bims-simsho Biomed News
on Systems immunology and sex hormones
Issue of 2026–03–08
35 papers selected by
Chun-Chi Chang, Lunds universitet



  1. J Immunol. 2026 Feb 09. pii: vkag010. [Epub ahead of print]215(2):
      Sex hormones are important for maintaining metabolic health. Females with low estrogen or high androgen levels exhibit an elevated risk for developing obesity-associated metabolic syndromes. Chronic low-grade inflammation in the visceral adipose tissue (VAT) is a major contributor to metabolic dysfunction during obesity. However, how sex hormones impact the VAT inflammatory environment to curtail obesity-associated pathology remain incompletely understood. Regulatory T cells (Tregs) expressing a clonally expanded T cell receptor (TCR) repertoire and high levels of the IL-33 receptor ST2 are highly enriched in male epididymal VAT (eVAT), in which they suppress tissue inflammation and protect against metabolic diseases. While TCR specificity and activation are critical for the accumulation of ST2+ eVAT Tregs in males, the factors governing Treg clonality in female ovarian VAT (oVAT) and their relevance to obesity-associated metabolic diseases remain largely unexplored. In this study, we used estrogen receptor α (ERα)-deficient mice, which exhibit impaired estrogen signaling and elevated androgen levels, to investigate the impact of sex hormone disruption on oVAT Tregs in lean and obese female mice. At steady state, ERα deficiency promoted age-dependent clonal expansion of specific ST2+ oVAT Treg subsets indirectly through modulating antigen presentation. However, combinations of obesity and ERα deficiency induced IFNγ production to deplete ST2+ oVAT Tregs, exacerbating oVAT inflammation and insulin resistance. Together, these findings reveal distinct, diet-dependent roles for sex hormones in regulating oVAT Tregs and suggest that loss of ST2+ oVAT Treg subsets during obesity may contribute to increased metabolic risk in females with disrupted sex hormone signaling.
    Keywords:  metabolism; regulatory T cells; sex hormones
    DOI:  https://doi.org/10.1093/jimmun/vkag010
  2. Front Immunol. 2026 ;17 1650527
      For decades, sex disparities have been acknowledged to influence immune regulation in health and disease throughout the life span, and contribute to variations in epidemiology, pathophysiology, manifestation, progression, and therapeutic response in multiple disorders. However, the underlying cellular and molecular mechanisms governing these disparities remain understudied. This review articulates the effects of sex as critical regulators of the major causes of morbidity and mortality in diseases. We summarize the key factors driving sex differences, including sexual hormones and sex chromosomes, as well as elaborate how these factors influence physiology and disease, especially by modulating the function and fate of immune cells. Our aim is to disentangle the intricacies of sexually-differentiated immune responses within physiological and pathological contexts, thereby establishing the groundwork for precision medicine approaches customized to sex-specific requirements in clinical settings.
    Keywords:  disease; immune cells; physiology; sex disparity; sexual hormone
    DOI:  https://doi.org/10.3389/fimmu.2026.1650527
  3. J Steroid Biochem Mol Biol. 2026 Feb 26. pii: S0960-0760(26)00038-5. [Epub ahead of print] 106972
      The androgen signaling pathway is probably the most important pathway in enabling prostate cancer progression but it also plays essential roles in numerous processes in normal physiology. Both testosterone and dihydrotestosterone are potent androgens that activate the androgen receptor (AR). The essentiality of the androgen pathway in prostate cancer is evidenced in part by the reactivation of AR in prostate cancer that becomes resistant to treatment by gonadal testosterone deprivation. Furthermore, steroid metabolic processes that allow the regeneration of potent androgens in prostate cancer tissues drive this treatment-resistant state, as is made clear by the survival benefit of blocking the synthesis of non-gonadal androgens, e.g., with abiraterone. Here, I narrate and review the process that led to a series of discoveries in androgen metabolism from our group. In this perspective and mechanistic narrative review, I give an honest description of the accidental nature of some of our initial findings, followed by data-driven hypothesis refinement and subsequent studies that illuminate elements of androgen metabolism, with a focus on metabolism of carbon 3, carbon 5 and carbon 17 of the steroid backbone.
    Keywords:  androgens; enzymes; metabolism; prostate cancer; steroids
    DOI:  https://doi.org/10.1016/j.jsbmb.2026.106972
  4. Genetics. 2026 Mar 02. pii: iyag058. [Epub ahead of print]
      Host sexual dimorphism in the outcome of infections is a ubiquitous phenomenon across taxa. However, the immunological differences between males and females and the mechanisms underlying them remain poorly characterized. Here, we used Drosophila melanogaster to test the hypothesis that sex differences in nutritional immunity, particularly iron sequestration, contribute to sexual dimorphism in infection outcome. Using the natural Drosophila pathogen Providencia alcalifaciens, which is controlled by host-mediated iron sequestration, we established an infection model in which males demonstrate increased resistance. Leveraging this model, we showed that males exhibit higher basal and infection-induced expression levels of Transferrin 1 (Tsf1) -an iron transporter mediating iron sequestration during infection. Consequently, males contained lower iron levels in the hemolymph compared to females. Importantly, sex differences in iron content and in survival after P. alcalifaciens infection were abolished in Tsf1 mutants, demonstrating that Tsf1 mediates sexual dimorphism in iron sequestration and susceptibility to P. alcalifaciens infection. Finally, we found that the Toll pathway mediates sex differences in Tsf1 expression and susceptibility to infection. Altogether, our study demonstrates that Tsf1-mediated iron sequestration differs between male and female D. melanogaster, thereby identifying nutritional immunity as a determinant of sexual dimorphism in the outcome of infection.
    Keywords:   Drosophila melanogaster ; immunity; infection; iron sequestration; nutritional immunity; sexual dimorphism; transferrin
    DOI:  https://doi.org/10.1093/genetics/iyag058
  5. Int J Cancer. 2026 Mar 06.
      Prostate cancer is the most prevalent malignancy among men and is driven by multiple factors, including androgen signaling and its receptor. Long non-coding RNAs, such as PVT1, play key roles in cancer, particularly by regulating gene expression. PVT1 is upregulated in several cancer types and has been shown to interact with the androgen receptor in prostate cells. This study investigates how PVT1 contributes to the prostate cancer phenotype under androgen stimulation. Knockdown of PVT1 was achieved using CRISPR-Cas13d in LNCaP prostate cancer cells subjected to androgen (R1881) or vehicle treatment. Cellular proliferation, invasion, and apoptosis rates were assessed, alongside RNA sequencing (RNA-seq) to analyze genome-wide transcriptomic changes. Six epigenetic marks-AR, EZH2, H3K4me1, H3K4me3, H3K27me3, and H3K27ac-were examined using CUT&RUN. PVT1 knockdown led to a significant reduction in cell proliferation and an increase in apoptosis signaling. Oncogenes such as MYC, AKT1, AKT2, cyclins CCNA2, CCNB1, CCNB2, CCNE1, CCNE2 and cyclin-dependent kinases CDK1 and CDK4, which were upregulated under androgen treatment, exhibited a significantly reduced expression following PVT1 knockdown, thereby modulating cancer-associated oncogenic pathways. Epigenetically, PVT1 knockdown markedly decreased the occupancy of transcriptionally activating epigenetic marks-H3K4me1, H3K4me3, and H3K27ac-on oncogenes, regardless of androgen presence. Analysis of enriched transcription factors associated with the altered genes revealed a regulatory network linked to prostate cancer pathogenesis. PVT1 drives a genome-wide epigenetic reprogramming in prostate cells, underscoring the role of PVT1 as a positive regulator of oncogenic pathways in prostate cancer and highlighting PVT1's potential as a therapeutic target.
