bims-simsho 2026-01-11 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2026–01–11
38 papers selected by
Chun-Chi Chang, Lunds universitet

Metabolic Messengers: testosterone.
Females with obesity exhibit greater influenza vaccine-induced immunity and protection than males in a mouse model.
Endometrial receptivity in polycystic ovary syndrome: altered biomarkers and underlying mechanisms.
Sex Differences in Asthma Pathogenesis.
Single cell RNA-sequencing reveals an association between testosterone treatment and reduced hormone signaling in the human mammary gland.
The impact of testosterone on paraventricular nucleus gene expression in male and female spontaneously hypertensive rats.
Androgen actions in metabolic tissues in polycystic ovary syndrome.
Sexual dimorphism in the DNA methylation pattern after immune stimulation in the zebrafish (Danio rerio) gonads.
Characterization of the follicular fluid microbiome in endometriosis patients undergoing in vitro fertilization.
Molecular Crosstalk Between Intrauterine hCG and Endometrial Receptivity: Signalling Pathways, Immune Modulation, and Translational Perspectives in IVF.
Impact of Anti-Endometrial Antibodies on IVF Implantation and Pregnancy Outcomes: A Retrospective Study.
Sex difference of the associations of sex hormone and their related indicators with all-cause mortality.
The nature of sex differences in catecholamine-induced lipolysis in subcutaneous fat cells.
Sex Hormones and the Liver: Implications for Disease Progression and Hormonal Therapy.
Machine Learning Reveals Sex-Biased Platelet-Associated Molecular Signatures in Systemic Lupus Erythematosus.
Genetic inactivation of the CRF1 receptor eliminates age-linked elevation of hippocampal 11β-hydroxysteroid dehydrogenase type 1 activity in female mice.
Correction for He et al., GATA2 facilitates steroid receptor coactivator recruitment to the androgen receptor complex.
Long-Term Impact of Western Diet on Right Ventricular Transcriptome: Uncovering Sex-Specific Patterns in C57BL/6J Mice.
Dynamic changes in the pregnancy microbiome and their role in preterm birth.
Changes in transposable elements expression in male and female mice liver throughout aging.
Sex Differences in Estimated Lean Body Mass of Captive and Wild Orangutans.
Sex-Specific Response to Predator Auditory Cues in Asian Corn Borer (Ostrinia furnacalis).
Sex and Stimulus-Specific Differences in Endothelial Cell Senescence Under Hormone-Free Conditions.
Cytokine-induced transcriptional changes in human neutrophils reveal immune regulatory plasticity.
TAM Plasticity under androgen deprivation therapy and PARP inhibition in prostate cancer: a multi-omics perspective.
Quantitative dissection of sexual dimorphism in mice through Y-linked gene knockouts and multivariate phenotyping.
24-Hydroxycholesterol suppresses steroid 5α-reductase-catalyzed conversion in human glioblastoma cell lines: a novel link between brain cholesterol homeostasis and androgen metabolism.
Single-cell map of the female brain across reproductive transitions.
Neonatal inflammation induces lasting sex- and region-dependent microglia activation and sex-dependent impairments in chemoreflexes.
Effect of probiotic Limosilactobacillus reuteri on a serum sex-hormone- and metabolic-syndrome-related health evaluation: a single-arm open-label pilot study.
Early-life sex hormone deficiency promotes beneficial remodeling in white adipose tissue and whole-body metabolism.
Aldehyde dehydrogenase 2 and sex influence blood acetaldehyde levels in mice, but not ethanol levels.
"Arising" Above Heart Failure: Sex Differences in Diabetic Cardiomyopathy.
The effects of endocrine disruptors on the female reproductive system.
Sex-specific differences in obesity among adults in Bangladesh: a nationally representative cross-sectional study.
The maternal microbiome influence on pregnancy success: breeding comparison of germ-free and conventionalized mice.
Cooperation of luteinizing hormone and estradiol in the promotion of goat oocyte maturation via regulation and activation of the GPR30 and EGFR signaling pathways.
Eutopic Endometrium Immune Changes Involved in Development and Progression of Endometriosis: A Review.

Nat Metab. 2026 Jan 09.

Metabolic Messengers: testosterone.

Franck Mauvais-Jarvis, Shalender Bhasin.

Testosterone, discovered during the endocrine gold rush of the 1930s, was the first hormone chemically synthesized for replacement therapy. In both men and women, testosterone functions directly through the androgen receptor (AR) and indirectly as a prohormone, converted by aromatase into 17β-oestradiol (oestradiol), which activates the oestrogen receptors ERα and ERβ. Testosterone is also metabolized to dihydrotestosterone-a potent, non-aromatizable AR agonist-through steroid 5α-reductases. Testosterone and its metabolites signal through AR- and ER-mediated genomic and rapid non-genomic actions. Long recognized for its role as a sex hormone, mounting evidence underscores the importance of testosterone in the regulation of systemic metabolism in both male and female organisms. Here, we highlight key milestones in the history of testosterone's discovery and therapeutic applications. Additionally, we synthesize the current understanding of testosterone as a key messenger promoting metabolic homeostasis in preclinical models and humans.

DOI: https://doi.org/10.1038/s42255-025-01431-6
Front Immunol. 2025 ;16 1699275

Females with obesity exhibit greater influenza vaccine-induced immunity and protection than males in a mouse model.

Brian Wolfe, Saurav Pantha, Saranya Vijayakumar, Shristy Budha Magar, Tawfik Aboellail, Santosh Dhakal.

