bims-simsho 2026-01-18 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2026–01–18
thirty-two papers selected by
Chun-Chi Chang, Lunds universitet

Sex in Immune Cells and Parasitic Diseases - A Complex Relationship.
Sex Hormones Attenuate Pro-Inflammatory Gene Expression in Nucleus Pulposus and Annulus Fibrosus Cells in a Cell-Type Specific Manner.
Maternal hypothyroidism and diabetes alter plasma concentration and placental signaling of sex steroids in rats.
Microbiota and infertility: a translational review of mechanisms and clinical applications in assisted reproduction.
Regulation of androgen receptor expression by enhancer elements in prostate cancer.
Brain-derived estrogens facilitate male-typical behaviors by potentiating androgen receptor signaling in medaka.
Sex-based hormonal influences on asthma biomarkers.
Chondroitin sulfate E activates IL-6/STAT3 signaling to drive androgen-independent growth in castration-resistant prostate cancer.
Drivers of systemic male-female allele frequency divergence in humans.
Gonadal and sex chromosomal contributions to sex differences in mammalian brain organization.
Neuroendocrine signaling as a pathological seed for the female bias of Alzheimer's disease and the concept of estrobolome.
The biology and clinical aspects of female infertility.
Serum uric acid is associated with ovarian reserve and neonatal outcomes in women undergoing IVF/ICSI: observational and genetic evidence.
TESTOSTERONE DOES NOT DRIVE PROSTATE CANCER: PRESENTING THE NEW FRAMEWORK OF ANDROGEN ADEQUACY VERSUS INADEQUACY.
Astrocytic responses to binge ethanol in male and female mice: An examination of astrocytic glutamate transporters and density changes in the dorsal hippocampus.
Understanding the Effect of Estrogen on B Cells: Implications for Immune Health and Autoimmunity.
Mapping the effects of gender-affirming sex hormone therapy.
Bacteria's babysitter role: Indole-driven immune truce in the womb.
The impact of growth hormone (GH) on immunosenescence: exploring the role of B and T cells.
Association of vaginal IL-4, IL-6, IL-8, IL-17, IFN-γ, and dietary intake with IBD status and vaginal microbiota in pregnant individuals.
To the nines: IL-9 boosts T cell function.
Mitochondrial AR overactivation coupled with uterine decidual mitochondrial defects in PCOS-associated pregnancy loss.
Inhibition of Growth and Induction of Apoptosis of Human Prostate Cancer Cells by Enzymatic Blockage of Kallikreins.
A novel model to study the impact of gender-affirming therapy on bone in young male mice.
Lactate derived from cancer-associated fibroblasts promotes alternative splicing and castration resistance in prostate cancer.
Immunometabolism: Is cyanide a missing link between metabolic pathways and immune function?
MASLD coexisting with PCOS increases cardiometabolic risk.
Systems Genomics Reveals Age- and Sex-Dependent Metabolic Dysregulation from Glo1 Reduction in Mice.
The influence of sex hormones and the menstrual cycle on women's athletic performance: A literature review.
Unveiling sex differences in pancreatic ductal adenocarcinoma: Current evidence and future directions (Review).
MECOM Function is Critical for AR-Driven Treatment-Resistant Prostate Cancer.
A distinct monocyte transcriptional state links systemic immune dysregulation to pulmonary impairment in long COVID.

Immunol Rev. 2026 Jan;337(1): e70097

Sex in Immune Cells and Parasitic Diseases - A Complex Relationship.

Barbara Honecker, Charlotte Sophie Hansen, Hanna Lotter.

  Epidemiological studies consistently show that many parasitic diseases affect males more frequently than females. These disparities are multifactorial, arising partly from gender-specific behaviors that influence exposure risk and health-seeking practices, especially in low- and middle-income countries. Increasing evidence also highlights that biological sex differences within the immune system significantly shape susceptibility to and control of parasitic infections. Recent advances combining classical immunology with single-cell transcriptomics have revealed hormonal and chromosomal factors driving sex-specific differences in innate and adaptive immune cells. These differences can critically influence the course and outcome of parasitic diseases. However, many studies on parasitic diseases still lack adequately sex-disaggregated data or fail to apply state-of-the-art immunological analyses needed to fully characterize biological sex effects. Studies in rodent models that mirror the sex bias observed in humans provide valuable tools to analyze immune mechanisms at the cellular level and dissect underlying biological differences. In this review, we summarize current knowledge on sex differences in key cellular components of innate and adaptive immunity and discuss their relevance for selected parasitic diseases of major global importance-leishmaniasis, Chagas disease, amebiasis, schistosomiasis, and malaria.

Keywords:  immune response; parasitic diseases; sex differences; sex hormones

DOI:  https://doi.org/10.1111/imr.70097
JOR Spine. 2026 Mar;9(1): e70152

Sex Hormones Attenuate Pro-Inflammatory Gene Expression in Nucleus Pulposus and Annulus Fibrosus Cells in a Cell-Type Specific Manner.

Jeffrey L Hutchinson, Andrew E Leung, Cheryle A Séguin.

   Background: Intervertebral disc (IVD) degeneration is a major contributor to back pain and disability. The cause of IVD degeneration is multifactorial, with no disease-modifying treatments. Sex steroids, primarily testosterone and its derivatives, are becoming increasingly common in the clinic for the treatment of low back pain and continue to be used as ergogenic aids in sport. While outcomes at the level of pain and athletic performance are promising, little research has investigated the effects of these hormones on the biology of the IVD and how sex hormones may directly influence joint health and homeostasis.
Methods: Primary bovine nucleus pulposus (NP) and annulus fibrosus (AF) cells were isolated from 18-month-old female bovine caudal IVDs for primary cell culture. These cells were subjected to sex hormone stimulation (5α-dihydrotestosterone or 17β-estradiol) at increasing doses (0, 25, 50, 75, 100, 125 nM) with or without a pro-inflammatory stimulus (IL-1β; 10 ng/mL or TNFα; 25 ng/mL) to model healthy and pro-inflammatory environments, respectively. Cells were harvested for analysis of gene expression, cytokine secretion, and to assess NF-κB signaling.
Results: In both NP and AF cells (dihydro)testosterone and 17β-estradiol decreased proinflammatory gene expression and cytokine release. Changes induced by sex hormones were cell-type dependent and specific to the inflammatory stimulus used. NP cells displayed a robust inflammatory response to IL-1β compared to TNFα, while AF cells responded to TNFα only, but only at the level of gene expression. Attenuation of inflammatory gene expression by sex hormone exposure was not associated with changes in p65 phosphorylation or NF-κB pathway associated gene expression.
Conclusion: Sex hormones such as dihydrotestosterone and estrogen play an important role mediating inflammatory signaling in cells of the IVD, finding which could lead to novel therapeutics for IVD degeneration.

Keywords:  annulus fibrosus; cytokines; estrogen; nucleus pulposus; testosterone

DOI:  https://doi.org/10.1002/jsp2.70152
Placenta. 2026 Jan 06. pii: S0143-4004(26)00010-X. [Epub ahead of print]174 235-244

Maternal hypothyroidism and diabetes alter plasma concentration and placental signaling of sex steroids in rats.

Jeane Martinha Dos Anjos Cordeiro, Bianca Reis Santos, Adriana Lopes da Silva, Luciano Cardoso Santos, Juneo Freitas Silva.

