinant of female reproductive health and fertility outcomes. While conventional infertility evaluations, encompassing medical history, ovulation assessment, uterine and tubal evaluation, genetic screening, hormonal profiling, and reproductive tract imaging, provide essential diagnostic information, a substantial proportion of infertility cases remain unexplained, prompting increased attention to microbial factors. This review provides a comprehensive, critical evaluation of methods for assessing the female reproductive microbiome, spanning traditional culture-based microbiology to contemporary molecular approaches. We systematically discuss the diagnostic performance, clinical utility, and established techniques, including microscopic examination, Nugent scoring, and Amsel criteria, alongside modern molecular methods such as quantitative PCR panels, 16S rRNA gene sequencing, shotgun metagenomics, and other multi-omics. Critically, we evaluate the current microbiome testing platforms in clinical validity and utility. We identify significant gaps between research-grade methodologies and clinically actionable diagnostics, including a lack of standardized protocols, inconsistent reporting of absolute bacterial loads versus relative abundances, and limited validation against reproductive outcomes. We propose evidence-based criteria for selecting appropriate diagnostic approaches based on clinical context and discuss emerging technologies, including multi-omics integration for implementing microbiome assessment in fertility care.
    Keywords:  Reproductive microbiome; fertility; molecular based methods
    DOI:  https://doi.org/10.1016/j.fertnstert.2026.02.015
  25. Fertil Steril. 2026 Feb 11. pii: S0015-0282(26)00107-X. [Epub ahead of print]
    The microbiome: a determinant of reproductive health and fitness?
    David A MacIntyre, Robert J Norman.
      There is growing appreciation of the importance played by the reproductive tract microbiome in shaping fertility and reproductive health. Historically viewed as a microbially simple niche, the lower female reproductive tract is now recognised to harbour dynamic microbial communities that interact with host physiology to influence fertility, pregnancy outcomes, and reproductive disorders. Increasing evidence also implicates the comparatively low biomass microbiomes of the upper female reproductive tract and the male reproductive tract in reproductive health. This Views and Reviews special edition is made up of four articles that critically examine the ecological drivers of vaginal microbiota composition, the strengths and limitations of current microbiome assessment tools in fertility care, links between dysbiosis and female reproductive disorders, and emerging evidence implicating the male reproductive microbiome in sperm function and fertility. Collectively, these contributions highlight both the promise and the current limitations of microbiome-informed reproductive care, underscoring the need for rigorous, standardised, and outcome-focused research to support clinical implementation.
    Keywords:  fertility; microbiome; reproduction
    DOI:  https://doi.org/10.1016/j.fertnstert.2026.02.017
  26. J Reprod Immunol. 2026 Feb 06. pii: S0165-0378(26)00023-9. [Epub ahead of print]174 104854
    Characterization of endometrial immune cells during the window of implantation in infertile women with adenomyosis.
    Shuyi Yu, Qiang Geng, Zijing Liu, Yaya Wu, Guanying You, Yuye Li, Tao Zhang.
      Adenomyosis, characterized by the invasion of endometrial cells into the myometrium, may disrupt immune homeostasis within the eutopic endometrium, thereby impairing endometrial receptivity. This retrospective case-control study aimed to investigate the endometrial immune cell profile during the window of implantation in infertile women with adenomyosis. Total 103 controls without adenomyosis who achieved live births following in vitro fertilization-embryo transfer treatment and 227 infertile women with adenomyosis underwent endometrial biopsies on days 7-9 after the luteinizing hormone surge. Pro- and anti-inflammatory endometrial immune cells were evaluated using immunohistochemistry and quantitative analysis. Compared with control women, women with adenomyosis exhibited significantly higher percentage of endometrial CD56+ NK cells, CD163+ M2 macrophages, CD1a+ immature DCs, CD8+ cytotoxic T lymphocytes and CD57+ cells. In contrast, the percentage of Foxp3+ Tregs was significantly lower in patients with adenomyosis. No significant differences were observed for CD68+ macrophages between the two groups. After adjusting for age, BMI, hormone levels and infertility duration via multivariable linear regression analysis, adenomyosis remained significantly associated with increased proportions of CD56+ NK proportions (P＜0.001), CD163+ M2 macrophages (P＜0.001), CD1a+ immature DCs (P = 0.002), CD8+ cytotoxic T lymphocytes (P < 0.001), and CD57+ cells (P= 0.031), while with decreased proportion of Foxp3+ Tregs (P= 0.009). In conclusion, the endometria of infertile women with adenomyosis exhibit increased densities of CD56+ NK cells, CD8+ T cells, CD1a+ immature DCs, and CD163+ M2 macrophages, alongside decreased Foxp3+ Tregs, resulting in an altered immune environment.