   Introduction: Obesity is increasing globally, and it negatively impacts influenza vaccine efficacy. Although sex differences in influenza vaccine responses are studied in non-obese hosts, studies investigating sex differences in influenza vaccine-induced immunity and protection during obesity are limited.
Materials and methods: Using the C57BL/6J mouse model of high-fat diet (HFD)-induced obesity or low-fat diet controls, we investigated sex differences in influenza vaccine-induced immunity and protection during obesity. Male and female mice with or without obesity were vaccinated intramuscularly twice at a 3-week interval with an inactivated 2009 H1N1 influenza A virus (IAV) vaccine. At 35 days post-vaccination (dpv), antibody responses in plasma and B- and T-cell responses in spleen and bone marrow were quantified. At 42 dpv, mice were intranasally challenged with a drift variant of the H1N1 IAV, and disease severity was assessed by monitoring the change in body mass up to 21 days post-challenge (dpc). Subsets of mice were euthanized at 3 dpc to determine pulmonary virus replication (TCID50 assay), histopathology (H&E staining), and cytokine/chemokine responses (multiplex ELISA).
Results: Female mice, irrespective of diet and obesity status, developed higher antibody responses and were better protected compared to males. Vaccinated males with obesity mounted the poorest antibody responses, experienced a more severe disease, were unable to clear replicating virus from the lungs effectively, and demonstrated heightened pulmonary inflammation. Despite these differences, splenic B- and T-cell frequencies were comparable, suggesting the inefficiency of B cells to produce antibodies in males but not in females with obesity.
Discussion: Our findings suggest that sex differences are observed in influenza vaccine-induced immunity and protection during obesity, where males are more severely affected. These findings highlight the importance of considering biological sex and obesity status in influenza vaccine design and testing.

Keywords:  B-cell responses; body mass index (BMI); influenza vaccines; vaccine efficacy; virus-neutralizing antibodies

DOI:  https://doi.org/10.3389/fimmu.2025.1699275
Gynecol Endocrinol. 2026 Dec 31. 42(1): 2610550

Endometrial receptivity in polycystic ovary syndrome: altered biomarkers and underlying mechanisms.

Huihuang Chi, Jiexue Pan, Zuwei Yang, Hefeng Huang.

  Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS are at an increased risk for adverse pregnancy outcomes, such as miscarriage and preterm birth. Endometrial receptivity plays a pivotal role in embryo implantation. However, there has been limited review or discussion regarding potential alterations in endometrial receptivity in PCOS patients, the nature of these changes, and their underlying mechanisms. In this review, we aim to summarize the alterations in endometrial receptivity associated with PCOS, highlight the impact of PCOS on endometrial receptivity, and explore the underlying mechanisms. Abnormal expression of key receptivity markers has been observed in both PCOS patients and animal models, which may contribute to reduced endometrial receptivity. The factors leading to impaired endometrial receptivity in PCOS are multifaceted, including hormonal imbalances, metabolic disturbances, chronic inflammation, and microbiota alterations. However, the intricate mechanisms behind PCOS-related endometrial dysfunction remain poorly understood. Further research is essential to unveil these complex mechanisms and improve fertility outcomes for women with PCOS.

Keywords:  Polycystic ovary syndrome; endometrial receptivity markers; hormone; inflammation; metabolism; microorganisms

DOI:  https://doi.org/10.1080/09513590.2025.2610550
Immunol Rev. 2026 Jan;337(1): e70100

Sex Differences in Asthma Pathogenesis.

Kaitlin E McKernan, Emely Henriquez Pilier, Dawn C Newcomb.

  There is a sex difference in asthma prevalence and asthma-related morbidity that changes from childhood into different reproductive stages of life. The impact of sex hormone signaling on asthma pathogenesis has been partially elucidated using large cohort human studies, human cells, and animal models. Androgens decreased airway inflammation by reducing type 2 inflammation and eosinophil infiltration as well as reducing neutrophil-induced airway inflammation in animal models. Estrogen signaling through ER-α increased IL-33 production, an alarmin produced by airway epithelial cells that increases type 2 inflammation and increased Th17 cell-mediated neutrophilic inflammation. Additional studies are needed to determine what happens to asthma control and asthma-induced inflammation in women during pregnancy and menopause as well as how sex differences in immune cell development and airway inflammation affect asthma incidence and onset during childhood. Collectively, understanding that sex differences in asthma risk and control exist throughout life is important to personalize therapies for males and females with asthma.

Keywords:  asthma; inflammation; sex differences; sex hormones

DOI:  https://doi.org/10.1111/imr.70100
bioRxiv. 2026 Jan 02. pii: 2025.12.31.697241. [Epub ahead of print]

Single cell RNA-sequencing reveals an association between testosterone treatment and reduced hormone signaling in the human mammary gland.

Kiet T Phong, Siyou Song, Esther Kim, Danny Conrad, Zev Gartner.

Testosterone is the most studied androgen in hormone replacement therapy in postmenopausal women. Many transgender men also receive long-term testosterone replacement therapy (TRT) and have high serum testosterone levels compared to the low levels seen in cisgender women. Compared to other sex hormones such as estrogen and progesterone, the effects of testosterone on the mammary gland have been relatively understudied and there is little data regarding the long term safety of this treatment. Comparison of mammary glands from transgender men on TRT and cisgender women can reveal the effects of testosterone treatment on mammary gland biology and provide critical information regarding the long-term effects of TRT on patient health and disease outcomes. In this study, we performed single-cell RNA sequencing of breast tissues from a demographics-matched cohort of cisgender women and transgender men on TRT. Surprisingly, participants on TRT had unchanged serum levels of estradiol compared to controls. Among the observed transcriptional differences for participants on TRT were a dramatically reduced expression of genes downstream of estrogen signaling pathways in hormone receptor positive (HR+) luminal epithelial cells, as well as a decreased overall menstrual cycle-related hormone signaling. We confirmed this finding experimentally by showing reduced expression of progesterone receptor a/b, a prominent marker of estrogen signaling, in donors on TRT. Our results support the hypothesis that high levels of testosterone in transgender men on TRT suppress sex hormone signaling in the breast as seen on their impact on HR+ mammary epithelial cells, with implications for TRT as an antagonist of estrogen signaling and protection against breast cancer.

DOI: https://doi.org/10.64898/2025.12.31.697241
Biol Sex Differ. 2026 Jan 08.

The impact of testosterone on paraventricular nucleus gene expression in male and female spontaneously hypertensive rats.

Alex Paterson, Su-Yi Loh, Shadi Kadijeh Gholami, Mark F Rogers, Dharmani Devi Murugan, Lam Sau-Kuen, Mohammad Rais Mustafa, Benjamin P Ott, Prusha Balaratnam, Andre S Mecawi, David Murphy, Charles C T Hindmarch.