   INTRODUCTION: Proper hormonal signaling at the maternal-fetal interface and adequate placental steroidogenesis are crucial for a successful pregnancy. However, the effects of maternal diabetes (MD) and hypothyroidism (MH) on placental steroidogenic pathways remain poorly characterized. This study investigated the expression of sex hormone receptors and key steroidogenic enzymes at the maternal-fetal interface in rat models of MH and MD.
METHODS: At GD18, in both MH (6-propyl-2-thiouracil-induced) and MD (streptozotocin-induced) conditions, maternal hormonal dosage (free T4 or insulin, and E2, P4, and testosterone) were performed, along with placental RT-qPCR and/or immunohistochemistry analyses for steroidogenic pathway markers (ERα/Esr1, PR/Pgr, AR/Ar, Star, Cyp11a1, Hsd17b3, and Hsd3b1).
RESULTS: Both MD and MH dams exhibited reduced fetal weight. These outcomes were associated with elevated plasma estradiol levels in MD rats and reduced testosterone levels in MH rats, while progesterone concentrations remained unchanged in both groups. Both MD and MH resulted in upregulated placental Esr1 expression, whereas MH additionally increased ERα protein levels in the metrial triangle. Regarding the progesterone receptor (PR), MH markedly increased its immunostaining throughout the maternal-fetal interface and both conditions elevated placental Pgr transcript levels. MH also upregulated androgen receptor (AR) protein expression in the decidua and increased placental expression of the steroidogenic enzyme Hsd3b1, while MD elevated placental Ar gene expression.
CONCLUSION: These findings demonstrate that both MD and, more profoundly, MH disrupt sex steroid homeostasis and receptor expression at the rat maternal-fetal interface.

Keywords:  Endocrine disruptions; Placental steroidogenesis; Propylthiouracil; Rat; Sex steroid receptors; Streptozotocin

DOI:  https://doi.org/10.1016/j.placenta.2026.01.003
Eur J Obstet Gynecol Reprod Biol. 2026 Jan 05. pii: S0301-2115(26)00007-2. [Epub ahead of print]318 114941

Microbiota and infertility: a translational review of mechanisms and clinical applications in assisted reproduction.

Bixiu Du, Yaru Yang, Lang He, Ying Tang.

  Infertility constitutes a major global health concern, affecting approximately 17.5% of couples of reproductive age. Although advances in assisted reproductive technologies (ART) have expanded treatment options, success rates remain highly variable due to host-specific and biological determinants. This review synthesizes current evidence on the reproductive impact of the human microbiota and its translational relevance to ART outcomes. Vaginal microbial communities dominated by Lactobacillus, particularly L. crispatus, are associated with improved conception and implantation, whereas genital or intestinal dysbiosis correlates with infertility and suboptimal treatment responses. The microbiota modulates reproductive competence through intertwined immune, endocrine-metabolic, and mucosal barrier pathways that regulate inflammation, hormonal balance, and epithelial integrity. Emerging findings indicate that gut microbial alterations linked to polycystic ovary syndrome (PCOS) and endometriosis are accompanied by insulin resistance and chronic inflammation, impairing ovulation, endometrial receptivity, and embryo viability. Interventions such as probiotics and synbiotics yield heterogeneous efficacy; individualized antimicrobial strategies, metabolic modulation, and lifestyle optimization may offer complementary benefit, while microbiota reconstruction remains experimental. Methodological limitations, including contamination in low biomass samples, variations in sequencing workflows, and population heterogeneity, still hinder data comparability and mechanistic interpretation. Future research should prioritize adequately powered randomized controlled trials using standardized microbiome metrics and live birth as a primary endpoint. Integrating microbiome profiling into ART workflows may refine patient stratification and inform precision adjuvant therapies. However, clinical implementation requires stronger causal evidence, validated biomarkers, and harmonized methodological frameworks to translate microbiome discoveries into reproducible reproductive gains.

Keywords:  Assisted reproduction; Clinical interventions; Infertility; Microbiota; Therapeutic targets

DOI:  https://doi.org/10.1016/j.ejogrb.2026.114941
Exp Mol Med. 2026 Jan 16.

Regulation of androgen receptor expression by enhancer elements in prostate cancer.

Sudeep Khadka, Hee-Young Jeon, Arif Hussain, Jianfei Qi.

Androgen receptor (AR) overexpression is a key mechanism driving the development of castration-resistant prostate cancer (CRPC). This can result from multiple factors, including enhanced AR transcription and increased stability of AR mRNA and protein. In clinical CRPC samples, one cause of AR overexpression is gene amplification at the AR locus, which leads to elevated AR transcript and protein levels. In addition, increased activity or copy number of enhancer elements near the AR gene has been associated with elevated AR transcription. These regulatory regions interact with the AR gene promoter through enhancer-promoter looping, thereby enhancing AR mRNA transcription. Elucidating the role of these enhancer elements in driving AR overexpression and aberrant AR signaling may uncover new therapeutic targets for CRPC.

DOI: https://doi.org/10.1038/s12276-025-01624-9
Elife. 2026 Jan 13. pii: RP97106. [Epub ahead of print]13

Brain-derived estrogens facilitate male-typical behaviors by potentiating androgen receptor signaling in medaka.

Yuji Nishiike, Shizuku Maki, Daichi Miyazoe, Kiyoshi Nakasone, Yasuhiro Kamei, Takeshi Todo, Tomoko Ishikawa-Fujiwara, Kaoru Ohno, Takeshi Usami, Yoshitaka Nagahama, Kataaki Okubo.

  In rodents, estrogens aromatized from androgens in the brain are essential for the development of male-typical behaviors. In many other vertebrates, including humans and teleost fish, however, androgens facilitate these behaviors directly via the androgen receptor without aromatization into estrogens. Here, we report that mutagenesis-derived male medaka fish lacking Cyp19a1b (a subtype of aromatase predominantly expressed in the brain) exhibit severely impaired male-typical mating and aggression, despite elevated brain androgen levels. These phenotypes can be rescued by estrogen administration, indicating that brain-derived estrogens are pivotal for male-typical behaviors even in teleosts. Our results further suggest that these estrogens facilitate male-typical behaviors by potentiating androgen action in the brain via the direct stimulation of androgen receptor transcription. Taken together, these findings reveal a previously unappreciated mode of action of brain-derived estrogens in facilitating male-typical behaviors.

Keywords:  aggression; androgen receptor; aromatase; brain-derived estrogens; mating; neuroscience

DOI:  https://doi.org/10.7554/eLife.97106
J Allergy Clin Immunol. 2026 Jan 14. pii: S0091-6749(26)00004-7. [Epub ahead of print]

Sex-based hormonal influences on asthma biomarkers.

Ishitha Jagadish, Divya Shah, Jennifer Priessnitz, Sergio E Chiarella.

  Asthma, a chronic inflammatory airway disease affecting 25 million people in the U.S., exhibits distinct sex differences in prevalence, phenotype, and treatment response. While asthma is more common in boys during childhood, adult women experience greater disease severity, likely due to hormonal and immunologic influences. Asthma biomarkers, including blood eosinophil count (BEC), fractional exhaled nitric oxide (FeNO), immunoglobulin E (IgE), and emerging markers provide insight into disease phenotypes and therapeutic response. This review synthesizes current evidence on sex-specific differences in asthma biomarkers and mechanisms underlying these variations. Sex hormones play a role in immune modulation, with estrogen and progesterone promoting type 2 inflammation, and testosterone exerting suppressive effects. Boys demonstrate higher levels of BECs, FeNO, total and allergen-specific IgE, and periostin, whereas post-pubertal females exhibit increased interleukin (IL)-5, leptin, serum amyloid A, and urinary leukotriene E4 (LTE4), along with lower adiponectin levels. In contrast, post-pubertal male asthmatics show higher ceramide concentrations. Additional biomarkers under investigation include microRNAs, neutrophils, tryptase, exhaled breath condensate analytes, and surfactant proteins. However, evidence supporting these research-based markers is often preclinical and/or lacks sex-stratified analyses, limiting clinical translation. Incorporating validated sex-specific biomarker patterns into asthma care may enhance phenotyping and support personalized management strategies.