    Keywords:  Adenomyosis; Endometrial receptivity; Immune cells; Infertility; Window of implantation
    DOI:  https://doi.org/10.1016/j.jri.2026.104854
  27. Proc Natl Acad Sci U S A. 2026 Feb 17. 123(7): e2519130123
    In vitro sex-specific function-structure relationship in neonatal rat cardiac monolayers.
    Mary Tran, Toby Viet Nguyen, Suhani Khandelwal, Anna Grosberg.
      Even though in vivo rodent studies have been instrumental in investigating sex-specific differences in cardiac health, function, and pathology, they fall short in providing a fast and flexible platform for investigating sex differences of cardiac anisotropic monolayer in isolation. In vitro platforms offer an accessible and more controlled alternative to dissect and study the mechanisms by which male and female cardiac tissue sheets differ from one another. Here, we have shown on an in vitro heart-on-a-chip platform, primary neonatal rat ventricular myocytes can serve as a viable model showing sex chromosome-driven characteristics when presented with identical experimental conditions. With controlled experimental conditions, the self-assembly of isolated cardiomyocytes resulted in morphological differences in the structure of the contractile apparatus. More importantly, the assembly of cardiac cells into confluent monolayers had a sex chromosome-driven divergence in both structure and the corresponding function. This work reports the characterization of the difference between sex-specific neonatal rat ventricular myocytes in in vitro culture. Thus, this offers an avenue to investigate sex-based variations in cardiac function that are otherwise difficult to study.
    Keywords:  cardiac structure and function; heart-on-a-chip; sex difference
    DOI:  https://doi.org/10.1073/pnas.2519130123
  28. Adv Sci (Weinh). 2026 Feb 13. e18185
    Identification of A p300-SP1-BRD4 Transcriptional Axis as a Key Driver of AR Hyperactivation in Polycystic Ovarian Syndrome.
    Zhengquan Zhu, Yihan Wang, Haiyun Chen, Xinye Yu, Tingyu Wang, Yajing Weng, Meihong Guo, Ying Huang, Gaojian Tao, Wangsen Cao, Yong Wang, Daojuan Wang.
      Persistent androgen receptor (AR) activation is an important contributor to polycystic ovary syndrome (PCOS) and is affected by transcriptional regulation via histone acetylation; however, the underlying mechanisms are partially understood. This study demonstrated that AR activation in ovarian granulosa cells (GCs) of both dehydroepiandrosterone (DHEA) and high-fat diet-induced PCOS mouse models correlated with a significant increase in the histone acetyltransferase p300 and histone acetylation. Conversely, GC-specific p300 knockout or pharmacological inhibition with C646/A-485 effectively reduced AR activation, histone 3 acetylation (H3K18ac/H3K27ac), and ovarian fibrosis in PCOS mice, highlighting p300 as a critical driver. ATAC-seq and RNA-seq identified "open" chromatin regions at the AR promoter in PCOS ovaries, corresponding with increased AR transcription and histone acetylation. p300, along with transcription factor SP1 and the acetyl-reader BRD4, bound to H3K18ac and H3K27ac of the AR promoter in PCOS-modeled ovaries and GCs, which was blocked by C646 and the SP1 inhibitor Plicamycin, respectively. Importantly, continuous AR activation by its ligand DHT largely diminished the anti-fibrotic and ovarian-protective effects of C646. These findings suggest that p300, SP1, and BRD4, form a critical transcriptional complex driving AR activation and PCOS development, and that targeting the p300/AR axis may present a promising therapeutic approach for treating PCOS.