   BACKGROUND: Hypertension is a polygenic, complex disease that impacts men and women differently; whilst the incidence of high blood pressure (BP) is roughly equal over a lifetime, men typically are at higher risk of developing the disease earlier in life, before 50 years of age. There is adequate evidence that the brain is critical for the BP setpoint. The paraventricular nucleus (PVN) of the hypothalamus is an integrative structure that can influence not only neurohumoral responses to blood pressure changes, but also sympathetic drive. Here we manipulate the androgenic status of both male and female spontaneously hypertensive rats (SHRs) to determine how this changes gene expression within the PVN of these animals.
METHODS: SHR (8-weeks old) were either sham-operated or orchiectomized, whereas all females were oophorectomized, half of which received 10 mg testosterone propionate subcutaneously. Mean arterial pressure (MAP) and testosterone (T) were measured by carotid cannulation and ELISA respectively. Sequencing was performed on hand-punched PVN sections and subjected to robust bioinformatic analysis.
RESULTS: in total, 6,571 differentially regulated genes (DRGs) are regulated in the PVN of male and female rats. High T (endogenous or replaced) correlates with higher MAP in both sexes. Orchidectomy-induced T depletion resulted in the significant regulation of 5,104 genes, involved in thousands of biological roles, including ones related to hormone and sex-hormone signalling. In the female SHR, testosterone replacement in oophorectomized animals induced the regulation of 1,727 genes, sharing many biological functions with those in the high T males. We validated key genes by qPCR to determine false discovery rate.
CONCLUSIONS: T status in hypertensive rats correlates with MAP, and consistent changes in PVN transcriptome.

Keywords:  Androgen; Angiotensin II (ANGII); Epoxyhydrolase 2 (Ephx2); Estrogen; Paraventricular nucleus (PVN); RNAsequencing; Sex; Spontaneously hypertensive rat (SHR); Testosterone (T)

DOI:  https://doi.org/10.1186/s13293-025-00818-0
Endocrinology. 2026 Jan 06. pii: bqag001. [Epub ahead of print]

Androgen actions in metabolic tissues in polycystic ovary syndrome.

Caitlin L MacRae, Rebecca E Campbell.

  Polycystic ovary syndrome (PCOS) is a common reproductive disorder characterised by irregular ovulation, cyst-like follicles on the ovaries, and hyperandrogenism. PCOS is also strongly associated with increased risk of obesity and metabolic diseases such as type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Hyperandrogenism independently associates with many of the metabolic symptoms observed in women with PCOS, and increased androgen signaling in the female brain is hypothesised to impair central homeostatic mechanisms controlling food intake and body weight. However, peripheral metabolic organs such as pancreas, liver, fat, and skeletal muscle all express the androgen receptor, suggesting that direct androgen signaling in these organs may disrupt peripheral metabolic health. While it is difficult to separate the impacts of hyperandrogenism from hyperinsulinaemia and insulin resistance, tissue explant studies and transgenic knockout models provide the ability to interrogate signaling through the androgen receptor in metabolic organs. This review will summarise and discuss recent evidence implicating hyperandrogenism as a driver of metabolic impairments in PCOS, with an emphasis on the molecular mechanisms by which androgens may alter metabolic function in the periphery in females.

Keywords:  PCOS; adipose tissue; androgen receptor; hyperandrogenism; liver

DOI:  https://doi.org/10.1210/endocr/bqag001
Front Cell Dev Biol. 2025 ;13 1720219

Sexual dimorphism in the DNA methylation pattern after immune stimulation in the zebrafish (Danio rerio) gonads.

M Salazar, M Caballero-Huertas, T A van Gelderen, M N Krabbe, M Gut, S Heath, A Esteve, L Ribas.

   Introduction: In fish, epigenetic modifications are fundamental for regulating development, growth and adaptation to environmental factors. Emerging evidence further suggests that epigenetic mechanisms may modulate how fish gonads respond to infectious agents. Gonadal factors-including reproductive hormones and cytokines-are known to influence immune-cell activities, regulate the production of immune molecules, affect the overall immune response, and participate in gonadal sex differentiation. Although interactions between the reproductive and immune systems are well established, the epigenetic mechanisms underlying this interaction remain insufficiently elucidated, both in fish and in mammals. This study investigates how immune stimulation affects sex differentiation and methylation patterns of innate-immune genes in zebrafish gonads.
Methods: To study the epigenetic events involved in the immune-reproduction interaction, zebrafish (Danio rerio) were immune-stimulated with lipopolysaccharide (LPS) using two experimental approaches. (1) To assess the effect of immune stimulation on sex ratio, larvae were bathed in LPS during gonadal development (17-30 days post-fertilization, dpf). (2) To examine DNA methylation patterns in response to immune stimulation in adulthood, sexually mature fish received intraperitoneal LPS injections. Methylation analyses focused on two key innate immune genes, caspase 9 (Casp9) and interleukin 1β (Il1β). DNA methylation was quantified using a candidate-gene approach at single-nucleotide resolution through sequencing of bisulfite-converted DNA.
Results: Immune stimulation during gonadal development did not produce a statistically significant difference in sex ratio, although a clear trend toward feminization was observed in LPS-treated fish. In adults, Casp9 exhibited significant DNA-methylation differences driven by the interaction between treatment and sex. Specifically, eight CpG sites were significantly altered in treated females, while three CpG sites were significantly altered in treated males. In contrast, Il1β showed a sexually dimorphic methylation pattern, but these differences were not attributable to immune stimulation.
Discussion: The results support the presence of an epigenetic interplay between sex and immune response in the fish gonads. Sex-dependent methylation changes in Casp9 following LPS exposure, together with the inherent sexual dimorphism observed in Il1β, indicate that immune stimulation and sex jointly shape epigenetic landscapes of innate immune genes in reproductive tissues. Although the feminization effect was not statistically significant, the observed trend suggests that immune activation during the critical gonadal differentiation window may influence sex outcomes. Overall, these findings contribute to a deeper understanding of the epigenetic mechanisms underlying sexually dimorphic immune responses in reproductive tissues and highlight important avenues for future research.