Keywords:  IL-13; IL-4; IL-5; adipokines; adiponectin; asthma; basophil activation markers; chemokines; chitinase-3-like protein 1; cysteinyl leukotrienes; cytokines; eosinophils; exhaled breath condensate markers; fractional exhaled nitric oxide; gender; immunoglobulin E; leptin; microRNA; myeloperoxidase; neutrophil elastase; periostin; serum amyloid A; sex; sex differences; sex hormones; sphingosine-1-phosphate; surfactant proteins; tryptase

DOI:  https://doi.org/10.1016/j.jaci.2025.12.1010
Cell Commun Signal. 2026 Jan 13.

Chondroitin sulfate E activates IL-6/STAT3 signaling to drive androgen-independent growth in castration-resistant prostate cancer.

Hayato Ota, Kazuo Yamamoto, Shoko Nishihara.

   BACKGROUND: Castration-resistant prostate cancer (CRPC) remains a major clinical challenge, as tumor growth persists despite androgen receptor (AR) pathway inhibition. Glycosaminoglycans, particularly chondroitin sulfate (CS), are increasingly recognized as modulators of oncogenic signaling. However, the contribution of distinct sulfation motifs to therapeutic resistance is poorly understood. Here, we identify the CS-E motif as a critical regulator of IL-6/STAT3 signaling and a driver of hormone-independent growth in CRPC.
METHODS: Transcriptomic profiling (RNA-seq), real-time PCR, and flow cytometry were employed to assess CS sulfation changes in C4-2 prostate cancer cells under androgen-deprived conditions. Because reliable tools to detect CS-E have been lacking, we engineered a novel mutant lectin (Cochlin B8) with selective affinity for CS-E. This innovation enabled precise monitoring and functional characterization of CS-E on the surface of cancer cells. Functional studies combined GALNAC4S-6ST knockdown, pharmacological inhibition with Chst15-IN-1, and signaling assays to examine effects on IL-6/STAT3 activation and cell proliferation.
RESULTS: Androgen deprivation induced upregulation of GALNAC4S-6ST and enhanced CS-E biosynthesis on the cell surface. Elevated CS-E facilitated IL-6 binding to the cell surface, potentiated STAT3 phosphorylation, and sustained androgen-independent proliferation. Genetic or pharmacological inhibition of GALNAC4S-6ST significantly reduced CS-E levels, impaired IL-6 binding, attenuated STAT3 activation, and selectively suppressed proliferation under hormone-depleted conditions (IC₅₀ = 1.39 µM under androgen-deprived conditions vs. 4.46 µM under androgen-replete conditions). These effects were specific to IL-6/STAT3, with no detectable impact on AR-independent EGFR or WNT signaling pathways.
CONCLUSIONS: This study reveals a previously unrecognized mechanism whereby CS-E sustains CRPC progression by selectively enhancing IL-6/STAT3 signaling when AR signaling is suppressed. Importantly, the development of Cochlin B8 overcomes a major technical barrier in CS-E research, providing a novel tool for its specific detection and functional analysis. Targeting CS-E biosynthesis represents a promising therapeutic strategy to counter resistance and improve prostate cancer treatment.

Keywords:  Castration-resistant prostate cancer; Chondroitin sulfate E; GALNAC4S-6ST; Glycosaminoglycan; IL-6/STAT3 signaling

DOI:  https://doi.org/10.1186/s12964-026-02657-x
bioRxiv. 2026 Jan 06. pii: 2026.01.06.698007. [Epub ahead of print]

Drivers of systemic male-female allele frequency divergence in humans.

Matthew Ming, Arbel Harpak.

Allele frequency differences between males and females in genetic studies have been interpreted as suggestive of sex differences in natural selection. However, systemic differences may also arise through sex differences in study participation as well as bioinformatic artifacts. To mitigate these confounding effects, we performed a meta-analysis of sex differences in allele frequencies across three genetic studies. We identify twelve concordant genes with cross-study evidence of sex differences in allele frequency. We propose four hypotheses for how and when sex differences in allele frequencies arise and point out the plausible hypotheses for subsets of the twelve candidates. For example, beyond candidates that plausibly reflect sex differences in viability selection, we also find candidate loci potentially under X/Y-differential selection in sperm populations. Taken together, our results offer clearer delineation of the factors driving sex differences in allele frequencies, including the timing and mechanisms of natural selection.

DOI: https://doi.org/10.64898/2026.01.06.698007
bioRxiv. 2026 Jan 10. pii: 2026.01.10.698782. [Epub ahead of print]

Gonadal and sex chromosomal contributions to sex differences in mammalian brain organization.

Jason P Lerch, Juliana Shin, Jacob Ellegood, Haley Hrncir, Brian Nieman, Allan J MacKenzie-Graham, Xia Yang, Arthur P Arnold, Armin Raznahan.

Sex differences in brain development may contribute to well-known sex differences in behavior and neuropsychiatric risk - making it important to comprehensively map and mechanistically annotate normative sex differences in brain organization. Most sex differences in mammalian brain organization have previously been attributed to differential effects of gonadal hormones based on outcomes from rodent endocrine manipulations at canonical subcortical foci of male-biased brain volume. However, a systematic quantification of both gonadal and sex chromosome dosage (SCD) contributions across all regions of sex-biased brain volume has been lacking. Here, using structural neuroimaging scans from wild-type (n=670) and transgenic mice that dissociate gonadal, X-, and Y-chromosome effects (n=181), we show that: many more brain regions are volumetrically sex-biased than previously recognized; gonadal effects dominate throughout this expanded map of sex differences; several regions also show prominent SCD contributions to anatomical sex differences, which can both reinforce or counteract gonadal effects in a regionally specific manner. Targeted single nucleus RNA sequencing at a region of female-biased cerebellar volume reveals that combined gonadal and SCD effects also drive sex-biased cellular gene expression. These findings revise our understanding of the spatial distribution and causal basis of sex-differences in the mammalian brain, illuminating a key axis of biological variation in health and disease.

DOI: https://doi.org/10.64898/2026.01.10.698782
Biomed Pharmacother. 2026 Jan 10. pii: S0753-3322(26)00031-4. [Epub ahead of print]195 118999

Neuroendocrine signaling as a pathological seed for the female bias of Alzheimer's disease and the concept of estrobolome.

Deepthi Rapaka, Arthur Saniotis, Monkgogi Thatayaone, Veera Raghavulu Bitra.

  The prevalence of Alzheimer's disease (AD) is anticipated to escalate with the global increase in life expectancy. Although sex-based differences in AD have been previously documented, doubts persist regarding the relationship between sex and pathophysiological pathways. Sex hormones may contribute to these disparities, with a heightened risk of AD-related dementia associated with oophorectomy before menopause. We cannot ascertain if estrogens alone are solely accountable for this accelerated pathological progression of the disease. Estrogens are regulated by the gut microbiota. Thus, the gut-estrogen-brain axis appears to be implicated as a potential new influencer in the pathophysiology of AD, as the female microbiome differs from the male gut microbiome. This suggests it could be a risk factor for the higher prevalence of AD in women. This review speculates on the possible mechanisms for AD prevalence in women, including both anatomical and neuroendocrinological perspectives.

Keywords:  Alzheimer’s disease; Blood-brain barrier; Estrobolome; Estrogen receptors; Gut-microbiome

DOI:  https://doi.org/10.1016/j.biopha.2026.118999
Syst Biol Reprod Med. 2026 Dec;72(1): 23-54

The biology and clinical aspects of female infertility.

Mitko Madjunkov, Svetlana Madjunkova, Clifford Librach.