    Keywords:  PVT1; androgen receptor signaling; epigenetic regulation; long non‐coding RNA; prostate cancer
    DOI:  https://doi.org/10.1002/ijc.70417
  6. Biol Reprod. 2026 Mar 02. pii: ioag051. [Epub ahead of print]
      Polycystic ovary syndrome is the most common endocrine condition in women and anovulatory cause of female infertility. While a pro-inflammatory cytokine and leukocyte bias in systemic circulation is well-documented in PCOS, it is not known how this inflammation extends to or affects the ovary. Additionally, the relationship between ovulation and inflammation in PCOS is not well-defined. We hypothesize that the ovarian follicular immune environment in PCOS is uniquely dysregulated, and that resolving anovulation through ovulation induction is not sufficient to alleviate this dysregulation. Using single-cell RNA and surface protein analysis of peripheral blood and follicular fluid from patients undergoing in vitro fertilization, we discovered that both control and PCOS follicles were immunologically distinct from circulation. At a systemic level, we find that ovulation induction in PCOS may alleviate systemic inflammation. In contrast, while healthy control ovaries experienced acute immune-directed ovulatory signaling, PCOS ovarian follicles were deficient in key pro-ovulatory cell to cell communication, and displayed instead a chronic low-grade inflammatory state with fibrotic features. Taken together, a picture emerges where acute ovulation demonstrates a well-ordered series of follicle-specific immune information flows, which are disrupted and replaced by low grade chronic inflammation in the PCOS follicle.
    Keywords:  infertility; inflammation; macrophage; monocyte; ovary
    DOI:  https://doi.org/10.1093/biolre/ioag051
  7. Psychoneuroendocrinology. 2026 Feb 24. pii: S0306-4530(26)00070-3. [Epub ahead of print]187 107810
       INTRODUCTION: Prominent sex differences exist in severe mental illness (SMI), with increasing evidence pointing towards a pivotal role for sex hormones. Elucidation of these hormonal influences is crucial to tailor sex-specific prevention and treatment.
    METHODS: To investigate potential shared genetics and bi-directional causal effects between sex hormone traits and SMI (depressive disorder, bipolar disorder and schizophrenia-spectrum disorder), we computed genetic correlations using linkage disequilibrium score regression and bi-directional summary-level Mendelian Randomization (MR). A range of sensitivity methods was applied and potential mediators were investigated using multivariable MR. Sex-stratified data from genome-wide association studies were used, if available further stratified on menopausal status. We also incorporated other sex hormone traits (progesterone, sex hormone-binding globulin, prolactin, age of menarche, age of menopause) in exploratory analyses.
    RESULTS: We found a widespread pattern of statistically significant, modest genetic correlations between oestrogen/testosterone levels and depressive disorder/schizophrenia-spectrum disorder, in both positive and negative directions and in both sexes (ranging between -0.22 and 0.13). With MR, evidence for causal effects was largely lacking; apart from weak evidence for a causal, increasing effect of testosterone levels on schizophrenia-spectrum disorder risk in males, which was mediated by CRP. Conversely, there was very weak evidence for a causal, increasing effect of liability to schizophrenia-spectrum disorder on testosterone levels in both sexes.
    CONCLUSION: This study offers new insights into the complex aetiology of SMI by comprehensively mapping genetic associations with sex hormone traits, emphasizing the need to further investigate sex hormones' impact on SMI using larger and more precisely phenotyped samples to identify individuals particularly vulnerable to hormonal disturbances.
    Keywords:  Depressive disorder; Genetic correlation; Genetics; Mendelian randomization; Schizophrenia; Sex hormones
    DOI:  https://doi.org/10.1016/j.psyneuen.2026.107810
  8. Front Endocrinol (Lausanne). 2026 ;17 1713408
       Background: Polycystic ovary syndrome (PCOS) is a multifactorial endocrine disorder affecting about 10% of reproductive-age women. It is defined by insulin resistance, androgen excess, and chronic inflammation, which drive both reproductive and metabolic complications. Growing evidence suggests that gut microbiome dysbiosis contributes to PCOS by altering intestinal permeability, promoting endotoxemia, and worsening hormonal and metabolic dysfunction. Diet, as a modifiable factor, may offer a therapeutic route to restore microbial balance and improve outcomes.
    Objectives: This review aims to (1) synthesize evidence on how diet shapes gut microbiome composition in PCOS; (2) evaluate the effects of specific dietary patterns on microbial diversity, insulin sensitivity, lipid metabolism, and hormonal regulation; and (3) identify dietary components that may improve clinical outcomes.
    Methods: Evidence from observational studies, randomized trials, and meta-analyses was reviewed to assess how dietary interventions influence gut microbiome modulation and PCOS outcomes. Dietary patterns-including the Mediterranean diet, low-glycemic index diets, anti-inflammatory diets, time-restricted eating, and probiotic supplementation-were examined for their effects on microbiota and metabolic or hormonal measures.
    Results: Dietary interventions can beneficially alter gut microbiota, reduce systemic inflammation, improve insulin sensitivity, and lower androgen levels. The Mediterranean diet enhances microbial diversity and is associated with reduced PCOS risk. Low-glycemic index diets improve metabolic and hormonal profiles by lowering insulin demand. Anti-inflammatory diets and time-restricted eating may restore microbial rhythmicity and reduce inflammatory and endocrine imbalances. Probiotic supplementation, particularly with Lactobacillus and Bifidobacterium, strengthens gut integrity and benefits metabolic and hormonal outcomes. A multi-component dietary plan integrating high-fiber foods, probiotics, anti-inflammatory nutrients, low glycemic load, and structured eating patterns is proposed.
    Conclusion: Modulating the gut microbiome through diet is a promising, non-invasive, cost-effective strategy for PCOS management. By targeting insulin resistance, androgen excess, and inflammation, nutrition-based interventions can improve metabolic and reproductive outcomes. Long-term randomized trials are needed to strengthen causal evidence and guide personalized dietary approaches.
    Keywords:  PCOS (polycystic ovarian syndrome); chronic inflammation; diet intervention; gut dysbiosis; gut microbiome
    DOI:  https://doi.org/10.3389/fendo.2026.1713408
  9. Nat Rev Urol. 2026 Mar 04.
      Androgen signalling is the primary driver of male sexual differentiation in mammals, directing masculinization during a crucial fetal window. In male fetuses, high levels of fetal androgens, mainly from the testes, promote male reproductive tract development through androgen receptor activation, whereas low levels of androgens in female fetuses enable the development along the female pathway. This androgen-centric view of reproductive development has long dominated the field, casting oestrogens as passive bystanders. However, both historical and emerging evidence challenges this narrative, pointing to an active role of oestrogens in shaping reproductive development through complex, tissue-specific interactions with androgen pathways. Oestrogen receptors are expressed in developing reproductive tissues of both sexes, and disruptions in oestrogen signalling - shown in genetic and pharmacological models - can lead to reproductive abnormalities. Oestrogens might counteract androgen action at the tissue level and modulate androgen receptor expression, independently of effects on androgen production. Moreover, combined exposure to anti-androgens and oestrogenic compounds can amplify developmental disruptions, underscoring the importance of hormonal crosstalk. These findings question the adequacy of an androgen-only model, especially when assessing endocrine disruptors. Understanding the role of oestrogens is essential for interpreting normal development and chemical risks. Reproductive differentiation seems to depend on the integrated balance between androgen and oestrogen pathways, rather than on isolated signals.