Keywords:  aquaculture; bacterial; early development; epigenetics; immune; reproduction; sex ratio

DOI:  https://doi.org/10.3389/fcell.2025.1720219
Gynecol Endocrinol. 2026 Dec 31. 42(1): 2612148

Characterization of the follicular fluid microbiome in endometriosis patients undergoing in vitro fertilization.

Wenjie Zhao, Yan Zhang, Huagang Ma, Pingping Sun, Yuhua Zhang.

   BACKGROUND: Endometriosis (EMs) is a common gynecological disorder associated with infertility. EMs patients often require assisted reproductive technology (ART) but exhibit lower success rates. This study aimed to characterize the follicular fluid microbiome in EMs patients undergoing in vitro fertilization (IVF) and provide insights into mechanisms underlying lower pregnancy rates.
METHODS: Follicular fluid samples were collected from EMs patients and control subjectsundergoing IVF. Microbial DNA was subjected to 16S rRNA gene sequencing. Bioinformatic analyses, including alpha and beta diversity analysis, microbial composition profiling and biomarker identification, were performed.
RESULTS: The follicular fluid microbiome in EMs patients exhibited altered alpha and beta diversity compared to controls. Distinct microbial compositions were observed at various taxonomic levels. Differentially abundant taxa were identified as potential biomarkers for EMs. Microbial profiles were associated with clinical parameters such as oocyte quality and fertilization rates. Models based on microbial profiles were constructed to elucidate the relationship between EMs and IVF outcomes. Functional predictions suggested alterations in metabolic pathways in the follicular fluid microbiome of EMs patients.
CONCLUSIONS: This study revealed significant alterations in the follicular fluid microbiome of EMs patients, providing a basis for further research into the role of the microbiome in EMs-related infertility.

Keywords:  16S rRNA sequencing; Endometriosis; fllicular fluid; in vitro fertilization; microbiome

DOI:  https://doi.org/10.1080/09513590.2025.2612148
Int J Mol Sci. 2025 Dec 26. pii: 278. [Epub ahead of print]27(1):

Molecular Crosstalk Between Intrauterine hCG and Endometrial Receptivity: Signalling Pathways, Immune Modulation, and Translational Perspectives in IVF.

Charalampos Voros, Fotios Chatzinikolaou, Georgios Papadimas, Spyridon Polykalas, Aristotelis-Marios Koulakmanidis, Diamantis Athanasiou, Vasiliki Kanaka, Maria Kanaka, Kyriakos Bananis, Antonia Athanasiou, Aikaterini Athanasiou, Ioannis Papapanagiotou, Charalampos Tsimpoukelis, Maria Anastasia Daskalaki, Marianna Theodora, Nikolaos Thomakos, Panagiotis Antsaklis, Dimitrios Loutradis, Georgios Daskalakis.

  A limited period of endometrial receptivity is defined by molecular interactions between the embryo and maternal tissues, which are crucial for successful implantation. The results of clinical studies assessing intrauterine human chorionic gonadotropin (hCG) as an endometrial priming agent in in vitro fertilisation (IVF) have been inconsistent, markedly affected by dose, timing, and cycle context. This narrative review summarises molecular data demonstrating that hCG modulates immunological, stromal, endothelial, and epithelial compartments in a coordinated manner, affecting essential endometrial processes. hCG promotes adhesion competence and proliferation in the epithelium via a microRNA-regulated signalling axis (miR-126-3p-PIK3R2-PI3K/Akt). Intrauterine hCG promotes controlled apposition and invasion at the vascular interface by selectively strengthening endothelial junctional cohesion via VE-cadherin and CD146, without promoting angiogenesis. hCG collaborates with ERK/mTOR signalling to regulate autophagy and apoptosis, alters steroid-receptor networks in the stroma, initiates early decidual and survival markers (ACTA2, NOTCH1, complement C3), and enhances stress resistance. hCG modifies the immunological milieu by enhancing the activity of regulatory T cells and altering the distribution of uterine natural killer cells. This facilitates immunological tolerance and the remodelling of spiral arteries. These pleiotropic effects together enhance biomarkers and provide a scientific justification for context-dependent clinical responses, including patient-chosen, directed methods for the delivery of intrauterine hCG during IVF.

Keywords:  PI3K/Akt/eNOS signalling; embryo implantation; endometrial receptivity; human chorionic gonadotropin; in vitro fertilisation; luteinising hormone/choriogonadotropin receptor; stromal decidualisation

DOI:  https://doi.org/10.3390/ijms27010278
Am J Reprod Immunol. 2026 Jan;95(1): e70202

Impact of Anti-Endometrial Antibodies on IVF Implantation and Pregnancy Outcomes: A Retrospective Study.

Xiaoxuan Yang, Yan Su, Yaping Guo, Mianqiu Zhang, Juan Zhang, Xiaojing Hou, Shuangshuang Zhao, Huiqing An, Xiufeng Ling, Rong Shen.

   PROBLEMS: To investigate the impact of anti-endometrial antibodies (EMAb) on pregnancy outcomes in infertile patients undergoing in vitro fertilization (IVF) and to assess the potential value of personalized treatment strategies.
METHOD OF STUDY: A total of 47 EMAb-positive and 166 EMAb-negative oocyte retrieval cycles were retrospectively included following propensity score matching (PSM) to control for basic clinical characteristics influencing pregnancy outcomes. The two groups were compared in terms of various aspects closely associated with IVF outcomes. Pregnancy outcomes were assessed based on implantation, clinical pregnancy, miscarriage, and ongoing pregnancy rates.
RESULTS: No significant differences were found between the two groups regarding infertility-related clinical characteristics, oocyte- and embryo-related indicators, endometriosis incidence, and so forth. Compared with the EMAb-negative group, the implantation rate in the EMAb-positive group was lower by 10.3 percentage points (p = 0.047), whereas the 8.2-point lower clinical pregnancy rate did not reach statistical significance (p = 0.234). There were no significant differences in ongoing pregnancy and miscarriage rates between the two groups.
CONCLUSIONS: Our study observed that the presence of EMAb was associated with less favorable IVF outcomes, primarily reflected in lower implantation and clinical pregnancy rates. However, once the implantation was successful, the risk of miscarriage did not increase. These findings suggest a potential role for EMAb screening in guiding personalized treatment strategies, such as increasing the number of embryos transferred or using immunosuppressive agents, to improve IVF outcomes. Future research should involve more extensive and diverse populations to explore the mechanisms of action of EMAb and their impact on IVF treatment outcomes.