  Female infertility is a multifactorial condition with complex biological and clinical underpinnings. Biologically, female-related infertility may stem from disruptions in the hypothalamic-pituitary-ovarian (HPO) axis, impaired folliculogenesis, oocyte maturation defects, uterine abnormalities, endometrial dysfunction, and fallopian tube abnormalities. This review highlights key genetic mechanisms contributing to reproductive dysfunction and their relevance to diagnosis and treatment. Chromosomal abnormalities, including Turner syndrome and X-autosome translocations, also contribute to infertility and recurrent pregnancy loss (RPL). Age-related declines in oocyte quality and quantity-due to increased aneuploidy significantly impact fertility after the mid-30s. Clinical causes such as polycystic ovary syndrome (PCOS), luteal phase defects, and endometriosis contribute to infertility through hormonal imbalance, inflammation, and impaired implantation. Environmental and lifestyle factors-like endocrine-disrupting chemicals, obesity, smoking, and stress-further influence reproductive function. Evaluation requires a multidisciplinary approach combining hormonal profiling, imaging, and genetic diagnostics. Ovarian reserve assessment using anti-Müllerian hormone (AMH) and antral follicle count (AFC), hormonal evaluation along with ultrasound and hysterosalpingography, are central to clinical workups. Next-generation sequencing is enhancing the role of genetic screening in unexplained infertility and specific conditions like POI and endometriosis. Treatment options-ranging from ovulation induction to surgery and assisted reproductive technologies (ART)-are increasingly personalized based on underlying causes and patient profiles. Despite advances, many cases remain idiopathic, highlighting the need for deeper molecular research and refined phenotyping. This review emphasizes the importance of precision medicine and an evidence-based, patient-centered approach to improve fertility outcomes across a broad spectrum of infertility etiologies.

Keywords:  Female infertility; endometriosis; genetics; ovarian aging; ovulatory dysfunction

DOI:  https://doi.org/10.1080/19396368.2025.2593345
Hum Fertil (Camb). 2026 Dec;29(1): 2610586

Serum uric acid is associated with ovarian reserve and neonatal outcomes in women undergoing IVF/ICSI: observational and genetic evidence.

Jialin Wu, Cheng Wang, Yanfang Wang, Tingting Li, Linan Xu, Rui Huang.

  Elevated serum uric acid (SUA) has been linked to adverse outcomes in polycystic ovary syndrome, yet its broader role in female fertility is unclear. This retrospective cohort study of 16,223 women undergoing a first in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) cycle investigated associations between pre-treatment SUA and reproductive parameters. Higher SUA levels were independently associated with elevated luteinizing hormone (LH), testosterone, and anti-Müllerian hormone (AMH), and with lower estradiol and follicle-stimulating hormone. Each 50 µmol/L SUA increase correlated with a 16-gram reduction in neonatal birth weight and a 0.06-week decrease in gestational age, with a threshold effect near 350 µmol/L. Bidirectional Mendelian randomisation analyses supported a causal effect of elevated SUA on increased LH and testosterone, while reverse analysis suggested lower AMH may elevate SUA. These findings identify SUA as a biomarker influencing ovarian reserve and neonatal outcomes through bidirectional mechanisms, including a potential SUA-AMH feedback loop. Routine SUA monitoring in fertility treatment is supported, and interventions for individuals with SUA ≥350 µmol/L warrant clinical investigation.

Keywords:  Serum uric acid; clinical pregnancy; mendelian randomisation; neonatal outcomes; ovarian reserve

DOI:  https://doi.org/10.1080/14647273.2025.2610586
J Urol. 2026 Jan 13. 101097JU0000000000004936

TESTOSTERONE DOES NOT DRIVE PROSTATE CANCER: PRESENTING THE NEW FRAMEWORK OF ANDROGEN ADEQUACY VERSUS INADEQUACY.

Abraham Morgentaler, Abdulmaged M Traish.

   PURPOSE: 1) To review the evidence whether "testosterone drives prostate cancer"; 2) to dissect the arguments supporting this belief; and 3) to present the new framework of androgen adequacy versus inadequacy to explain the relationship of testosterone and prostate cancer.
MATERIALS AND METHODS: A MEDLINE review of the literature was performed.
RESULTS: The belief that testosterone (T) drives prostate cancer (PCa) originated with Charles Huggins in 1941, led to a near-complete prohibition against T therapy (TTh) for 60 years, and persists today in regulatory warnings, guideline restrictions, and widespread clinical concerns. However, the evidence is now overwhelming that T does not drive PCa. Biopsy studies show PCa risk is unrelated to endogenous androgen concentrations. Large RCTs reveal identical PCa rates in men receiving TTh versus placebo. TTh in men with known PCa has not shown increased rates of recurrence or progression. While androgens are required for PCa growth, PCa growth also requires other chemicals, e.g., calcium. What is unique to androgens is it is the only required chemical that does not cause loss of life with severe deprivation. The key concept to understand the relationship of androgens and PCa is adequacy versus inadequacy. Adequate T concentrations for optimal PCa growth occur at a low concentration called the saturation point. Below this, cellular metabolism is compromised and cell death may occur depending on degree of deprivation.
CONCLUSIONS: Testosterone does not drive prostate cancer. Androgen adequacy versus inadequacy provides a scientifically sound framework to understand the relationship of testosterone and prostate pathophysiology.

Keywords:  dihydrotestosterone; prostate; prostate cancer; testosterone; testosterone therapy

DOI:  https://doi.org/10.1097/JU.0000000000004936
Alcohol Clin Exp Res (Hoboken). 2026 Jan;50(1): e70224

Astrocytic responses to binge ethanol in male and female mice: An examination of astrocytic glutamate transporters and density changes in the dorsal hippocampus.

Candace Swepson, DaQuan R Mebane, Diego Correia, Esohe H Imafidon, Christopher P Trevisani, James Nelson, S Alex Marshall.

   BACKGROUND: Excessive alcohol consumption has been associated with a proinflammatory neuroimmune response and deficits in glutamate transporters. While astrocytes regulate the neuroimmune response and glutamatergic tone, estrogen can promote neuroprotective and neurotrophic effects on astrocytes. However, studies in alcohol use disorders (AUDs) have primarily focused on males, and given the more escalated rate at which females display signs of AUDs compared with males, this study examines sex-based differences in astrocytic responses to ethanol following a nondependent binge drinking paradigm.
METHODS: Male and female mice consumed either 20% ethanol (v/v) or 3% sucrose (w/v) for three cycles in the Drinking in the Dark paradigm. The brains of these mice were collected for immunohistochemistry and qRT-PCR for markers of astrocyte activity, cytokines, and astrocytic glutamate transporters. ELISAs were performed on hippocampal tissue to measure cytokines and glutamate transporters.
RESULTS: Ethanol exposure caused an increase in glial fibrillary acidic protein (GFAP) immunoreactivity and GFAP+ cell counts in the hippocampus that were more robust in females. Ethanol's influence on S100B+ cell counts was subregional and sex-specific. Changes in astrocytes were accompanied by a decrease in glutamate transporter 1 (GLT-1) mRNA but not protein with no changes in glutamate aspartate transporter (GLAST). However, cystine/glutamate antiporter (xCT) expression increased specifically in female mice days following ethanol exposure.
CONCLUSIONS: These data suggest that nondependent binge drinking alters astrocytes in the hippocampus that can lead to dysregulation of glutamate transporters and cytokine synthesis. Moreover, there were sex-specific effects shown in binge-like exposure's effects, highlighting the need to consider sex as a biological variable in the neuroimmune response in AUDs.

Keywords:  binge ethanol; cytokines; glutamate transporters; sex as biological variable

DOI:  https://doi.org/10.1111/acer.70224
Am J Physiol Cell Physiol. 2026 Jan 14.