    DOI:  https://doi.org/10.1038/s41585-026-01132-z
  10. Biol Sex Differ. 2026 Mar 04.
       BACKGROUND: Females undergo hormonal fluctuations throughout every menstrual cycle and numerously report corresponding symptoms of negative mood or decreased motivation, indicating an increased risk for affective disorders associated with altered motivational behaviour. Understanding whether sex hormones modulate sex/gender-specific behavioural variability in motivation could inform personalised interventions.
    METHODS: To assess whether steroid hormone fluctuations and menstrual cycle phase modulate sex/gender-specific motivation, we examined 48 naturally cycling cisgender females and 46 cisgender males, aged 18-34, who performed a physical effort task while fasted (part 1, T0) and across four weeks (part 2, T1-T4). We obtained objective (invigoration and effort maintenance) and subjective (wanting and exertion) measures of motivation in response to food and monetary rewards. Menstrual cycle phases were determined based on cycle-day counting methods alongside plasma levels of estradiol, progesterone, and testosterone. We tested whether females show higher effort maintenance, males exhibit greater reward sensitivity, and explored whether motivational behaviour differs by sex/gender, cycle phase and hormonal variation.
    RESULTS: Cross-sectionally, we replicated sex/gender specific reward sensitivity and valuation: Females showed more sustained effort, especially for small rewards, while males displayed more opportunistic approaches seeking monetary rewards. Longitudinally, motivation decreased during periovulatory and luteal phases, whereas levels of endogenous hormones explained little variance in instrumental effort beyond task incentives and sex/gender associations.
    CONCLUSIONS: Motivational behaviour in effort-based decision-making is more related to dynamic sex/gender-related factors and menstrual cycle phases overall than to short-term steroid hormone fluctuations. Our findings emphasise the importance of integrating biological, psychosocial, and physiological factors when investigating motivation. Our research has potential implications for personalised interventions and treatment of motivational deficits.
    Keywords:  Estradiol; Menstrual cycle; Motivation; Reward sensitivity; Sex/gender characteristics; Steroid hormones
    DOI:  https://doi.org/10.1186/s13293-026-00853-5
  11. Invest New Drugs. 2026 Mar 03.
      ONCT-534 is a dual-action androgen receptor inhibitor (DAARI) that combines AR antagonism and degradation via N-terminal domain binding, additionally targeting AR splice variants. In this study patients received ONCT-534 daily ranging from 40 to 1200 mg. The primary objectives were safety and dose-limiting toxicities (DLTs). Additional objectives included antitumor activity and AR signaling biomarkers. Adverse events (AEs) were assessed within the first 28 days for DLTs. Clinical activity was evaluated by PSA and radiographic progression per PCWG3 and RECIST v1.1. The trial was stopped early and not all patients were evaluated per protocol. Twenty-one patients received ONCT-534 across six doses. The most common AEs were anemia, back pain, and fatigue. While no DLTs were observed within 28 days, Grade 3/4 AEs occurred later in 9 patients (anemia most frequently). One patient discontinued due to treatment-related AE. No radiographic or PSA-based responses were observed; however, three patients showed PSA declines at week 4, with one achieving a PSA50 at time of study closure. Of 10 patients with baseline AR protein data, the median change was - 40.59% in AR protein levels at week 4. In the 300 mg cohort, 3 patients showed concordant decreases in AR protein and AR gene expression. Here, PSA levels correlated positively with AR target gene and AR gene expression. ONCT-534 had acceptable safety and demonstrated biological activity through AR protein degradation and AR signaling suppression in mCRPC patients. Although clinical responses weren't observed, these findings provide proof-of-concept for examining AR protein changes in patients receiving DAARIs.
    Keywords:  Dual-action androgen receptor inhibitor; Hormonal therapies; MCRPC
    DOI:  https://doi.org/10.1007/s10637-026-01600-8
  12. Biol Sex Differ. 2026 Mar 03.
       BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder with established sex differences in incidence and progression. Epidemiological evidence suggests nicotine may confer protection against PD, but its mechanisms, particularly regarding sex-specific effects, remain unclear. This study investigated the neuroprotective mechanisms of nicotine in a rotenone-induced PD rat model, with a specific focus on evaluating sex-dependent modulation across behavioral, pathological, and gut-related outcomes.
    METHODS: Male and female Sprague-Dawley rats were administered rotenone (2 mg/kg/day, s.c.) for four weeks to induce PD. Nicotine (0.5 mg/kg/day, s.c.) was administered 30 min after rotenone. Motor function was assessed using rotarod and CatWalk XT gait analysis. Neuropathology in the substantia nigra was evaluated via immunofluorescence for α-synuclein and tyrosine hydroxylase (TH). Gut pathology was analyzed through colon histopathology (H&E staining) and ELISA for IL-6 and α-synuclein. Gut microbiota composition was assessed by 16 S rDNA sequencing, and serum metabolomics was performed using UPLC-MS/MS. Data were analyzed by two-way ANOVA with Tukey's post-hoc test.
    RESULTS: Nicotine significantly attenuated rotenone-induced motor impairments: males showed a superior response in balance-related parameters, while females exhibited enhanced efficacy in dynamic gait metrics. Pathologically, nicotine reduced nigral α-synuclein accumulation and TH depletion in both sexes, with males showing greater α-synuclein accumulation following rotenone exposure. Crucially, nicotine exclusively ameliorated colon histopathology, reduced plasma α-synuclein, and suppressed colon IL-6 in females, while attenuating intestinal α-synuclein accumulation in both sexes. Microbiota analysis revealed sex-divergent taxonomic shifts with nicotine treatment. Metabolomics showed significantly more extensive metabolic reprogramming in females, particularly affecting indole derivatives. Pearson correlations revealed significant sex-specific associations between altered serum indole derivatives and gut microbiota genera.
    CONCLUSIONS: Nicotine exerts neuroprotection in PD through sex-dependent modulation of multiple pathological pathways, primarily involving the gut-microbiota-metabolite axis. Females benefit from enhanced gastrointestinal protection and metabolic reprogramming, while males show preferential motor balance restoration. These findings underscore the critical importance of sex-stratified therapeutic strategies for PD.