Keywords:  anti‐endometrial antibodies; immunology; implantation; infertility; pregnancy outcome

DOI:  https://doi.org/10.1111/aji.70202
Nutr Metab (Lond). 2026 Jan 07.

Sex difference of the associations of sex hormone and their related indicators with all-cause mortality.

Yu Sun, Meng Zhang, Mengying Niu, Xiaofei Zhang, Zhi Mao, Chang He, Shiyin Ma, Chucheng Jiao, Jiahao Chen, Xudong Pan, Xiaoyan Zhu.

   BACKGROUND: Sex hormones are critical health determinants in both sexes. Some studies have found the association between sex hormones and all-cause mortality. However, the evidence of these association is limited and there is a lack of comprehensive investigation of various sex hormones.
METHODS: Our study included a total of 7,294 participants from the 2013 to 2016 National Health and Nutrition Examination Survey (NHANES). The total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG) levels were obtained from laboratory data, free testosterone (FT), free estradiol (FE2), free androgen index (FAI) and the ratio of TT to E2 (TT/E2) were calculated. Cox proportional hazards regression models and restricted cubic spline were used to analysis the association between various sex hormones and all-cause mortality, and stratified analyses according to age, sex, race, and history of diabetes and hypertension were performed.
RESULTS: The final study sample included 3,473 male and 3,821 female from the NHANES. In the multivariate-adjusted model, male participants with higher FT and higher FAI had an obvious lower incidence of all-cause mortality [FT: HR, 0.41 (95% CI, 0.36-0.79); FAI: HR, 0.34 (95% CI, 0.25-0.92)], but these associations were not significant in female. And there was a positive correlation between SHBG concentration and mortality rate in both male and female participants, but the HR in males was higher than that in females [2.45 (95% CI, 1.69-6.23) vs 1.81 (95% 1.53-3.21)].
CONCLUSION: Our study found sex differences in the association of sex hormones and their related indicators with all-cause mortality, providing new insights for future research in this field.

Keywords:  Mortality; NHANES; Sex hormones

DOI:  https://doi.org/10.1186/s12986-025-01071-3
iScience. 2025 Dec 19. 28(12): 113988

The nature of sex differences in catecholamine-induced lipolysis in subcutaneous fat cells.

Lucas Massier, Daniel P Andersson, Nathalie Viguerie, Jiawei Zhong, Danae Zareifi, Alastair G Kerr, Dominique Langin, Peter Arner.

  Women demonstrate a more efficient energy metabolism than men, which is important for sex differences in metabolic health. This dimorphism involves a greater capacity to mobilize lipids from adipose tissue through triglyceride lipolysis following catecholamine stimulation. Herein, we examined the cellular nature of this dimorphism of catecholamine action in human adipocytes from subcutaneous adipose tissue by combining extensive pharmacological experiments with descriptive proteome and transcriptome analyses in large cohorts. We observed two sex-dependent differences in catecholamine-stimulated adipocyte lipolysis: in women, the lipolytic sensitivity (half maximum effective hormone concentration) was 50% decreased, involving increased coupling of antilipolytic alpha-2A adrenoceptors to adenylyl cyclase. However, the maximum lipolytic hormone effect was 50% increased and linked to more efficient mono- and triacylglycerol lipases. Treatment targeting adipocyte lipolysis might be used in men to diminish sex differences in the regulation of lipid metabolism.

Keywords:  Human metabolism; Lipid; Omics

DOI:  https://doi.org/10.1016/j.isci.2025.113988
Liver Int. 2026 Feb;46(2): e70509

Sex Hormones and the Liver: Implications for Disease Progression and Hormonal Therapy.

Special Interest Group Gender in Hepatology of the Italian Association for the Study of the Liver (AISF)

  The liver is central to sex hormone metabolism, and sex hormones in turn modulate hepatic physiology and disease processes. Oestrogens are often protective, while androgens tend to worsen disease progression. The clinical implications of hormonal therapies in patients with liver disease remain an area of active investigation. To review current evidence on the interplay between sex hormones and liver disease, with a focus on the safety and impact of hormonal therapies, including contraception, hormone replacement therapy, assisted reproductive technology and gender-affirming treatments. Prolonged or high-dose oestrogen exposure, particularly via oral contraceptives, has been associated with intrahepatic cholestasis and hepatocellular adenoma (HCA), especially in predisposed individuals. In contrast, hormone replacement therapy in postmenopausal women is generally safe and may confer metabolic and hepatic benefits. Oestrogens appear to slow fibrosis progression and reduce hepatocellular carcinoma risk, whereas androgens can promote steatosis and HBV-related oncogenesis. Hormonal therapies are safe in most patients with compensated chronic liver disease but require caution in settings such as in polycystic liver disease, where oestrogens can accelerate cyst growth. Emerging data also indicate a role of sex hormones in autoimmune and cholestatic diseases, as well as in outcomes of assisted reproduction and gender-affirming therapy. Hormonal therapies are feasible in most liver disease contexts, but individualised assessment, awareness of genetic predisposition, and disease-specific risks are essential to optimise safety and therapeutic benefit.

Keywords:  assisted reproductive technology; contraception; hormone replacement therapy; liver diseases; liver transplant; pregnancy; sex hormones

DOI:  https://doi.org/10.1111/liv.70509
Immunol Lett. 2026 Jan 06. pii: S0165-2478(26)00009-X. [Epub ahead of print] 107136

Machine Learning Reveals Sex-Biased Platelet-Associated Molecular Signatures in Systemic Lupus Erythematosus.

Shuping Li, Hui Ouyang, Tianjiao Cui, Jiawen Lin, Keping Wu, Enyi Zhu, Yuan Sui, Mingcheng Huang.