    Keywords:  PCOS; SP1; acetylation modification; androgen receptor; p300
    DOI:  https://doi.org/10.1002/advs.202518185
  29. Front Cell Infect Microbiol. 2026 ;16 1720894
    Gut microbiota composition and systemic immune-inflammatory marker correlations in infertile women with endometriosis: a pilot case-control study.
    Xiaoli Dong, Xiaozhen Chen, Yingpei Xu, Defei Zeng, Ping Li.
       Background: The specific gut microbial signatures and their correlation with immune-inflammatory markers in infertile women with endometriosis remain underexplored.To investigate the differences in gut microbiota and their associations with biochemical immune markers in infertile women with endometriosis compared to controls.
    Methods: This case-control study enrolled 32 infertile women with endometriosis and 13 control women with male-factor infertility. Fecal samples were collected for 16S rRNA sequencing to profile the gut microbiota, and serum samples were obtained to measure inflammation-related biomarkers. Bioinformatics analyses were applied to compare gut microbial community structures and to examine correlations between differentially abundant bacteria and immune markers.
    Results: The endometriosis group exhibited significant enrichment of Lachnospira, Bacilli, Lactobacillales, Parasutterella, Enterococcus, and Veillonella. Comparative analysis revealed significantly altered abundances of multiple taxa, including Lachnospira, Parasutterella, Alistipes, Enterococcus, Veillonella, Streptococcus, Desulfovibrionaceae, Ruminococcaceae, Bilophila, and Peptoniphilus (all P < 0.05). Several inter-species correlations were identified among these bacteria. Importantly, specific microbiota were correlated with immune markers: Streptococcus and Veillonella were positively correlated with macrophage migration inhibitory factor (MIF); Bilophila and Enterococcus were positively correlated with TNF-α and IL-6; Veillonella was positively correlated with TNF-α; Desulfovibrionaceae was negatively correlated with TNF-α and IL-6; and Parasutterella was negatively correlated with CA125.
    Conclusion: In this exploratory investigation, specific gut microbial signatures were observed in infertile patients with endometriosis, showing correlations with select systemic immune-inflammatory biomarkers. These initial observations point to a possible association between gut microbiota imbalance and the inflammatory aspects of endometriosis-associated infertility. Consequently, microbial modulation merits further investigation as a potential strategy to alleviate inflammation and potentially enhance reproductive outcomes.
    Keywords:  endometriosis; gut microbiome; gut–immune axis; interleukin-6; macrophage migration inhibitory factor; short-chain fatty acids; tumor necrosis facto
    DOI:  https://doi.org/10.3389/fcimb.2026.1720894
  30. NPJ Vaccines. 2026 Feb 12.
    Re-shaping the immune response to influenza vaccination in a host with immune memory from influenza infection.
    Chantelle L White, Lara Mengu, Ishraj S Sidhu, Siva K Gandhapudi, Katherine A Richards, Andrea J Sant.
      Although CD4 T cells are critical orchestrators of protective immunity, vaccine strategies that optimize generation of these cells are not yet prioritized. In this manuscript, to mimic the typical human vaccine recipient using a mouse model, we evaluated the impact of previous influenza infection on the adaptive immune response elicited by the recombinant influenza vaccine Flublok, co-delivered with AddaVax, an MF59 mimetic or with a nanolipoparticle innate activator R-DOTAP. In the context of influenza B infection memory, a repolarization and dramatic change in the fate of the vaccine-elicited CD4 T cells was discovered. A rapidly evolving CD4 T cell response enriched in TNF-α and IFN-γ was observed, with the CD4 T cells also displaying increased expression of chemokine receptors associated with lung homing potential and ultimate accumulation in the lung tissue. Unexpectedly, similar shifts in the features of the H3-specific CD4 T cell and antibody response were also observed, drawn from the naïve repertoire. These results suggest that the microenvironment of the vaccine draining lymph node, developed in the context of immune memory, rather than infection-induced CD4 T cell imprinting, plays the decisive role in the functional phenotype, magnitude, and fate of vaccine-elicited CD4 T cells.