    Keywords:  16S rDNA sequencing; Gut-brain axis; Metabolomics; Nicotine; Parkinson's disease; Sex differences
    DOI:  https://doi.org/10.1186/s13293-026-00865-1
  13. J Reprod Immunol. 2026 Feb 28. pii: S0165-0378(26)00036-7. [Epub ahead of print]174 104867
      Adverse perinatal outcomes of preterm birth (PB), premature rupture of membranes (PROM), intrauterine growth restriction (IUGR), and preeclampsia contribute to a growing number of maternal and fetal deaths each year. Altered immunological regulation of the maternal innate and adaptive immune systems has been implicated in the pathological inflammation dictating obstetrical complications, but the pathogenesis of aberrant maternal immune activation has not been fully elucidated. Microbial dysbiosis within the female reproductive tract may alter the regulation of immunological tolerance at the maternal-fetal interface, mediating maternal inflammation that precipitates obstetrical disorders. Development of a more comprehensive understanding on how microbial communities influence immune regulation during pregnancy may create avenues for therapeutic modulation of the maternal immune system to promote immune tolerance throughout gestation and decrease obstetrical complications. In this review we characterize the modulation of maternal immunological function by microbial communities and how these pathways may precipitate the development of obstetrical disorders.
    Keywords:  Dysbiosis; Immunology; Microbiota; Perinatal outcomes; Tolerance
    DOI:  https://doi.org/10.1016/j.jri.2026.104867
  14. Am J Reprod Immunol. 2025 Aug;94(2): e70145
       PROBLEM: Menstrual effluent (ME) is widely used to study immune-related reproductive disorders. However, women using contraceptives are often excluded from such studies due to limited knowledge of their impact on the endometrial immune cell composition. This gap in knowledge restricts our ability to include women using contraceptives in the scientific investigations and account for potential immunological variations associated with contraceptive use. Therefore, we aim to investigate whether contraceptive use is associated with differences in the uterine immune system.
    METHOD OF STUDY: ME was collected from women using combined oral contraceptives (COC, n = 5), a copper intrauterine device (IUD, n = 3), or no contraceptives (n = 5). Immune cells were isolated from ME and analyzed using flow-cytometry. Data were analyzed using an unpaired t-test, followed by multiple testing correction using the false discovery rate (FDR) method.
    RESULTS: Women using COCs exhibited a marked reduction in the frequency of the immunoregulatory CD56brightCD16- endometrial Natural Killer (eNK) cells compared to women using no contraceptives (30.1% ± 5.99 and 66.0% ± 10.6; p = 0.001). Additionally, women using copper IUD showed elevated frequencies of proliferating Ki-67+CD8+ T cells compared to COC users and controls (19.8% ± 4.3, 2.69% ± 1.23, and 3.77% ± 4.4).
    CONCLUSIONS: This pilot study highlights the importance of considering contraceptive use when studying immune-related reproductive problems.
    Keywords:  combined oral contraception; copper intra‐uterine device; endometrial immune cells; menstrual effluent; uterine immune system
    DOI:  https://doi.org/10.1111/aji.70145
  15. Basic Clin Pharmacol Toxicol. 2026 Apr;138(4): e70218
      Sex hormone-binding globulin (SHBG) is a sex hormone carrier. We aimed to characterize the role of pregnane X receptor (PXR), a major regulator of drug metabolism, in SHBG regulation. Serum SHBG was measured in four clinical trials (n = 61) and expression in in vitro experiments in human 3D hepatocyte spheroids and HepG2 cells. We also analysed previously published chromatin immunoprecipitation sequencing data from cryopreserved human hepatocytes. One-week dosing of PXR ligand rifampicin increased SHBG in all but one healthy volunteer (geometric mean induction 2.0-fold; SHBG concentration 70.5 ± 34.1 nmol/L with rifampicin and 36.1 ± 19.0 nmol/L with control; p < 0.0001; 95% confidence interval of the mean of differences between arms 31.9-42.0). In men, serum total testosterone increased and free androgen index decreased. In 3D human hepatocyte spheroids, rifampicin caused a clear induction of SHBG mRNA, while SPA70, a PXR antagonist, decreased both basal and rifampicin-induced SHBG mRNA expression. Analysis of ChIP-sequencing data identified a rifampicin-induced PXR binding site within the SHBG gene. These results show that PXR is a novel regulator of serum SHBG in humans. This mechanism may mediate effects of PXR-activating drugs and other chemicals on sex hormone balance and have implications for metabolic health.
    Keywords:  endocrine‐disrupting chemicals; pregnane X receptor; sex hormone–binding globulin; testosterone; thyroxine
    DOI:  https://doi.org/10.1111/bcpt.70218
  16. J Reprod Immunol. 2026 Feb 24. pii: S0165-0378(26)00034-3. [Epub ahead of print]174 104865
      Chronic low-grade inflammation along with gut microbial dysbiosis, plays a crucial role in the development and progression of polycystic ovary syndrome (PCOS), the complex endocrine disorder associated with long-term metabolic consequences. S. boulardii is a promising yeast in the correction of gut dysbiosis. The present study aimed to test the efficacy of S. boulardii in managing PCOS in PCOS-IR rats induced by letrozole (1 mg/kg/day) and a high-fat diet (40%). Subsequently, the rats were co-administered with lyophilized S. boulardii at a dosage of 1.8 × 107 CFU/kg/Day. The changes in organosomatic indices, plasma glucose, serum hormones, systemic LPS level, oxidative and inflammatory response, estrous cycle, ovarian histo-architecture, and mRNA expression of TNFα and NFκB were studied. The findings suggest that S. boulardii effectively interrupts the further progression of PCOS by correcting the metabolic endotoxemia, inflammation, and endocrine imbalances. An improved insulin sensitivity, along with the correction in serum LPS and body weight, was noted. This ameliorative effect was accompanied by the suppression of inflammatory cytokines (TNFα, IL-6, IL-1β, and NFκB). This probiotic was also found to exert antiandrogenic activity, regulating LH:FSH ratio, modulating the ovarian expression of CYP17A1 and NR3C4 remarkably, with further influence on serum estradiol level. Additionally, the corrected ovarian expression of SOD and catalase was observed with improved histomorphology. Present findings indicate the therapeutic potential of S. boulardii against PCOS, plausibly attributed to the correction of inflammation subsequent to its influence on the crosstalk within the metabolic and reproductive cascades associated with PCOS.
    Keywords:  Inflammation; Insulin resistance; PCOS; PCOS-IR; Probiotic; S boulardii
    DOI:  https://doi.org/10.1016/j.jri.2026.104865
  17. Int J Reprod Biomed. 2025 Dec;23(12): 995-1006
       Background: Polycystic ovary syndrome (PCOS) is a leading cause of anovulatory infertility. In women undergoing frozen embryo transfer, the method of endometrial preparation (hormone replacement therapy [HRT] or mild ovarian stimulation [MOS]) can affect pregnancy outcomes. Letrozole-based MOS protocols may improve endometrial receptivity and reduce miscarriage rates by upregulating key implantation markers leukemia inhibitory factor, dickkopf-related protein 1, leukemia inhibitory factor receptor, fibroblast growth factor 22, integrin alpha V beta 3.
    Objective: This study aimed to compare the frozen embryo transfer outcomes in 2 endometrial preparation methods: HRT and MOS in infertile women with PCOS.
    Materials and Methods: This double-blind randomized trial included 100 infertile women with PCOS and frozen embryos who referred to Al-Zahra hospital, Tabriz, Iran between October 2024 and 2025. Participants were assigned to HRT or MOS for endometrial preparation. In HRT, oral estradiol followed by injectable progesterone was used; in MOS, letrozole +  follicle-stimulating hormone stimulation continued until follicle   >  17 mm and endometrium   ≥   7.5 mm, then human chorionic gonadotropin was given. Cleavage-stage transfer was performed in both groups, and pregnancy outcomes (chemical, clinical, and final) were compared.