   OBJECTIVES: Autoimmune diseases (ADs) demonstrate a higher prevalence in women than men. Systemic Lupus Erythematosus (SLE) stands out among multiple ADs as an extreme case of the imbalanced sex ratio observed at disease onset, predominantly affecting females. This discrepancy can be ascribed to genetics, hormonal influences, environmental triggers, and more. Despite numerous studies aiming to uncover the sex differences in SLE, comprehensive bioinformatics integration for understanding its biological heterogeneity remains largely unexplored.
METHODS: Transcriptomic data of 338 individuals (175 normal and 163 SLE) from the six SLE studies (GSE154851, GSE20864, GSE99967, GSE39088, GSE72754, and GSE81622) from the Gene Expression Omnibus were analyzed to uncover sex-specific candidate genes using differential gene expression analysis. Machine learning algorithms selected the candidate genes, and their performance was evaluated using receiver operating characteristic curves. Analyses were done by ADEx, GEO2R, and scRNA-seq.
RESULTS: 72 enriched terms are shared between the female subgroup and the overall dataset, but none are shared between the male subgroup and the overall dataset. We identified differential expression of platelet glycoprotein VI (GP6) in male SLE, but not in the females, with GP6 predominantly expressed in platelets. Moreover, the correlation between GP6 and pre-T cell antigen receptor alpha (PTCRA) was significantly more pronounced in male SLE patients (r=0.7004, p=0.0053) compared to females (r=0.5741, p<0.0001). Additionally, GP6 and PTCRA were positively associated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in male SLE patients, but not in females.
CONCLUSIONS: There is a sex-based bias in SLE. GP6 marks a PTCRA-expressing platelet subset that is differentially altered in male SLE compared with controls, but not in female SLE, indicating a sex-dependent platelet molecular phenotype. The differential GP6 expression on PTCRA-expressing platelets between male and female SLE patients may contribute to differences in their clinical manifestations.

Keywords:  SLE; bioinformatics; machine-learning; molecular signatures; transcriptome

DOI:  https://doi.org/10.1016/j.imlet.2026.107136
J Neuroendocrinol. 2026 Jan;38(1): e70131

Genetic inactivation of the CRF1 receptor eliminates age-linked elevation of hippocampal 11β-hydroxysteroid dehydrogenase type 1 activity in female mice.

Julie Brossaud, Alessandro Piccin, Angelo Contarino, Marie-Pierre Moisan.

  Glucocorticoids are produced through activation of the hypothalamic-pituitary-adrenal (HPA) axis, initiated by the release of corticotropin-releasing factor (CRF) from the hypothalamus. CRF acts through two receptor subtypes, CRF1 and CRF2. However, the specific contributions of CRF1 and CRF2 receptors to age-related changes in brain glucocorticoid activity remain largely unexplored. In certain tissues, including the hippocampus, glucocorticoid signaling is further amplified by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regenerates inactive glucocorticoid metabolites into their active form. Notably, prior research investigating the role of hippocampal 11β-HSD1 in aging has focused exclusively on male subjects. In this study, we used genetic mouse models lacking functional CRF1 or CRF2 receptors to investigate their respective roles in regulating hippocampal 11β-HSD1 activity and glucocorticoid levels across age and sex. Mice of both sexes at 6 and 18 months of age were analyzed. Hippocampal 11β-HSD1 activity was assessed by measuring the ratio of corticosterone to dehydrocorticosterone using mass spectrometry in tissue extracts from CRF1 and CRF2 wild-type (WT), heterozygous (HET), and knockout (KO) mice. Our results demonstrate that hippocampal 11β-HSD1 activity increases with age in female CRF1 WT and HET mice but not in CRF1 KO females. In contrast, aged males exhibit elevated 11β-HSD1 activity regardless of CRF1 genotype. In CRF1 males, the age-related increase in hippocampal 11β-HSD1 activity is associated with higher hippocampal corticosterone levels, whereas in CRF1 females, it corresponds with a decrease in hippocampal dehydrocorticosterone. CRF1 deficiency leads to reduced hippocampal levels of both corticosterone and dehydrocorticosterone in males and females at both ages. CRF1 deficiency is also associated with decreased plasma corticosterone levels in both male and female mice. Male, but not female, CRF2 mice show an age-dependent increase in hippocampal 11β-HSD1 activity, which is not altered by CRF2 deficiency. Moreover, CRF2 deficiency results in increased plasma corticosterone in female, but not in male, mice. Overall, our findings reveal that hippocampal 11β-HSD1 activity increases with age in both sexes. In females, this increase is dependent on the presence of functional CRF1 receptors. In contrast, males exhibit age-related increases in 11β-HSD1 activity independent of CRF1 function. These findings underscore the importance of considering sex as a biological variable when developing therapeutic strategies targeting 11β-HSD1 to mitigate age-related memory decline.

Keywords:  11β‐hydroxysteroid dehydrogenase; aging; corticotropin‐releasing factor receptors; glucocorticoids; sex

DOI:  https://doi.org/10.1111/jne.70131
Proc Natl Acad Sci U S A. 2026 Jan 13. 123(2): e2528643122

Correction for He et al., GATA2 facilitates steroid receptor coactivator recruitment to the androgen receptor complex.

DOI: https://doi.org/10.1073/pnas.2528643122
Int J Mol Sci. 2025 Dec 26. pii: 259. [Epub ahead of print]27(1):

Long-Term Impact of Western Diet on Right Ventricular Transcriptome: Uncovering Sex-Specific Patterns in C57BL/6J Mice.

Ani Stepanyan, Siras Hakobyan, Agnieszka Brojakowska, Malik Bisserier, Roksana Zakharyan, Suren Davitavyan, Tamara Sirunyan, Gisane Khachatryan, Mary K Khlgatian, Shihong Zhang, Ania Baghoomian, Susmita Sahoo, Lahouaria Hadri, Venkata Naga Srikanth Garikipati, Arsen Arakelyan, David A Goukassian.