Understanding the Effect of Estrogen on B Cells: Implications for Immune Health and Autoimmunity.

Hasret Gunduz, Amber Sun, Betty Diamond.

  Estrogen is a steroid hormone involved in the regulation of multiple systems in the body. Among these, the immune system is of particular interest due to the significant female predominance seen in many autoimmune diseases. Since B cells and B cell driven antibody responses are central to the development of autoimmune diseases, the influence of estrogen on B cells has been extensively investigated. Throughout B cell development, estrogen exerts complex and contrasting effects depending on the level of exposure to estrogen and the stage of development of the B cell. For instance, at early stages, high concentrations of estrogen negatively regulate early B cell precursor development, while low baseline concentrations are stimulatory and essential. Conversely, estrogen exposure at later stages leads to increased rescue of autoreactive B cells, enabling their maturation and subsequent autoantibody production, a mechanism that contributes to development of a Systemic Lupus Erythematosus (SLE)-like phenotype in murine models. Beyond rescuing autoreactive cells, estrogen can also modulate the function of germinal centers, where autoreactive antibodies may arise through somatic hypermutation. The complex interplay of these effects sets the stage for both the heightened immune response and increased autoimmunity observed in females. In this review, we will explore the various effects of estrogen on B cells to provide a comprehensive overview of the role of estrogen in shaping immune function and enhancing autoimmunity.

Keywords:  Autoimmunity; B lymphocyte; Estrogen; Estrogen Receptor alpha; Estrogen Receptor beta

DOI:  https://doi.org/10.1152/ajpcell.00831.2025
Nat Med. 2026 Jan 13.

Mapping the effects of gender-affirming sex hormone therapy.

Petter Brodin.

DOI: https://doi.org/10.1038/s41591-025-04146-z
Cell Host Microbe. 2026 Jan 14. pii: S1931-3128(25)00526-8. [Epub ahead of print]34(1): 4-6

Bacteria's babysitter role: Indole-driven immune truce in the womb.

Christa I DeVette, Marisol Castillo-Castrejon, Jacob E Friedman.

Maternal immune tolerance of the fetus is critical to a successful pregnancy. In this month's issue of Cell, Brown et al. showed that the maternal microbiota, specifically tryptophan derivatives produced by commensal bacteria, promote maternal tolerance of the fetus to improve pregnancy outcomes.

DOI: https://doi.org/10.1016/j.chom.2025.12.007
Pituitary. 2026 Jan 12. 29(1): 30

The impact of growth hormone (GH) on immunosenescence: exploring the role of B and T cells.

Badra Bashir, Marcella van Hoolwerff, Fabian Benencia, Silvana Duran-Ortiz, Edward O List, John J Kopchick, Darlene E Berryman.

   PURPOSE: Immunosenescence is a gradual decline in immune function, leading to increased susceptibility to infections and autoimmune conditions. Growth hormone (GH) has been shown to have an effect on both immune function and aging. In fact, the absence of GH-induced intracellular signaling can slow the aging process, as demonstrated by the longest-lived laboratory mouse (GH receptor gene disrupted or GHR-/- mice). Because GH receptors (GHR) are expressed in B and T cells, and these cells undergo age-related changes that impact immune function, we hypothesized that decreased GH action protects from immunosenescence. To validate this hypothesis, this study aimed to characterize differences in B cell and T cell populations within the lymphoid organs of aged female GHR-/- mice (24 months of age) compared to wild-type controls.
METHODS: B and T cell populations in mouse blood, spleen, thymus, and bone marrow (BM) were analyzed by multicolor flow cytometry.
RESULTS: The current study showed significantly higher levels of anti-inflammatory follicular (FO) B cells in spleens and BM and lower levels of pro-inflammatory aging-associated B cells (ABC) in the spleens, BM, and blood of aged GHR-/- mice compared to WT mice. In addition, T cell populations in aged GHR-/- mice showed higher levels of naïve T cells and lower levels of memory T cells in the thymus, BM, spleen, and blood.
CONCLUSION: Female GHR-/- mice are protected from age-related shifts in lymphocyte populations, suggesting that the absence of GH action mitigates immunosenescence. These results offer novel insights into mechanisms and therapeutic strategies to preserve immune balance and combat age-related immune dysfunction.

Keywords:  Aging; Aging-associated b cells (ABC); B cells; GHR-/- mice; Growth hormone; Immunosenescence; T cells

DOI:  https://doi.org/10.1007/s11102-025-01632-y
PLoS One. 2026 ;21(1): e0335178

Association of vaginal IL-4, IL-6, IL-8, IL-17, IFN-γ, and dietary intake with IBD status and vaginal microbiota in pregnant individuals.

Daniela Vargas-Robles, Yan Rou Yap, Biplab Singha, Joyce Tien, Mallika Purandare, Mayra Rojas-Correa, Camilla Madziar, Mellissa Picker, Tina Dumont, Heidi K Leftwich, Christine F Frisard, Doyle V Ward, Inga Peter, Barbara Olendzki, Ana Maldonado-Contreras.

BACKGROUND: Pregnant individuals with inflammatory bowel diseases (IBD) exhibit gut inflammation and dysbiosis; however, there is limited knowledge about their vaginal environment. This is important as vaginal inflammation and high vaginal microbiota diversity are associated with adverse pregnancy outcomes.
OBJECTIVES: We aimed to compare vaginal inflammatory markers and microbiota diversity of pregnant individuals with and without IBD in their third trimester of pregnancy and determine the role of diet in the vaginal microbiota diversity.
METHODS: We recruited pregnant individuals who provided vaginal swabs at 27-29 weeks of pregnancy. We characterized the vaginal microbiota by sequencing the V3-V4 region of the 16S rRNA and surveyed nine key pro and anti-inflammatory cytokines by qRT-PCR from the vaginal mucosa. Participants completed three validated interviewer-led nutrition assessments of 24-hour dietary intake around the same time as the collection of vaginal samples. The nutritional assessments were used to estimate dietary quality using the validated Healthy Eating Index (HEI-2015).
RESULTS: The cohort included 23 pregnant individuals with IBD (18 with Crohn's disease and 5 with ulcerative colitis) and 25 healthy controls (HC); 56.5% of the IBD cases were in remission. Vaginal microbiota diversity and composition did not differ significantly between individuals with IBD and HC. However, the vaginal mucosa of the IBD individuals showed increased expression of Th17 pro-inflammatory cytokines (i.e., IL-6, IL-8, IL-17) and decreased expression of Th1 (IFN-γ) and Th2 (IL-4) compared to HC. Expression of IL-6 and TNF- α correlated positively with vaginal microbial diversity. The beneficial Lactobacillus crispatus dominated the vaginal microbiota of individuals with either high dietary quality or those consuming more vegetables or low added sugar, regardless of IBD status. In IBD cases, consumption of vegetables and added sugars were associated with reduced expression of the pro-inflammatory IFN-γ and an increased expression of anti-inflammatory IL-4.
CONCLUSION: The vaginal microbiome did not differ between individuals with IBD and HC; however, IBD cases exhibit a pro-inflammatory tone in the vagina (high IL-6) that is associated with higher vaginal microbial diversity. Regardless of IBD status, healthier diets are positively associated with an increased abundance of the beneficial L. crispatus in the vagina.

DOI: https://doi.org/10.1371/journal.pone.0335178
Immunity. 2026 Jan 13. pii: S1074-7613(25)00562-X. [Epub ahead of print]59(1): 14-16

To the nines: IL-9 boosts T cell function.

Elizabeth Wickman, Maksim Mamonkin.