    Results: The number of transferred embryos (p = 0.771) and their quality (types 1 and 2) (p = 0.857) were similar between groups. The number of chemical pregnancies in the MOS group (25 cases) was non-significantly higher than in the HRT group (20 cases) (p = 0.078). However, the number of clinical pregnancies (p = 0.045) and the number of successful pregnancies (p = 0.049) were significantly higher in the MOS group compared to the HRT group.
    Conclusion: This study showed that MOS achieved higher clinical and successful pregnancy rates than HRT in women with PCOS.
    Keywords:   Frozen embryo; Hormonal therapy; Mild ovarian stimulation protocol.; Endometrium; Polycystic ovary syndrome
    DOI:  https://doi.org/10.18502/ijrm.v23i12.20712
  18. Int J Mol Med. 2026 May;pii: 107. [Epub ahead of print]57(5):
      Adenomyosis (AM), an estrogen‑dependent chronic inflammatory disease with a rising incidence, has emerged as a major cause of infertility and reduced clinical pregnancy rates in reproductive‑aged women, severely impairing reproductive health and quality of life. The core pathological mechanisms of AM are closely linked to aberrant local expression of inflammatory cytokines, including interleukin (IL)‑6, C‑X‑C motif chemokine ligand 8 (CXCL8), IL1B, tumor necrosis factor‑α, NF‑κB, cyclooxygenase‑2 and TGF‑β, which disrupt the immune barrier at the endometrial‑myometrial junction. This disruption further breaks the critical balance between proinflammatory and anti‑inflammatory cytokines, ultimately fostering an immune microenvironment hostile to embryo survival. Concurrently, inflammatory cytokine‑activated cellular processes, including proliferation, invasion, tissue injury and repair, epithelial‑mesenchymal transition and fibrosis, further induce pathological neovascularization and impair blood perfusion in the junctional zone. These pathological changes, in turn, compromise endometrial receptivity and inhibit decidualization, ultimately resulting in implantation failure. Based on these mechanisms, key inflammatory cytokines such as IL‑6, CXCL8, IL1B and IL‑10 hold potential as diagnostic biomarkers for AM‑related infertility and provide a theoretical basis for developing fertility‑preserving therapies targeting the inflammatory cascade (such as IL‑6 receptor monoclonal antibodies and TGF‑β inhibitors). These findings offer new approaches to achieve the dual goals of lesion control and fertility preservation in clinical practice.
    Keywords:  adenomyosis; immune cells; infertility; inflammatory cytokines; tissue injury and repair
    DOI:  https://doi.org/10.3892/ijmm.2026.5778
  19. Open Biol. 2026 Mar 04. pii: 250419. [Epub ahead of print]16(3):
      The existence of sex differences in human pre-implantation development remains an open question, with previous attempts based on human observations yielding inconclusive results. In this study, we combined manual annotation and deep learning analysis of a dataset comprising 515 time-lapse embryo movies to investigate whether birth sex influences early developmental dynamics. While manual assessment did not identify any developmental timing parameters that reliably distinguish male from female embryos, a deep learning model trained and tested on these videos achieves a statistically significant sex prediction accuracy of 61%. Importantly, our analyses identified the period after the eight-cell stage as critical for accurate prediction, indicating that subtle sex-related differences may begin to emerge around day 3 of human embryogenesis. Studying sex differences at this early stage may enhance our understanding of why some embryos fail to develop and why sex ratios can be skewed in the context of in vitro fertilization. More broadly, our findings open the possibility for an early, non-invasive detection tool that could assist in identifying and addressing sex-related embryonic developmental abnormalities.
    Keywords:   in vitro fertilization (IVF); deep learning; zygotic genes
    DOI:  https://doi.org/10.1098/rsob.250419
  20. JCO Precis Oncol. 2026 Mar;10 e2500756
       PURPOSE: This study aimed to define molecular subtypes of prostate cancer by integrating androgen receptor (AR) signaling, neuroendocrine prostate cancer (NEPC) transcriptional signatures, and genomic alterations to inform biomarker-driven therapies in metastatic castration-resistant prostate cancer.
    METHODS: We analyzed 8,019 prostate tumors using DNA/RNA sequencing (Caris Life Sciences), classifying them into four molecular subtypes (AR+/NE-, AR-/NE+, AR+/NE+, AR-/NE-). Genomic alterations, cell surface target expression, and overall survival (OS) were evaluated.
    RESULTS: Of the 8,019 tumors, 87.2% were adenocarcinoma, 1.9% NEPC, and 0.4% had mixed histology; 63% were from primary sites and 36.5% from metastases. The median age was 68 years; 63% were White, 15% Black, and 2.6% Asian or Pacific Islander. Most tumors were classified as AR+/NE- (91%), and 4.6% were AR-/NE+. TP53 and PTEN alterations were enriched in AR-negative subtypes, whereas SPOP mutations were more frequent in AR+ tumors. FOLH1 (prostate-specific membrane antigen) expression was the highest in AR+ tumors, whereas DLL3 expression was elevated in NE+ tumors. Median OS was significantly longer in tumors with high AR signaling (55.0 v 14.0 months, P < .00001) and lower with the NEPC signature (54.3 v 16.1 months, P < .00001). Combined stratification showed the most favorable outcome in AR+/NE- tumors (55.3 months) and the poorest in AR-/NE+ tumors (12.0 months).
    CONCLUSION: Prostate cancer exhibits distinct molecular subtypes defined by AR signaling activity, NEPC transcriptional profiles, and genomic alterations. These biologically and clinically relevant subgroups provide a framework for precision oncology approaches and inform patient selection for biomarker-driven trials such as the ongoing PREDICT study (ClinicalTrials.gov identifier: NCT06632977).
    DOI:  https://doi.org/10.1200/PO-25-00756
  21. Gut Microbes. 2026 Dec 31. 18(1): 2637316
      The role of the microbiota‒gut‒brain axis in the pathophysiology of anorexia nervosa has emerged in recent decades. Increased expression of Toll-like receptor 4 (TLR4) has been reported in the intestinal epithelial cells (IEC) of activity-based anorexia (ABA) mice. The inducible TLR4 knockout in IEC (TLR4IEC-/-) was subsequently associated with behavioral and energy balance changes in ABA mice. Our study aimed to assess the intestinal response to TLR4IEC-/- in both male and female ABA mice by focusing on three components: inflammation, the gut barrier, and the gut microbiota composition. After 12 d of undernutrition with free wheel access, the colonic expression of 43 markers was measured by RT-qPCR. The gut microbiota composition was analyzed by Illumina sequencing of the 16S rRNA gene. First, TLR4IEC-/- was associated with more marked alterations in male control mice compared to females. Indeed, a reduction in the mRNA expression of eight inflammatory factors, seven tight junction proteins and fecal calprotectin levels was observed in males. Control TLR4IEC-/- females showed increased expression of four inflammatory markers and one target involved in the gut barrier. The levels of the Bacillota phylum and the Deltaproteobacteria class and their subdivisions, up to the Desulfovibrio genus, increased in the control TLR4IEC-/- males compared to wt. In females, only an increase in the Alcaligenaceae genus, which ranks from the Betaproteobacteria phylum, was observed. Interestingly, in both males and females, these alterations were not observed in response to ABA model in TLR4IEC-/- mice. Similarly, ABA increased Tjp1 expression and Lactobacillus abundance, both of which were decreased by TLR4IEC-/-. Our study shows for the first time the impact of inducible TLR4IEC-/- on the intestinal response. TLR4IEC-/- induced sex-specific colonic alterations and changes in the gut microbiota, which disappeared after the ABA model. Further studies are warranted to decipher the underlying mechanisms.