  The Western diet (WD) has been linked to various structural and functional alterations in the left ventricle (LV), but the molecular response of the right ventricle (RV) remains largely unknown. Given the RV's distinct anatomical and functional characteristics, it is crucial to understand how long-term WD exposure affects RV gene expression, especially in a sex-specific context. Our objective was to perform gene expression profiling of the RV late responses to WD in wild-type mice. Male and female C57BL/6J mice were fed a WD for 125 days from 300 to 425 days of age, and RV tissues were collected at 530 and 640/750 (female/male) days. mRNA sequencing was performed on RV tissues to identify differentially expressed genes (DEGs) between WD-fed and normal diet (ND)-fed groups. Data processing and analysis were conducted using the STAR aligner and DESeq2. WD-induced RV transcriptomic changes were characterized by differential expression of genes associated with cardiac remodeling and transcriptional regulation in both sexes. In females, additional genes showing altered expression were associated with immune response, whereas in males, changes were more limited, primarily involving genes related to circadian rhythm and cardiac remodeling. Echocardiography revealed modest, sex-specific differences: WD-fed females showed a decrease in right-ventricular internal diameter in diastole and a trend toward increased pulmonary trunk diameter, whereas males showed no notable changes. These exploratory results suggest that WD is associated with modest transcriptomic changes in the RV in both sexes, with only minor structural differences observed in females, indicating subtle sex-specific effects after a switch to normal chow.

Keywords:  Western diet; right ventricle; sex; transcriptome

DOI:  https://doi.org/10.3390/ijms27010259
Front Cell Infect Microbiol. 2025 ;15 1683610

Dynamic changes in the pregnancy microbiome and their role in preterm birth.

Zhuojun Xie, Zhongsheng Chen, Guangyu Ma.

  Preterm birth (PTB) remains a leading cause of neonatal morbidity and mortality worldwide, posing significant challenges to maternal and child health. Recent advances have highlighted the critical role of the maternal microbiome-encompassing vaginal, gut, and oral microbial communities-n influencing pregnancy outcomes. This review comprehensively summarizes the dynamic changes of the pregnancy microbiome and elucidates its association with PTB. During healthy pregnancy, the vaginal microbiome is dominated by Lactobacillus with low diversity, while dysbiosis with fewer Lactobacilli and more anaerobes increases PTB risk. The gut microbiome also shifts, with reduced beneficial bacteria and more pro-inflammatory species linked to adverse outcomes. Changes in the oral microbiome and periodontal disease can promote systemic inflammation contributing to PTB. Microbial imbalance may trigger PTB through inflammation, immune changes, and microbial spread to the uterus. Targeting the microbiome via probiotics shows promise, but more clinical studies are needed. This review highlights the pregnancy microbiome as a key biomarker and intervention target to reduce PTB.

Keywords:  gut microbiome; oral microbiome; preterm birth; probiotics; vaginal microbiome

DOI:  https://doi.org/10.3389/fcimb.2025.1683610
Geroscience. 2026 Jan 06.

Changes in transposable elements expression in male and female mice liver throughout aging.

Bairon Hernandez-Rojas, Paola Murgas, Gonzalo Riadi.

  Aging has traditionally been studied through the lens of protein-coding genes, with a strong bias toward data derived from male organisms. As a result, the role of non-coding elements and potential sex-specific differences remains largely unexplored. Transposable elements (TEs), mobile sequences capable of altering genome structure and regulating gene expression, have recently gained attention for their roles in development and aging. However, despite this growing interest, key aspects of TE expression dynamics are still poorly characterized, particularly in female tissues. To address this gap, we analyzed TE expression in RNA-Seq liver tissue from male (8, 26, 60, 78, and 104 weeks) and female (3, 24, 48, and 72 weeks) mice. Our results reveal distinct TE expression trends between sexes. While previous studies report increased TE expression with aging, we identified a subset of TEs with decreasing expression over time, differing between males and females. We also observed inverse expression trends between a few TEs and their nearby genes, supporting a potential regulatory relationship. We identified TEs with changing expression (CE TEs) through age associated with nearby genes showing strong expression correlations (|ρ|≥ 0.6). In males, correlated genes such as Txnrd2, Mthfd1, and Dkk3 are involved in redox regulation, one-carbon metabolism, and Wnt signaling, respectively, while in females, Thrb and Cd55 are linked to metabolic regulation and immune protection. These associations suggest that TE activity may be functionally coupled to transcriptional programs relevant to liver physiology and aging. These findings highlight the importance of examining TE expression in both sexes and suggest their potential regulatory roles in age-related liver physiology.

Keywords:  Ageing; Time course analysis; Transposable elements; Transposable elements expression

DOI:  https://doi.org/10.1007/s11357-025-02065-y
Am J Biol Anthropol. 2026 Jan;189(1): e70173

Sex Differences in Estimated Lean Body Mass of Captive and Wild Orangutans.

Faye S Harwell, Janine L Brown, Stephen Paris, Nicole P Boisseau, Erin Kane, Tri Wahyu Susanto, Endro Setiawan, Cheryl D Knott.

   OBJECTIVES: Male and female primates experience different ecological and reproductive constraints, which often lead to differences in how they allocate energy. Since testosterone promotes muscle growth, male primates generally possess greater relative muscle mass than females. Orangutans exhibit a rare phenomenon called male bimaturism, where there are two adult male morphs. Male orangutans reach adulthood as the unflanged morph and may transition to the flanged morph during their lifetime. Here, we investigated muscle mass differences of wild and captive orangutans among the age-sex classes while accounting for flange status.
METHODS: Estimated lean body mass (ELBM) can be obtained by comparing urinary creatinine (CR) residuals using specific gravity (SG). We analyzed 2329 urine samples collected from 51 orangutans under human care and 279 samples from 29 wild Bornean orangutans at Gunung Palung National Park, Borneo, Indonesia.
RESULTS: In both datasets, flanged males had the greatest mean ELBM followed by females and unflanged males. Flanged males had significantly greater ELBM than adult females and unflanged males in both captive and wild environments.
CONCLUSIONS: Flanged males have greater ELBM than unflanged males, suggesting increased energetic investment in muscle mass. Differences in body composition likely reflect the distinctive reproductive strategies and behavioral niches utilized by the two morphs. Flanging is an energetically costly process to undergo and maintain and is associated with a costly reproductive strategy. Because of these sex/morph differences, we recommend indexing urine samples against SG to avoid potential sex biases when indexing with CR.