    DOI:  https://doi.org/10.1038/s41541-026-01397-w
  31. Prostate. 2026 Feb 10.
    Loss of GPR133 Promotes Enzalutamide Resistance in Prostate Cancer by Upregulating HSD3B1 and Intratumoral Androgen Synthesis.
    Lai Wei, Ziwei Wang, Dajun Gao, Jianchao Ge, Xiaomin Chen, Huan Xu, Bin Xu.
       BACKGROUND: The progression of prostate cancer (PCa) to a castration-resistant state (CRPC) remains a major clinical challenge. Resistance to second-generation androgen receptor (AR) antagonists like enzalutamide often involves the reactivation of AR signaling, frequently through intratumoral androgen synthesis. The molecular drivers that regulate this adaptive resistance mechanism are not fully understood. GPR133 (also known as ADGRD1) is an adhesion G protein-coupled receptor with emerging roles in various cancers, but its function in prostate cancer is unknown. While androgen signaling is classically mediated by the nuclear AR, GPR133 has recently been identified as a novel membrane androgen receptor, though its functional relationship with the AR pathway in prostate cancer is unknown.
    METHODS: We analyzed GPR133 expression in patient-derived PCa tissues and its correlation with clinical outcomes using publicly available datasets and our patients' samples. We employed gain- and loss-of-function approaches in vitro to test whether GPR133 specifically mediates resistance to enzalutamide. RNA sequencing was used to identify downstream pathways regulated by GPR133. The role of the downstream effector HSD3B1 was assessed using siRNA-mediated silencing. The therapeutic implications of GPR133 expression were validated in vivo using xenograft mouse models.
    RESULTS: GPR133 expression is significantly downregulated in prostate cancer tissue compared to benign tissue and is further decreased in CRPC. Low GPR133 expression correlates with poorer disease-free survival. Silencing GPR133 conferred robust resistance to enzalutamide in vitro and in vivo. Conversely, overexpression of GPR133 could further sensitize cancer cells to enzalutamide. Mechanistically, loss of GPR133 transcriptionally upregulated key enzymes in the steroid hormone biosynthesis pathway, most notably HSD3B1. This upregulation led to elevated intracellular testosterone levels and sustained androgen receptor (AR) signaling, characterized by the persistent expression of AR target genes despite enzalutamide treatment. Silencing HSD3B1 reversed the enzalutamide resistance induced by GPR133 knockdown.
    CONCLUSIONS: Our findings identify GPR133 as a novel tumor suppressor in prostate cancer. Loss of GPR133 expression is a key event in the progression to CRPC that promotes therapeutic resistance by activating the intratumoral androgen synthesis pathway. GPR133 may serve as a valuable prognostic biomarker and a potential therapeutic target for advanced prostate cancer.
    Keywords:  GPR133; HSD3B1; castration resistant prostate cancer; enzalutamide resistance; intratumoral androgen synthesis
    DOI:  https://doi.org/10.1002/pros.70138
  32. Ann Neurol. 2026 Feb 10.
    Sex-Specific Genetic Architecture of ALS: Evidence of a Female Protective Effect?
    Maurizio Grassano, Francesca Palumbo, Gabriele Mora, Salvatore Gallone, Giovanni De Marco, Ilaria Merulla, Claudia Paolantonio, Alessandra Maccabeo, Antonio Canosa, Umberto Manera, Rosario Vasta, Barbara Iazzolino, Marcella Testa, Giuseppe Fuda, Paolina Salamone, Giulia Marchese, Federico Casale, Cristina Moglia, Andrea Calvo, Giuseppe Borghero, Adriano Chiò.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) shows sex differences in incidence and age of onset, yet the underlying biological mechanisms remain poorly understood.
    METHODS: We investigated sex-specific genetic architecture in an Italian ALS cohort with whole-genome sequencing (1,333 ALS cases, 755 controls). We performed a sex-stratified burden analysis of rare variants in ALS-associated genes and compared the proportions of male and female ALS patients carrying pathogenic or rare damaging variants. Key findings were replicated in the AnswerALS cohort (n = 723). Gene-specific sex ratios and familial history for C9ORF72, SOD1, and TARDBP were examined in an expanded dataset of 2,301 Italian ALS patients.