    Keywords:  Anorexia nervosa; TLR4; activity-based anorexia mice; gut barrier; gut inflammation; gut microbiota
    DOI:  https://doi.org/10.1080/19490976.2026.2637316
  22. J Immunother Cancer. 2026 Mar 04. pii: e013790. [Epub ahead of print]14(3):
       BACKGROUND: In murine studies, we demonstrated that a DNA vaccine encoding the androgen receptor (pTVG-AR) given prior to androgen deprivation elicited prostate tumor-infiltrating lymphocytes and an antitumor response. The current trial evaluated this approach, with or without programmed cell death protein-1 (PD-1) blockade, in patients with high-risk newly diagnosed prostate cancer.
    METHODS: In the first stage of a two-stage protocol, 24 patients were randomized to treatment with (1) degarelix alone (n=6); (2) pTVG-AR followed by degarelix (n=9); or (3) pTVG-AR, degarelix and nivolumab (n=9), each delivered over 12 weeks prior to prostatectomy. The primary objectives were safety and pathological complete response or minimal residual disease (MRD). Secondary endpoints were residual cancer burden (RCB) <0.25 cm3 and 1-year prostate-specific antigen (PSA) progression-free survival.
    RESULTS: Adverse events were almost exclusively in Arm 3, attributed to nivolumab. One patient achieved MRD (Arm 2), and three patients had an RCB <0.25 cm3 (all in Arm 2). At 1 year after surgery, the PSA progression-free survival rate was 33% (2/6) in Arm 1, 89% (8/9) in Arm 2, and 33% (3/9) in Arm 3 (p=0.039). Tissue analysis at prostatectomy demonstrated reduced CD4+cells with a regulatory phenotype in patients in Arm 2.
    CONCLUSION: In this first stage of a pilot study that awaits confirmation with larger numbers of patients, our results suggest that vaccination targeting AR given prior to androgen deprivation therapy might improve outcome for patients with high-risk prostate cancer. Contrary to our initial hypothesis, this was not improved with the addition of PD-1 blockade, possibly due to the activation of regulatory CD4+T cells.
    TRIAL REGISTRATION NUMBER: NCT04989946.
    Keywords:  Nivolumab; Prostate Cancer; T regulatory cell - Treg; Tumor infiltrating lymphocyte - TIL; Vaccine
    DOI:  https://doi.org/10.1136/jitc-2025-013790
  23. Eye Vis (Lond). 2026 Mar 03. pii: 10. [Epub ahead of print]13(1):
       BACKGROUND: Keratoconus (KC) is a vision-threatening condition with a higher prevalence and earlier onset in males than in females. The study aims to investigate sex-associated transcriptomic features of KC and assess whether sex hormones modulate stromal remodelling.
    METHODS: We performed whole-transcriptome sequencing of human corneal tissues from patients with KC and matched controls (n = 20; five males and five females per group), followed by weighted gene co-expression network analysis, Gene Ontology, Kyoto Encyclopaedia of Genes and Genomes enrichment, and competitive endogenous RNA (ceRNA) network construction. Our findings were functionally probed in primary human corneal stromal fibroblasts (HCSFs) using testosterone, β-oestradiol, and their antagonists. Key nodes were validated by reverse transcription-quantitative polymerase chain reaction analysis, Western blotting, and immunofluorescence.
    RESULTS: Across 17,496 genes, we identified 3,345 differentially expressed genes (adjusted P < 0.01, |log2 fold-change|≥ 2). Module analyses highlighted pathways related to intracellular transport, energy metabolism, and hormone responses. Sex-stratified analyses revealed male-specific up-regulation of gonadal development programs and female-specific down-regulation of immune and hormonal processes. In HCSFs, testosterone down-regulated type I collagen but up-regulated type III collagen and α-smooth muscle actin; these effects were mitigated by flutamide. Conversely, oestrogen inhibition reproduced altered stromal remodelling, which was rapidly reversed by β-oestradiol. A female-specific ceRNA axis (circEPB41L2_0001-miR-942-5p-DCP1A) was identified and validated by performing perturbation experiments.
    CONCLUSIONS: KC exhibited sex-biased molecular programs consistent with androgen-driven and oestrogen-deficiency-related stromal remodelling. These findings elucidate hormone-driven mechanisms underlying KC and suggest that sex-associated hormonal regulation could inform future personalised therapeutic strategies.
    Keywords:  Competitive endogenous RNA; Keratoconus; Sex hormones; Sexual dimorphism
    DOI:  https://doi.org/10.1186/s40662-026-00478-0
  24. Int J Reprod Biomed. 2025 Nov;23(11): 927-936
       Background: Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in women, associated with insulin resistance, ovulatory dysfunction, hyperandrogenism, and inflammation. Current treatments often focus on symptoms rather than underlying causes, emphasizing the need for comprehensive strategies. Recently, probiotics have emerged as a safe and cost-effective nutritional option for managing metabolic issues.
    Objective: This study aims to evaluate the effects of Lactobacillus helveticus and Bifidobacterium longum supplementation on the cardiometabolic profile, hormonal status, oxidative stress, and quality of life in women with PCOS.
    Materials and Methods: We will conduct a double-blind, placebo-controlled, randomized trial involving 90 women with PCOS from Shahid Beheshti hospital, Isfahan, Iran. Recruitment will begin on June 20, 2024, and is expected to be completed by June 20, 2025. Participants will be randomly assigned to receive either a daily probiotic capsule containing Lactobacillus helveticus and Bifidobacterium longum or a placebo. The study will assess the impact of these probiotic strains on cardiometabolic profile, hormonal status, oxidative stress, mental health, quality of life, sleep quality, and clinical symptoms in women with PCOS. All parameters will be evaluated before and after the intervention.
    Discussion: Elevated insulin levels and gut microbiota imbalances significantly contribute to the development of PCOS. Growing evidence suggests that gut dysbiosis is linked to sex hormone levels and estrous cycles. We hypothesize that probiotic supplementation in individuals with PCOS will improve hormonal, metabolic, inflammatory, and antioxidant markers compared to those receiving a placebo.
    Keywords:   Polycystic ovary syndrome; Randomized clinical trial.; Sex hormone-binding globulin; Testosterone; Probiotics
    DOI:  https://doi.org/10.18502/ijrm.v23i11.20547
  25. Endocrinol Diabetes Metab. 2026 Mar;9(2): e70185
       INTRODUCTION: Evidence showed that microbial dysbiosis may lead to poor fertility outcomes. Today, therapy with probiotics, especially when using assisted reproductive technologies, is considered a potential method to improve outcomes. This study aimed to evaluate the effectiveness of probiotic consumption on reproductive outcomes in women with polycystic ovary syndrome (PCOS) who are candidates for Intrauterine Insemination (IUI).