IL-9 is canonically associated with anti-helminth and allergic immunity. However, in this issue of Immunity, Jiang et al. and Castelli et al. demonstrate how integrating IL-9 signaling in T cells enhances their persistence and anti-tumor function in solid cancer models.

DOI: https://doi.org/10.1016/j.immuni.2025.12.006
J Endocrinol. 2026 Jan 14. pii: JOE-25-0287. [Epub ahead of print]

Mitochondrial AR overactivation coupled with uterine decidual mitochondrial defects in PCOS-associated pregnancy loss.

Yuehui Zhang, Min Hu, Linus R Shao, Lingjing Lu, Jing Han, Tingting Guo, Meng Jiang, Yao Wu, Han Han, Peng Cui, Mats Brännström, Amanda Nancy Sferruzzi-Perri, Håkan Billig.

  Nuclear androgen receptor (AR) dysregulation characterizes polycystic ovary syndrome (PCOS) pathophysiology and contributes to mitochondrial dysfunction-related adverse pregnancy outcomes. However, ARs also localize to mitochondria in many cell types, and mitochondrial dysfunction is implicated in the underlying pathogenesis of PCOS. In this study, human endometrial decidual basalis tissues and rat gravid uterine tissues were collected, and subcellular fractionation, Western blot, quantitative real-time polymerase chain reaction (qPCR), electron microscopy, and enzyme-linked immunosorbent assay (ELISA) were conducted. PCOS patients with early pregnancy exhibited increased expression of AR mRNA and mitochondrial AR protein in decidual basalis. Similar alterations of AR levels were also observed in gravid uterus of 5α-dihydrotestosterone (DHT)+insulin-exposed pregnant rats with fetal loss. In both PCOS patients and DHT+insulin-exposed pregnant rats, uterine mitochondria displayed disorganized cristae along with decreased uterine mitochondrial DNA (mtDNA) content, and reduced expression of mitochondrial morphogenesis (mito-morphosis) genes [sorting and assembly machinery component 50 (Samm50), coiled-coil helix coiled-coil helix domain-containing protein 3 (Chchd3), and dynamin-related protein 1 (Drp1)], and total adenosine triphosphate (ATP) levels. Additionally, there was dysregulated expression of mitochondrial fusion and fission, biogenesis, mitophagy, and mitochondrial ribosome protein (MRP) gene. In DHT+insulin-exposed pregnant rats, treatment with flutamide prevented fetal loss and partially rescued mitochondrial morphological abnormalities in uterine decidual stromal cells. In addition, flutamide normalized uterine Ar mRNA and mitochondrial AR protein expression; inner membrane mitochondrial protein (Immt), ras homolog enriched in brain protein (Rheb), and Mrp7 mRNA expression; and the Parkin: PTEM-induced putative kinase 1 (Pink1) ratio and restored total nicotinamide adenine dinucleotide (NAD) and ATP contents. Collectively, this work identifies mitochondrial AR in the uterus and implicates hyperandrogenism-induced, AR-dependent mitochondrial dysfunction in decidual stromal cells as a key mechanism underlying pregnancy loss in PCOS.

Keywords:  androgen receptor; gravid uterus; mito-morphosis; mitochondrial function; polycystic ovary syndrome; pregnancy loss

DOI:  https://doi.org/10.1530/JOE-25-0287
Prostate Cancer. 2026 ;2026 7871208

Inhibition of Growth and Induction of Apoptosis of Human Prostate Cancer Cells by Enzymatic Blockage of Kallikreins.

Fabienne Lehner, Souzan Salemi, Christopher Millan, Christoph Kündig, Daniel Eberli.

   Background: Most therapy options for castration-resistant prostate cancer (CRPCa) target the androgen axis. Human kallikrein-related peptidase (KLK) 2, a serine protease, is a downstream target gene of the androgen receptor (AR) involved in cancer progression, but also known to have an AR-independent function. Tissue KLKs, especially KLK2, are promising targets for therapy in advanced PCa because of their high PCa specificity and their correlation to the rising cancer grade and stage. By inhibition with the recombinant protease inhibitor MDPK67b targeting KLK2 and other trypsin-like KLKs including KLK4 and KLK14, we investigated the antitumor response and the influence on AR downstream target genes with MDPK67b in PCa cell lines in vitro.
Methods: Human PCa cells were cultured in a charcoal-stripped media and treated with MDPK67b (0.75 mg/mL). Cell viability was measured by CellTiter-Glo luminescent assay, cell death by flow cytometry. Gene analysis of AR, PSA, and PSMA was performed by qPCR. Correlating protein levels were evaluated by immunoblotting and confirmed by immunocytochemical staining.
Results: Treatment with 0.75 mg/mL MDPK67b led to a reduction of cell proliferation of 40% by day 5 in androgen-sensitive LNCaP cells. Immunostaining confirmed the decrease in cell proliferation by antibody labeling of Ki-67. Treatment induced apoptosis, which was visible by flow cytometry of annexin V in LNCaP cells. Further, MDPK67b induced a reduction in AR and PSA gene and protein expression but upregulated PSMA, a target for PCa imaging and therapy.
Conclusion: Treatment with MDPK67b demonstrates a significant antitumor effect by relevant reduction in cell proliferation and upregulation of apoptosis in LNCaP cells. Blockage of secreted KLKs can downregulate the AR and thereby influence its downstream target genes like PSA and PSMA. Upregulation of PSMA can lead to a theranostic, that is, therapeutic and diagnostic, advantage in clinics in a CR setting. Therefore, inhibition of KLKs represents a promising and AR-independent approach to treat advanced and CRPCa.
Trial Registration: ClinicalTrials.gov ID: NCT04644770.

Keywords:  androgen receptor; apoptosis; kallikrein 2; prostate-specific membrane antigen; theranostics

DOI:  https://doi.org/10.1155/proc/7871208
J Bone Miner Res. 2026 Jan 16. pii: zjag009. [Epub ahead of print]

A novel model to study the impact of gender-affirming therapy on bone in young male mice.

Lieve Verlinden, Sandra Calvo Blanco, Toke Liekens, Ingrid Stockmans, Karen Moermans, Dieter Schollaert, Chris Vercruysse, Tom Fiers, Tim Reyns, Nick Narinx, Tom De Waal, Leen Antonio, Ruslan I Dmitriev, Frank Claessens, Dirk Vanderschueren, Geert Carmeliet, Vanessa Dubois, Steve Stegen.

  Transgender individuals are increasingly seeking gender-affirming therapy. For children and adolescents, this typically involves puberty suppression followed by hormone treatment. However, potential long-term adverse effects on the growing skeleton remain poorly characterized, largely due to the lack of appropriate preclinical animal models. Existing models often rely on surgical puberty suppression and, in the case of estradiol (E2) administration, cause a high bone mass-phenotype that is not observed in the clinical setting. To address this, we developed a novel preclinical mouse model that mimics the medical approach used in transgirls and analyzed the effects of gender-affirming therapy on bone. Four-week-old male mice were treated with the gonadotropin-releasing hormone analogue degarelix (DGX) for pharmacological puberty suppression. After 4 weeks, E2 was administered at different doses, and bone properties were analyzed after an additional 8 weeks. DGX treatment effectively suppressed sex steroid signaling, leading to reduced bone mass and strength, which were dose-dependently restored by E2. While high E2 doses resulted in an excessive increase in bone mass, thereby precluding further mechanistic study, lower doses resulted in a bone phenotype resembling that of native females. At the cellular level, DGX-mediated puberty suppression resulted in increased bone resorption that exceeded bone formation, and also caused an accumulation of marrow adipocytes. Subsequent low-dose E2 administration reduced bone resorption, stimulated bone formation, and prevented the increase in bone marrow adiposity. In summary, we established and validated a mouse model that accurately mimics gender-affirming therapy initiated during early puberty and enables the study of its effects on bone.