    RESULTS: Sex-stratified burden testing revealed that rare variants in ALS genes were enriched in female cases versus controls (odds ratio [OR] 5.47, 95% confidence interval [CI] 1.60-34.29) but not in male cases. Female ALS patients more frequently carried rare damaging variants compared to males (23.2% vs 18.3%; OR 1.38, 95% CI 1.05-1.81), a finding that was replicated in the AnswerALS cohort (18.9% vs 12.4%; OR 1.58, 95% CI 1.10-2.26). Gene-level analyses of TARDBP carriers revealed a male predominance (2.1:1), yet a higher rate of familial history among females (40.4% vs 24.5%; OR 2.13, 95% CI 1.03-4.39).
    INTERPRETATION: Females with ALS exhibited a higher overall burden of rare damaging variants, suggesting sex-related differences in genetic liability. Gene-level analyses indicate that the influence of sex varies across ALS genes, particularly TARDBP. These findings help explain epidemiological patterns and have implications for the identification of sex-linked protective mechanisms. ANN NEUROL 2026.
    DOI:  https://doi.org/10.1002/ana.78172
  33. NPJ Breast Cancer. 2026 Feb 13.
    Androgen receptor expression and immune characteristics of HER2-low metastatic triple-negative breast cancer.
    Paolo Tarantino, Jaeyoon Cha, Busem Binboga Kurt, Xiangying Chu, Bojana Jovanović, Andrew Zhou, Melissa Hughes, Douglas Russo, Molly DiLullo, Eileen Wrabel, Rinath Jeselsohn, Nancy U Lin, Jamie Carter, Yisang Serenity Chen, Tianyu Li, Nabihah Tayob, Elizabeth A Mittendorf, Stuart J Schnitt, Shom Goel, Sara M Tolaney.
      HER2-low expression is associated with hormone receptor (HR) expression in HR-positive breast cancer. We aimed to evaluate its association with androgen receptor (AR) among 196 patients with metastatic triple-negative breast cancer (mTNBC). Central determination of AR showed significant enrichment in HER2-low compared with HER2-0 mTNBC (mean: 33.7% vs. 21.4%, p = 0.038), whereas no significant immunological differences were observed. HER2-low/AR-positive patients trended towards longer overall survival, highlighting the potential relevance of these biomarkers.
    DOI:  https://doi.org/10.1038/s41523-026-00913-4
  34. J Biochem Mol Toxicol. 2026 Feb;40(2): e70730
    Sex Hormone-Dependent Modulation of Nrf2 and Its Association With Apoptosis, Metastasis, and Drug Resistance in Hepatocellular Carcinoma.
    Ala Alban, Fereshteh Barjesteh, Yaser Mohammadi, Afsaneh Dashtaki, Elham Bahreini.
      Hepatocellular carcinoma (HCC) exhibits a gender disparity, with a 2- to fourfold higher incidence in men, as attributed by previous studies to estrogen-mediated hepatoprotection versus the tumor-promoting role of androgens. This study investigated the effects of these sex hormones-testosterone and β-estradiol-on Nrf2 expression and its relation to key factors in metastasis, apoptosis, and drug resistance in HepG2 HCC cell line. HepG2 cells were exposed to testosterone or β-estradiol at viability-equivalent doses. Oxidative stress was quantified by total oxidant status (TOS), malondialdehyde (MDA), and total antioxidant capacity (TAC) assays. Apoptosis was evaluated by Annexin V/PI flow cytometry. mRNA levels of Nrf2, MRP-1 (multidrug resistance protein 1), MMP-9 (matrix metalloproteinase-9), BCL2, and SIRT1 were assessed via qRT-PCR. At viability-equivalent doses, β-estradiol elicited dose-dependent apoptosis in HepG2 cells (total: 47.4% at V₅₀ vs. 32.7% for testosterone; p < 0.001), predominantly late-stage (34.5% vs. 21.8%; p < 0.0001). Concomitantly, β-estradiol decreased TOS (maximal at V₄₀, p < 0.05) and MDA (all doses, p < 0.05) while increasing TAC (medium/high doses, p < 0.05)-effects not observed with testosterone (p > 0.05). β-estradiol induced downregulation of Nrf2, BCL2, MMP-9, and MRP-1 mRNA (moderate/high doses; p < 0.05 vs. control). Conversely, testosterone upregulated SIRT1 across doses (p < 0.05), unaffected by β-estradiol (p > 0.05). β-Estradiol mitigates oxidative stress, induces apoptosis, and suppresses pro-survival, metastatic, and chemoresistant pathways-contrasting testosterone's minimal effects. These findings align with HCC's male predominance and highlight the hormone-modulated strategies' potential for future therapeutic exploration.