    METHODS: In this randomized, double-blind clinical trial, 100 women aged 19 to 37 years with PCOS who were candidates for IUI were studied in two groups (1:1): intervention and placebo. After ovulation induction and IUI, the study outcomes including chemical and clinical pregnancy rates, number of dominant follicles, and endometrial thickness were examined and compared in the two groups.
    RESULTS: No difference was observed between the intervention and control groups in terms of basic demographic findings and paraclinical evaluation (p > 0.05). The chemical pregnancy rate in the intervention group was higher than in the placebo group, but no statistically significant difference was observed (16% vs. 12%; p = 0.564). The clinical pregnancy rate in the intervention group was higher than in the placebo group (14% vs. 4%; p = 0.081). The mean endometrial thickness in intervention groups was significantly higher than placebo group (p = 0.028), while the mean dominant follicle between the two groups was almost the same (p > 0.05). The regression model showed that only the probiotic supplementation had a significant positive effect on endometrial thickness in the intervention than the placebo groups (β = 0.618, 95% CI: 0.167-1.069, p = 0.008).
    CONCLUSION: Probiotic supplementation for 8 weeks in women with PCOS who were candidates for IUI was associated with higher endometrial thickness, indicating a potential role in improving endometrial receptivity.
    Keywords:  assisted reproductive techniques; infertility; intrauterine insemination; polycystic ovary syndrome; probiotics
    DOI:  https://doi.org/10.1002/edm2.70185
  26. Intern Med. 2026 Mar 03.
      Long COVID (post-COVID-19 condition) is a heterogeneous syndrome of persistent or new symptoms after SARS-CoV-2 infection. While men have higher risks of severe acute COVID-19 and mortality, epidemiological studies consistently show a female predominance in Long COVID, especially among middle-aged women. Interpretation is complicated by variable case definitions (WHO, CDC, NICE) and variant-era differences; however, sex disparities persist across both pre-Omicron and Omicron periods. We review evidence on sex differences in epidemiology, symptom clusters, and longitudinal trajectories, incorporating recent RECOVER findings and emerging data from Japanese cohorts. Potential mechanisms include sexually dimorphic antiviral immunity, hormonal and X-chromosome-linked immunoregulation, autoimmunity, autonomic dysfunction, and gender-related social exposures and health-care access. Recognizing sex- and gender-related determinants can improve differential diagnosis, risk stratification, and individualized management, and should be embedded as core variables in future mechanistic studies and clinical trials.
    Keywords:  Japan; Long COVID; Omicron; dysautonomia; gender; post-COVID-19 condition; sex differences
    DOI:  https://doi.org/10.2169/internalmedicine.6969-25
  27. Neurochem Int. 2026 Mar 04. pii: S0197-0186(26)00027-6. [Epub ahead of print] 106136
      Traumatic brain injury (TBI) initiates complex neuroinflammatory cascades that significantly influence recovery outcomes. Although sex differences in neuroinflammation have been reported previously, findings remain inconclusive as the role of the female estrous cycle in post-injury responses is not well understood. In this study, we aimed to characterize sex-based differences in neuroinflammatory, vascular, and behavioral outcomes following TBI, with particular emphasis on the different phases of the estrous cycle in female mice. Male and female mice were subjected to controlled cortical impact (CCI) and subsequently assessed for behavioral deficits, cerebral blood flow (CBF), immune cell infiltration, and inflammatory genes expression. Although TBI induced robust neuroinflammation and reduction in CBF in both sexes, female mice showed significantly increased myeloid, microglial and T-cell presence, as well as elevated expression of key inflammatory transcripts (Btk, Inpp5d, and Tmem173), while downregulation in Grm2 expressions. Stratified cohort of female mice as per phases in estrous cycle (proestrus, estrus, metestrus, and diestrus) before injury showed alterations in Inpp5d, Csf3r, Csf1r, CD84, Tmem173, Homer1, Grm2 and Supt7l. Notably, female injured mice showed differential improvements in select parameters, although estrous cycle phase at the time of impact had limited but phase-dependent impact on CBF. Female mice did not show significant changes in the behavioral tests as compared to male or different estrous phenotypes. However, female mice showed higher frequency to visit center in an open arena. These findings highlight sex-specific neuroinflammatory and transcriptional responses to TBI, with moderate modulation by estrous cycle. Our study further suggests that one estrous phase could be more vulnerable to neuroinflammation or neurovascular injury than others on cellular and molecular level. However, this interphase difference might be masked in the studies including randomly cycled female population. Thus, our results underscore the importance of incorporating sex, estrous and hormonal status into sex-dependent studies on TBI and other brain diseases research to inform the development of targeted therapeutic strategies.
    Keywords:  Behavior; CBF; Estrous cycle; Neuroinflammation; Sex-dependent difference; Transcriptional analysis; Traumatic brain injury (TBI)
    DOI:  https://doi.org/10.1016/j.neuint.2026.106136
  28. Adv Sci (Weinh). 2026 Mar 02. e16411
      Androgen receptor (AR) signaling is a primary oncogenic driver of castration-resistant prostate cancer (CRPC), yet the mechanism remains incompletely understood. Through proteomic profiling of CRPC and primary PCa cells, we identify G Protein Nucleolar 3 (GNL3) as a novel AR coregulator. GNL3 physically interacts with AR, enhances its chromatin occupancy, and directly coactivates transcriptional programs that promote cell proliferation, including NEK2 and CDC20. Concurrently, GNL3 functions as a corepressor of immune-responsive genes such as CXCL10 and TAP1 via class I histone deacetylases (HDACs), thereby facilitating CD8+ T cell elimination and establishing an immunosuppressive tumor microenvironment. GNL3 expression and AR-GNL3 complex formation progressively increase from normal prostate to CRPC and correlate with poor clinical outcomes. Functionally, GNL3 knockdown sensitizes CRPC cells to AR antagonists and impairs tumor growth and metastasis. Furthermore, we demonstrate that combinatorial inhibition of NEK2, class I HDACs, and AR signaling can be a potential therapeutic strategy for CRPC. Overall, these findings establish GNL3 as a dual-function AR coregulator and therapeutic target, providing mechanistic insights into transcriptional regulation and immune evasion in advanced PCa.