Keywords:  Gender-affirming therapy; bone; estrogen

DOI:  https://doi.org/10.1093/jbmr/zjag009
Sci Adv. 2026 Jan 16. 12(3): eady5324

Lactate derived from cancer-associated fibroblasts promotes alternative splicing and castration resistance in prostate cancer.

Diwei Zhao, Zijun Mo, Tianyou Zhang, Xinyang Cai, Zhenyu Yang, Dong Chen, Junliang Zhao, Yuanwei Li, Fangjian Zhou, Zhen Li, Yonghong Li, Jun Wang.

Lactate in the tumor microenvironment (TME) is typically generated by cells exhibiting high glycolytic flux, exemplified by tumor cells. However, in glycolysis-low malignancies such as prostate cancer, stroma-derived lactate may drive noncanonical signaling and functions that remain unclear. Here, we identified APCDD1+ cancer-associated fibroblasts (CAFs) as a distinct stromal population that secretes lactate into the TME in response to androgen deprivation therapy (ADT). Lactate uptake by prostate cancer cells induces androgen receptor variant 7 expression, thereby conferring resistance to ADT. Mechanistically, lactate-induced lactylation of the spliceosome component SNRPA at Lys123 (K123) enhances its recognition of cis-acting elements, increases chromatin binding, and promotes androgen receptor splicing. Targeting lactate transport with monocarboxylate transporter inhibitors effectively restores ADT sensitivity. These findings reveal a metabolic-epigenetic axis linking lactate in the microenvironment to alternative splicing regulation and suggest a promising therapeutic strategy to overcome ADT resistance.

DOI: https://doi.org/10.1126/sciadv.ady5324
Biochem Pharmacol. 2026 Jan 08. pii: S0006-2952(26)00025-0. [Epub ahead of print]245 117694

Immunometabolism: Is cyanide a missing link between metabolic pathways and immune function?

Brian J Day.

  Immunometabolism is an emerging field that explores how metabolic pathways shape immune cell function, fate, and response. Immune cells undergo dynamic metabolic reprogramming to meet the energetic and biosynthetic demands of activation, differentiation, and effector activity. While glycolysis and oxidative phosphorylation (OxPhos) are well-established regulators of immune responses, recent discoveries suggest that endogenously produced cyanide may serve as a novel modulator of mitochondrial metabolism. Traditionally viewed as a toxic compound, cyanide is now being recognized for its potential role in regulating OxPhos through inhibition of complex IV in the electron transport chain, thereby influencing the balance between glycolysis and mitochondrial respiration. This review synthesizes current knowledge on the metabolic regulation of immune cells-including T cells, macrophages, dendritic cells, B cells, and natural killer (NK) cells-and highlights the role of core pathways such as glycolysis, fatty acid oxidation (FAO), and amino acid metabolism. It also explores how cyanide formation and metabolism intersect with innate immunity, particularly through the generation of thiocyanate and its role in antimicrobial defense. Furthermore, the review discusses how nutritional status integrate with metabolic cues to fine-tune immune responses. Finally, the clinical implications of immunometabolic regulation are examined in the context of autoimmune diseases, cancer, infections, and metabolic disorders. The potential of cyanide as a therapeutic modulator of immune metabolism is considered, offering new perspectives on immune regulation and disease intervention.

Keywords:  Cancer; Immunity; Infection; Inflammation; Metabolic disorders; Metabolic switch; Therapeutics

DOI:  https://doi.org/10.1016/j.bcp.2026.117694
J Clin Endocrinol Metab. 2026 Jan 13. pii: dgag008. [Epub ahead of print]

MASLD coexisting with PCOS increases cardiometabolic risk.

Oyekoya T Ayonrinde, Trevor A Mori, Leon A Adams, Lawrence J Beilin, John K Olynyk, Roger Hart.

 BACKGROUND AND AIMS: In women in their reproductive years, metabolic dysfunction-associated steatotic liver disease (MASLD) and polycystic ovary syndrome (PCOS) are the most common chronic liver and endocrine disorders respectively. MASLD and PCOS are associated with longer-term risk of cardiometabolic complications. We aimed to determine whether PCOS co-existing with MASLD (PCOS+MASLD) predicts greater risk of future cardiometabolic adverse parameters than either condition alone after 10 years in a longitudinal study of adolescents in the Raine Study.
METHOD: One hundred and ninety-nine community-based female adolescents participating in the Raine Study had assessments for both PCOS and MASLD, including anthropometry, blood tests, pelvic and abdominal ultrasound. Using updated diagnostic criteria, diagnoses of PCOS at age 14-years and MASLD at age 17-years, were retrospectively determined. At age 27-years, 148 participants had further anthropometry, cardiovascular and fasting blood assessments.
RESULTS: At age 17-years, 37 (18.6%) had MASLD, 32 (16.1%) had PCOS, 20 (10.1%) had PCOS without MASLD and 142 (71.4%) had neither. Among adolescents with PCOS, 12/32 (37.5%) had PCOS+MASLD, associated with obesity, higher serum remnant lipoprotein cholesterol, free and total testosterone, but lower sex hormone binding globin, compared with those with only MASLD, PCOS or neither (p<0.05 for all). By age 27-years, those with PCOS+MASLD (10/148) during adolescence, were more insulin resistant and had higher serum remnant lipoprotein cholesterol and triglyceride/high-density lipoprotein cholesterol ratio (p<0.05 for all), compared with those with only PCOS or MASLD or neither. PCOS without MASLD or obesity in adolescence did not predict future insulin resistance.
CONCLUSION: PCOS+MASLD in adolescents, but not PCOS alone, increases the likelihood of obesity, insulin resistance and an adverse cardiometabolic phenotype during adulthood.

Keywords: Metabolic dysfunction-associated steatotic liver disease; Raine Study; insulin resistance; obesity; polycystic ovary syndrome; testosterone

DOI: https://doi.org/10.1210/clinem/dgag008
Physiol Genomics. 2026 Jan 16.

Systems Genomics Reveals Age- and Sex-Dependent Metabolic Dysregulation from Glo1 Reduction in Mice.

Ingrid Cely, Montgomery Blencowe, Le Shu, Graciel Diamante, In Sook Ahn, Guanglin Zhang, Jonnby LaGuardia, Ruoshui Liu, Owen Briscoe, Zara Saleem, Susanna Wang, Richard C Davis, Hongxiu Qi, Aldons J Lusis, Xia Yang.

  Objectives:Glyoxalase 1 (Glo1) detoxifies reactive dicarbonyl compounds such as methylglyoxal, a precursor of advanced glycation end products (AGEs), which contribute to metabolic disorders. However, the contribution of AGE-independent mechanisms to Glo1-related metabolic dysfunction remains unclear. Methods: We conducted a longitudinal study in male and female Glo1 heterozygous knockdown (Glo1+/-) mice (~50% Glo1 expression). Metabolic phenotypes, including body weight, adiposity, glycemic control, and plasma lipid levels, were assessed over time. Atherosclerotic burden, AGE levels, and gene expression profiles in liver, adipose, muscle, kidney, and aorta were examined to identify pathway alterations and regulatory genes affected by Glo1 reduction. Results: Partial Glo1 loss resulted in obesity, hyperglycemia, dyslipidemia, and altered lipid metabolism in an age- and sex-dependent manner, with most phenotypes emerging after ~14 weeks. Glo1+/- females exhibited impaired glycemic control and elevated triglycerides, along with perturbations in adipogenesis, PPARγ signaling, insulin signaling, and fatty acid metabolism in liver and adipose tissue. Glo1+/- males displayed increased skeletal muscle mass and visceral adiposity with changes in lipid metabolic pathways. Methylglyoxal-derived AGE accumulation was altered only in male skeletal muscle and did not explain broader phenotypes. Transcriptomic analyses suggest altered glucose and lipid metabolism may be partially driven by alternative detoxification of methylglyoxal to metabolites such as pyruvate. Transcription factor analysis identified Hnf4a (across tissues) and Arntl (in aorta, liver, and kidney) as female-biased regulators altered by Glo1 deficiency. Conclusions: Glo1 reduction disrupts metabolic health through sex- and age-dependent pathways largely independent of AGE accumulation, involving tissue-specific metabolic reprogramming and transcriptional regulation.