    Keywords:  lipid droplets; non‐alcoholic fatty liver; sex hormones
    DOI:  https://doi.org/10.1002/jbt.70730
  35. Am J Hum Biol. 2026 Feb;38(2): e70224
    Second to Fourth Digit Ratio (2D:4D) in Female Patients With Systemic Sclerosis: Evidence for Prenatal Androgen Exposure.
    Ramazan Fazil Akkoc, Ahmet Karatas, Burak Oz.
       OBJECTIVES: Systemic sclerosis (SSc) demonstrates marked female predominance, suggesting hormonal influences in disease pathogenesis. The second-to-fourth digit ratio (2D:4D), a biomarker of prenatal androgen exposure, has been associated with various autoimmune conditions. This study investigated whether 2D:4D ratios differ between female SSc patients and healthy controls.
    METHODS: This case-control study enrolled 33 women with SSc (2013 ACR/EULAR criteria) and 30 age-matched healthy female controls. Second and fourth digit lengths were measured bilaterally using digital calipers, and 2D:4D ratios were calculated. Between-group differences were analyzed using Welch's t-test and Mann-Whitney U test.
    RESULTS: SSc patients demonstrated significantly lower 2D:4D ratios than controls bilaterally (right hand: 0.950 ± 0.029 vs. 1.022 ± 0.012, p < 0.001; left hand: 0.951 ± 0.030 vs. 1.022 ± 0.012, p < 0.001). Effect sizes were substantial (Cohen's d > 2.8). The lower ratios resulted from longer fourth digits rather than shorter second digits, consistent with elevated prenatal androgen exposure.
    CONCLUSIONS: Female SSc patients exhibit significantly lower 2D:4D ratios than healthy controls, suggesting higher prenatal testosterone exposure. These findings support the hypothesis that the prenatal hormonal environment may contribute to autoimmune disease susceptibility.
    Keywords:  2D:4D; autoimmune disease; prenatal androgen; systemic sclerosis; testosterone
    DOI:  https://doi.org/10.1002/ajhb.70224
  36. bioRxiv. 2026 Jan 31. pii: 2026.01.30.702608. [Epub ahead of print]
    The progression of sex differences in brain networks across the lifespan.
    Ke Huang, Keith W Jamison, Emily Jacobs, Nina Miolane, Amy Kuceyeski.
      Sex differences in brain connectivity are well documented, yet how these differences evolve across the human lifespan remains poorly understood. Rigorously assessing sex-dependent trajectories of brain network organization is challenging due to difficulty in acquiring, processing, and modeling high-dimensional connectomes. Here, we analyzed 15 types of functional and structural connectivity networks from 1286 healthy individuals aged 8-100+ years, using our new AI-based Krakencoder to derive a low-dimensional multimodal "fusion" connectome representation. Sex differences were minimal in early childhood, pronounced in young to mid-adulthood, and diverged across modalities in later life: functional connectivity grew less distinct and structural connectivity grew more distinct from midlife onward. Functional differences were driven predominantly by higher-order association networks (default mode, control), while structural differences concentrated in lower-order cerebellar and subcortical pathways. These findings provide a lifespan-wide, multimodal map of sex differences in brain networks which may help inform sex-specific vulnerability and resilience to brain disorders.
    DOI:  https://doi.org/10.64898/2026.01.30.702608
  37. Eur J Nutr. 2026 Feb 12. 65(2): 41
    High-protein diets increase microbiota associated p-cresol production in the colon and reduce gut barrier function in a sex-dependent manner.