    Keywords:  AR coregulator; GNL3; castration‐resistant prostate cancer; immunosuppression
    DOI:  https://doi.org/10.1002/advs.202516411
  29. BMC Endocr Disord. 2026 Mar 04.
      
    Keywords:  Androgen; Glucose and lipid metabolism; Inflammatory response; Intestinal flora; Meta-analysis; Reproductive hormones
    DOI:  https://doi.org/10.1186/s12902-025-02153-2
  30. Immunol Cell Biol. 2026 Mar 02.
      Tissue-resident memory (Trm) CD8+ T cells in the upper and lower respiratory tract play an instrumental role in combatting influenza virus. While CD8+ Trm populations in these compartments differ in longevity and developmental requirements, it remains unclear whether they share clonotypes, indicating a common origin, or are seeded by distinct T-cell clones. Using a mouse model of influenza virus infection, we investigated the T-cell receptor (TCR) composition of CD8+ Trm specific for two immunodominant influenza-specific CD8+ T-cell epitopes, derived from the nucleoprotein (NP366-374) and polymerase acidic protein (PA224-233). TCRαβ repertoire analysis of NP366-374-specific CD8+ T cells from the nasal mucosa, lung and spleen revealed substantial clonal overlap across resident and circulating subsets, consistent with derivation from a shared precursor pool. In contrast, PA224-233-specific responses showed minimal clonal sharing across tissues and subsets, reflecting a more diverse and private repertoire. Thus, nasal and lung CD8+ Trm can arise from either shared or distinct clonotypes, with their profiles shaped primarily by the antigen specificity rather than tissue location. This allows barrier tissues to be seeded by both highly conserved, public NP366-374-specific CD8+ TCRs and a more diverse, private PA224-233-specific repertoire, together forming an optimal pool capable of providing broadly cross-reactive T-cell immunity and limiting viral escape.
    Keywords:  Influenza; TCR repertoire; resident memory T cells
    DOI:  https://doi.org/10.1111/imcb.70098
  31. J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70244
       BACKGROUND: Lung transplant recipients are at increased risk of sarcopenia and osteoporosis, which may negatively influence respiratory outcomes. Although muscle health is known to affect lung function, little is known about the long-term interplay between muscle parameters and pulmonary volumes, especially across sexes. The objective of this study is to evaluate the longitudinal relationship between muscle mass and strength and respiratory function in lung transplant patients, with sex-specific analysis.
    METHODS: This prospective cohort included three assessments (baseline ≥ 3 months after transplant, ~1 year and 2-3 years). The primary outcome was the longitudinal change in pulmonary function (VC, FVC, FEV1 and TLC) in relation to appendicular skeletal muscle mass index (ASMMI) and handgrip strength (HGS). Associations at baseline were tested with multivariable linear regression. Analyses were performed with linear mixed-effects models (LMM) including random intercepts for subject, time as a fixed effect and interactions between time and muscle parameters, adjusted for age, ADL, corticosteroid dose, vertebral fractures, osteoporosis, comorbidities and time since transplant.
    RESULTS: We studied 155 recipients (43.2% women, age 48.7 ± 13.3 years). Primary indications were cystic fibrosis (30.1%), restrictive (22.2%), obstructive (15.7%), miscellaneous (26.8%) and vascular diseases (5.2%). At baseline, HGS was independently associated with higher VC (R2: 0.63, β = 0.35, p = 0.001 in women; R2: 0.58, β = 0.16, p < 0.001 in men) and FEV1 (R2: 0.51, β = 0.08, p = 0.020 in women; R2: 0.57, β = 0.19, p = 0.009 in men). ASMMI was independently associated with VC in both sexes (women: R2: 0.58, β = 0.31, p = 0.003; men: R2: 0.40, β = 0.16, p = 0.023). Longitudinally, LMMs showed that higher HGS was associated with more favourable trajectories of pulmonary function over follow-up. Specifically, among women with restrictive disease, lower ASMMI predicted higher FEV1 (β = -4.95, 95% CI -6.93 to -2.97, p = 0.007) and higher TLC (β = -2.22, 95% CI -4.56 to -1.12, p = 0.04) over time. In women with cystic fibrosis, stronger HGS was associated with improved TLC (β = 0.38, p = 0.04). All associations persisted after full adjustment.
    CONCLUSION: Muscle mass and strength are associated with lung function after lung transplantation. These findings underscore the clinical importance of muscle health and support its integration into post-transplant management.
    Keywords:  COPD; cystic fibrosis; lung transplant; sarcopenia; vertebral fractures
    DOI:  https://doi.org/10.1002/jcsm.70244
  32. Cephalalgia. 2026 Mar;46(3): 3331024261425258
      ObjectiveHuman provocation models are widely used to investigate migraine mechanisms and validate therapeutic targets. Despite well-known sex differences in migraine, concerns persist regarding sex representation and reporting in experimental research. This systematic review evaluated sex distribution, sex-specific analyses, and the consideration of female-specific biological factors in randomized, placebo-controlled migraine provocation studies.MethodsPubMed and Embase were systematically searched for randomized, placebo-controlled provocation studies in adults with migraine, following PRISMA 2020 guidelines. Data were extracted on participant sex distribution, sex-stratified outcome reporting, and consideration of female-specific variables, including menstrual cycle, hormonal contraception, and pregnancy status.ResultsFifty-eight studies published between 1972 and 2025 were included. Women represented 82% of participants, while men accounted for 18%. No study performed sex-stratified analyses of provoked headache or migraine outcomes. Sex was rarely discussed as a biological variable or limitation. Female-specific factors were largely overlooked, with menstrual cycle phase unreported in over 90% of studies and inconsistent reporting of hormonal contraception and pregnancy status.ConclusionsMigraine provocation studies show marked sex imbalance and a systematic lack of sex-disaggregated analyses. Although these models have demonstrated substantial translational relevance, particularly in supporting the development of anti-CGRP therapies, the absence of sex-disaggregated analyses and limited consideration of biological sex constrain the assessment of translational applicability across sexes.
    Keywords:  CGRP; gender; headache; pain
    DOI:  https://doi.org/10.1177/03331024261425258
  33. Trends Immunol. 2026 Mar 02. pii: S1471-4906(26)00014-1. [Epub ahead of print]
      During pregnancy, complex interactions of maternal immune cells and fetal extravillous trophoblasts (EVTs) orchestrate placentation, immune tolerance, and immune defense. This forum article highlights important discoveries and outstanding questions on how the activation of decidual natural killer and T cells, through recognition of key EVT ligands, promotes placentation, tolerance, and immunity.
    Keywords:  HLA-C; cytotoxicity; extravillous trophoblasts; natural killer cells; regulatory T cells
    DOI:  https://doi.org/10.1016/j.it.2026.01.011
  34. Int J Womens Health. 2026 ;18 581964
       Objective: To explore the impact of trigger-day luteinizing hormone (LH) levels on pregnancy outcomes in antagonist and long protocols during in vitro fertilization (IVF) and determine protocol-specific LH thresholds.
    Methods: This retrospective analysis covered 217 IVF/ICSI cycles from January 2023 to April 2024. The relationships between trigger-day LH levels and pregnancy outcomes in the two protocols were compared using ROC curves, multivariate logistic regression, and mediation models.
    Results: In the antagonist protocol, LH > 1.45 IU/L was linked to lower oocyte yield, reduced high-quality embryo rates, and a higher risk of clinical pregnancy failure (RR = 2.34, p = 0.006). In the long protocol, LH > 1.0 IU/L was associated with higher clinical pregnancy rates (OR = 2.61, p = 0.026), with 68% of the effect mediated by increased oocyte yield. Age ≤ 35 significantly enhanced these effects (three-way interaction OR = 6.55, p = 0.003).
    Conclusion: The antagonist and long protocols should adopt LH thresholds of 1.45 IU/L and 1.0 IU/L, respectively. Age is a key moderator, providing evidence for individualized IVF trigger strategies.
    Keywords:  age interaction; antagonist protocol; clinical pregnancy; in vitro fertilization; long protocol; luteinizing hormone
    DOI:  https://doi.org/10.2147/IJWH.S581964