Keywords:  Aging; Glyoxalase 1; Metabolic syndrome; Sex Differences; Transcriptome

DOI:  https://doi.org/10.1152/physiolgenomics.00106.2025
Wiad Lek. 2025 ;78(11): 2433-2441

The influence of sex hormones and the menstrual cycle on women's athletic performance: A literature review.

Jakub Kiwior, Maria Malina, Wojciech Liszka, Kinga Kosiń, Alicja Polak.

  The cyclical nature of female sex hormones - primarily estradiol and progesterone - exerts a multidimensional influence on physiological processes relevant to sports performance. This narrative review summarizes the current understanding of how different phases of the menstrual cycle affect energy metabolism, cardiovascular dynamics, neuromuscular function, thermoregulation, and psychological responses in physically active women. Estrogen-dominant phases, especially the late follicular stage, are generally associated with enhanced aerobic capacity, improved vasodilation, mood stabilization, and more efficient motor control. Conversely, progesterone-dominant phases - most notably the mid-to-late luteal stage - are characterized by increased core temperature, fluid retention, fatigue, and greater reliance on carbohydrate metabolism. The review also evaluates the effects of hormonal contraceptives, particularly oral contraceptives, on athletic performance and training adaptations. While individual responses vary, hormonal fluctuations create predictable patterns of performance variability that can be leveraged through phase-aware training. Based on the reviewed literature, the paper suggests practical training strategies, including phase-specific adaptations, nutritional support, and attention to menstrual symptoms. The review further highlights methodological limitations in the literature, including small sample sizes, inconsistent hormone validation, and underrepresentation of elite athletes. A personalized understanding of menstrual physiology enables more effective planning of training loads and recovery strategies, benefiting both professional and recreationally active women.

Keywords:   exercise physiology ; progesterone ; athletic performance ; estradiol ; menstrual cycle

DOI:  https://doi.org/10.36740/WLek/211463
Int J Oncol. 2026 Mar;pii: 35. [Epub ahead of print]68(3):

Unveiling sex differences in pancreatic ductal adenocarcinoma: Current evidence and future directions (Review).

Sophie Rauschenberg, Elisabeth Orgler-Gasche, Didem Karakas Zeybek, Ivonne Regel, J-Matthias Löhr, Daniel Öhlund, Michael Günther, Lina Aguilera Munoz.

 Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer‑related death worldwide in both men and women. While sex‑specific differences are increasingly recognized as critical determinants of health and disease, particularly in oncology, they remain markedly underexplored in PDAC. Emerging evidence suggests that sex differences influence numerous aspects of PDAC, including treatment response and prognosis. This knowledge gap represents a notable barrier to the development of effective, personalized therapeutic strategies for both sexes. The present review provides a comprehensive overview of the current knowledge on sex‑based differences in PDAC, encompassing epidemiology, risk factors, chemotherapy pharmacokinetics and toxicity, prognosis, therapeutic response, immune interactions, tumor microenvironment, tumor microbiota and molecular biomarkers..

Keywords: pancreatic cancer; pancreatic ductal adenocarcinoma; precision oncology; sex differences; sex‑based medicine

DOI: https://doi.org/10.3892/ijo.2026.5848
Cancer Res. 2026 Jan 13.

MECOM Function is Critical for AR-Driven Treatment-Resistant Prostate Cancer.

Surendra Gulla, Tej Sharma, Ephraim Gardner, Chennan Li, Tanaya A Purohit, Chao Xue, Sean Colligan, Shreya Shyam Sundar, Bing Yang, Shana Y Trostel, Brian Capaldo, Jonathan E Bard, Tobilola Ogunbowale, Abbas Jawadwala, Min Ma, Jun Qu, Fatima Karzai, Roberto Pili, David F Jarrard, Adam G Sowalsky, David J VanderWeele, Remi Adelaiye-Ogala.

Reprogramming of the androgen receptor (AR) cistrome is associated with prostate cancer progression, and advanced castrate-resistant prostate cancers (CRPC) tend to rely on reprogrammed/non-canonical AR signaling that remains active under treatment with AR signaling inhibitors (ARSI). Here, we identified EVI1, an oncogenic nuclear transcription factor encoded by MECOM, as an AR-recruited co-activator of non-canonical signaling. In prostate cancer, MECOM was exclusively overexpressed in both CRPC and enzalutamide-resistant CRPC and interacted with AR in the nucleus. MECOM depletion in prostate cancer cells decreased proliferation, altered cell survival transcriptional programs, and reduced the number of super-enhancers (SEs), leading to a dynamic change in the SE landscape and a decrease in the expression of SE-regulated oncogenic transcription factors, along with increased pro-apoptotic signatures. Notably, cells overexpressing MECOM and its protein, EVI1, were susceptible to PARP inhibitors regardless of their DNA damage response or homologous recombination repair (HRR) gene mutation status. These insights reveal the crucial role of EVI1 in regulating cell survival within the context of an AR-reprogrammed chromatin landscape. More importantly, the findings suggest that MECOM overexpression may be another biomarker that could significantly broaden the use of PARP inhibitors beyond those with HRR gene mutations.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-1720
Nat Immunol. 2026 Jan 14.

A distinct monocyte transcriptional state links systemic immune dysregulation to pulmonary impairment in long COVID.

Saumya Kumar, Chaofan Li, Liang Zhou, Qiuyao Zhan, Ahmed Alaswad, Sonja Volland, Bibiana Costa, Simon Alexander Krooss, Isabel Klefenz, Hagen Schmaus, Antonia Zeuzem, Dorothee von Witzendorff, Helena Lickei, Lea Pueschel, Anke R M Kraft, Markus Cornberg, Andreas Rembert Koczulla, Isabell Pink, Marius M Hoeper, Cheng-Jian Xu, Susanne Häussler, Miriam Wiestler, Mihai G Netea, Thomas Illig, Jie Sun, Yang Li.

The mechanisms driving immune dysregulation in long COVID disease remain elusive. Here we integrated single-cell multiome data, immunological profiling and functional assays to investigate immune alterations across multiple cohorts. A transcriptional state in circulating monocytes (LC-Mo) was enriched in individuals with mild-moderate acute infection and accompanied by persistent elevations of plasma CCL2, CXCL11 and TNF. LC-Mo showed TGFβ and WNT-β-catenin signaling and correlated with fatigue severity. Protein markers of LC-Mo were increased in individuals with pronounced fatigue or dyspnea, and those with severe respiratory symptoms showed higher LC-Mo expression. Epigenetically, LC-Mo exhibited AP-1- and NF-κB1-driven profibrotic programs. LC-Mo-like macrophages in bronchoalveolar lavage samples from individuals with severe respiratory symptoms displayed a profibrotic profile, and individuals with a high LC-Mo transcriptional state showed impaired interferon responses after stimulation. Collectively, our findings define a pathogenic monocyte transcriptional state linking systemic immune dysfunction to persistent long COVID disease, providing mechanistic insights and potential therapeutic targets.

DOI: https://doi.org/10.1038/s41590-025-02387-1