    Daniel James, Maria Batool, Carlos Poveda, Zeynep Hayirli, Chloe Callow, Munawar Abbas, Brandon Linden, John Gibson, Bruce A Griffin, J Stephen Elmore, Gemma E Walton, M Denise Robertson, Marie C Lewis.
      Protein is an essential nutrient, but the detrimental effects of excess dietary protein on gut health are often overlooked. Protein fermentation by colonic microbiota may impair barrier function by increasing toxic metabolite production. We previously identified sex-by-protein interactions affecting the microbiota and its metabolites in vitro. Do sex-by-protein interactions in colonic protein fermentation lead to a sexually dimorphic response in gut barrier function in vivo? We hypothesised that high-protein diets would elicit sex-specific effects on microbiota and barrier function. Twenty sibling-matched male (n = 10) and female (n = 10) piglets were fed high-protein (28%) or standard-protein (SP; 18%) diets for four weeks. Bacterial populations were assessed using 16 S rRNA sequencing, urinary metabolites via SPME/GC-MS, and gut barrier proteins via quantitative fluorescence immunohistology. High-protein diets increased bacteria-derived p-cresol and reduced E-cadherin and CD45 + protein expression without altering microbiota composition. Females on high-protein diets had greater abundances of Staphylococcus and Chryseobacterium, elevated p-cresol, and reduced ZO-1 expression compared to males. High-protein diets appear to reduce barrier function and increase protein-associated toxic metabolite production in sexually dimorphic manners in pigs. If these results are replicated in humans, it indicates requirements for sex-specific nutritional strategies.
    Keywords:  Dietary protein; Gut microbiota; Microbial-derived metabolic end products; Piglet model; Sexual dimorphism
    DOI:  https://doi.org/10.1007/s00394-025-03885-6
  38. Infect Immun. 2026 Feb 09. e0060825
    Underexplored maternal microbiomes: immune, metabolic, and microbial pathways shaping pregnancy outcomes.
    Rafael Tomoya Michita, Nicole Jimenez, Melissa M Herbst-Kralovetz, Indira U Mysorekar.
      Maternal microbial ecosystems play critical roles in shaping reproductive physiology and pregnancy outcomes. During the pre-conception and prenatal periods, these communities modulate maternal physiology by regulating immune tolerance, nutrient metabolism, and susceptibility to pregnancy complications such as preterm birth, hypertensive disorders, and gestational diabetes. While the gut microbiota has been extensively studied, the roles of cervicovaginal, urinary, respiratory, oral, and upper reproductive tract microbiomes remain less clear. In this minireview, we synthesize current knowledge on these underexplored maternal microbiomes, with an emphasis on the cervicovaginal and urinary microbiota and their interactions with the placenta and fetus. We discuss cross-niche microbial signaling, the role of environmental and social determinants in shaping these ecosystems, and mechanisms by which microbes or their products influence host physiology without direct colonization. We also consider the translational potential of microbiota-based interventions to safely improve pregnancy outcomes. Finally, we identify major knowledge gaps and research priorities necessary to advance a more integrated understanding of maternal microbial influences on reproductive and neonatal health. Our synthesis reframes the maternal microbiome as a coordinated, multi-site network that modulates systemic immune and metabolic pathways critical for reproductive success. Understanding these connections will open new avenues for predicting, preventing, and treating pregnancy-related disorders through precision microbiome science.
    Keywords:  cervicovaginal microbiota; gut microbiota; maternal microbiome; oral microbiome; respiratory microbiome; urinary microbiota
    DOI:  https://doi.org/10.1128/iai.00608-25
  39. Hormones (Athens). 2026 Feb 13.
    Biologic sex and health differences, diabetes, metabolic syndrome, and cancer.
    Constantine A Stratakis.
      
    Keywords:  Diabetes; Gender; Hormones; Neoplasia; Sex
    DOI:  https://doi.org/10.1007/s42000-026-00769-0
  40. J Clin Med. 2026 Feb 06. pii: 1301. [Epub ahead of print]15(3):
    The Role of Sex Hormone-Binding Globulin (SHBG) as a Marker of Metabolic Dysfunction-Associated Steatotic Liver Disease, with an Extended Analysis in Both Men and Women.
    Ljiljana Fodor Duric, Zrinka Čolak Romić, Dino Pavičić, Josip Čurić, Velimir Belčić, Ivija Rajković, Irijana Rajković, Jelena Muslim, Nikolina Basic Jukic, Bozidar Vujicic, Tonko Gulin, Matko Gulin, Mladen Grgurević, Anja Oberiter Korbar.
      Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with insulin resistance and metabolic disturbances. Sex hormone-binding globulin (SHBG) is closely linked to metabolic regulation and has been shown to differ between individuals with and without MASLD. Objective: This study aimed to investigate the associations between SHBG and MASLD and their relationships with insulin resistance, body mass index (BMI), age, and sex in a combined male-female cohort. Patients and Methods: We studied 98 men and 54 women with MASLD and 74 men and 55 women without MASLD (aged 25-64 years). Participants underwent abdominal ultrasonography and fasting blood sampling, including measurements of glucose, liver enzymes, lipids, insulin, SHBG, estradiol, and testosterone. Results: SHBG levels were lower in individuals with MASLD than in controls, with a more pronounced reduction in women. MASLD status was associated with an approximately 10 nmol/L lower SHBG concentration (p < 0.0001; gender × MASLD interaction p = 0.0462). Higher estradiol levels were associated with higher SHBG concentrations (p = 0.0009), although this association differed by sex (gender × log-estradiol interaction p = 0.0147). Older age and higher total cholesterol levels were associated with higher SHBG levels, whereas higher triglyceride levels were associated with lower SHBG levels. Conclusions: SHBG showed significant associations with MASLD and with key metabolic and hormonal factors, including BMI, age, and sex. Inclusion of both men and women extends prior male-only research and provides a broader characterisation of sex-specific associations in MASLD.
    Keywords:  MASLD; insulin resistance; metabolic disturbances; sex differences; sex hormone-binding globulin (SHBG)
    DOI:  https://doi.org/10.3390/jcm15031301
  41. Animals (Basel). 2026 Jan 23. pii: 371. [Epub ahead of print]16(3):
    Commensal Microbiota and Reproductive Health in Livestock: Mechanisms, Cross-System Crosstalk, and Precision Strategies.
    Xiaohan Zhou, Jinping Cao, Guanghang Feng, Yaokun Li, Dewu Liu, Guangbin Liu.
      Reproductive performance in livestock and poultry is a core determinant of economic efficiency in the animal industry. While traditional research has primarily focused on genetics, endocrinology, and immune regulation, emerging microbiome studies reveal that commensal microbiota within the gut and reproductive tracts play an underestimated yet pivotal role in host reproductive health. This review systematically synthesizes recent advances regarding the relationship between the microbiome and reproductive functions in major livestock species (cattle, pigs, sheep, and chickens). We first delineate the theoretical basis and mechanisms of the "gut-reproductive axis," highlighting cross-system communication mediated by microbial metabolites, including short-chain fatty acids (SCFAs), indoles, and bile acids. Subsequently, we provide an in-depth comparative analysis of the microecological features of both female (vagina/uterus) and male (semen/epididymis) reproductive systems, examining their impacts on fertility, sperm quality, and pregnancy outcomes. Furthermore, we explore the molecular and systemic mechanisms governing microbial regulation of reproduction, encompassing the modulation of the hypothalamic-pituitary-gonadal (HPG) axis, the balance of local mucosal immunity and inflammation, and epigenetic regulation. Finally, we address current challenges-such as causal validation and the scarcity of multi-species databases-and propose future directions, including spatial multi-omics, AI-integrated analysis, and microbial intervention strategies. Ultimately, this review aims to offer a theoretical foundation and translational insights for elucidating reproductive regulatory networks and developing microbiome-driven precision strategies to enhance reproductive performance.
    Keywords:  HPG axis; SCFAs; gut-reproductive axis; livestock and poultry reproduction; microbiome; precision breeding
    DOI:  https://doi.org/10.3390/ani16030371
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