Keywords:  body composition; creatinine; lean muscle mass; sex differences; sexual dimorphism

DOI:  https://doi.org/10.1002/ajpa.70173
Ecol Evol. 2026 Jan;16(1): e72783

Sex-Specific Response to Predator Auditory Cues in Asian Corn Borer (Ostrinia furnacalis).

Li Wang, Qiang Qu, Qiulin Guo, Junhao Guan, Jiayi Zhao, Yue Zhu, Tinglei Jiang, Jiang Feng, Hui Wu.

  Predation risk has profound effects on prey from phenotype to gene expression. Prey may respond differently to predation risk on the basis of sex, especially those species with obvious sexual size dimorphism. However, whether such responses are sex-specific still lacks systematic research. In this study, we continuously exposed a female-larger species Asian corn borer (ACB, Ostrinia furnacalis) to bat foraging ultrasound from the larval stage through adulthood, monitoring phenotypic and gene expression changes in exposed males and females compared to normally reared adults. The results revealed that adults in the ultrasound-stressed group exhibited significant changes in both phenotypic traits and gene expression profiles, with marked sex-specific responses to auditory predation cues. Specifically, males demonstrated significant increases in body weight, body length, and ecdysteroid titer, whereas females displayed a marked reduction in fecundity (egg production). Female adults exhibited a predominance of downregulated differentially expressed genes (DEGs), with greater total DEG numbers compared to males. Male adults showed primarily upregulated DEG profiles. Females appear to utilize LOC114365575 and LOC114352210 as key regulators in modulating growth and juvenile hormone levels, whereas males may rely on LOC114349799 and LOC114351933 to regulate growth and electrophysiological response amplitude under predation risk. Our results suggest that sex-specific responses may be an important component of inter-individual differences in prey responses to risk and influence prey population growth and demography.

Keywords:  Ostrinia furnacalis; bat ultrasound; ecology of fear; gene expression; risk‐induced trait response; sex dimorphism

DOI:  https://doi.org/10.1002/ece3.72783
Am J Physiol Heart Circ Physiol. 2026 Jan 09.

Sex and Stimulus-Specific Differences in Endothelial Cell Senescence Under Hormone-Free Conditions.

Anna Quarder, Khaoula Talbi, Hannah Bartmann, Esther Beuke, Constantin von Kaisenberg, Manuel M Vincente, Sara Todorovic, Anette Melk.

  Sex differences in cardiovascular disease are well documented, with females often considered hormonally protected. However, some differences persist even after menopause, indicating non-hormonal influences. Endothelial dysfunction is an early contributor to cardiovascular disease, with endothelial cell senescence playing a key role. Senescence, an irreversible cell cycle arrest, can be replicative or stress-induced. This study investigates whether sex differences in endothelial senescence exist independent of hormonal influence and vary by stimulus. Senescence was induced by replication or irradiation in female and male HUVECs (up to n=7 each) cultured under hormone-free conditions. SA-β-Gal staining, telomere length, RT-qPCR of p21, p14, p16, and crystal violet assays were used to assess senescence. Replicative senescence was analyzed across passages 1-20 and stress-induced senescence 5 days post-irradiation. Female HUVECs had a significantly longer replicative lifespan than male cells (p=0.0012) despite similar proliferation. Telomere attrition occurred faster in male cells (p=0.0034), with earlier expression of senescence markers. In contrast, after irradiation, female cells exhibited stronger senescence responses, including increased SA-β-Gal staining and elevated p21, p14, and p16 levels. This study identifies sex differences in endothelial cell senescence under hormone-free conditions, pointing to intrinsic cellular factors. While male cells exhibited earlier senescence under replicative stress, female cells were more vulnerable to stress-induced senescence. Together, these results highlight the importance of sex- and stimulus-specific mechanisms in vascular aging.

Keywords:  Cellular senescence; Endothelial cells; Endothelial senescence; Sex differences; Vascular aging

DOI:  https://doi.org/10.1152/ajpheart.00646.2025
Discov Immunol. 2025 ;4(1): kyaf013

Cytokine-induced transcriptional changes in human neutrophils reveal immune regulatory plasticity.

Huw B Thomas, Steven W Edwards, Helen L Wright.

   Introduction: Neutrophils are innate immune cells that play a central role in the inflammatory response. They produce an array of destructive molecules and anti-microbial proteases that characterize the cells as front-line defenders, crucial to host defence. It is now appreciated that neutrophils produce and respond to a variety of inflammatory signals and are able to regulate both the innate and adaptive immune responses. However, the mechanisms by which neutrophils respond to different inflammatory signals to regulate their own function and the functions of other immune cells are incompletely defined.
Methods: In this study, we performed RNA sequencing of healthy human neutrophils exposed for 1 h to a range of pro-inflammatory cytokines.
Results: Granulocyte/macrophage colony-stimulating factor and tumour necrosis factor alpha induced significant changes in 1651 and 693 genes, respectively (adj. P < 0.05) including activation of genes regulating apoptosis and encoding cytokines and chemokines that can drive the differentiation and activation of CD4 T-cells. Stimulation of neutrophils with granulocyte colony-stimulating factor, interferon alpha, interferon gamma, interleukin-1 beta, or interleukin-8 resulted in expression of discrete gene sets and differential activation of signalling pathways including changes in cell adhesion and migration, immune receptor expression, apoptosis, and production of pro-inflammatory prostaglandins.
Conclusion: This work defines the differential gene expression patterns in neutrophils exposed to different regulatory cytokines. This is important in both increasing our understanding of the role of neutrophils in driving innate and adaptive immune responses and, importantly, for deconvoluting the neutrophil gene expression signatures observed in inflammatory diseases.

Keywords:  RNA-Seq; cytokines; interferons; neutrophils

DOI:  https://doi.org/10.1093/discim/kyaf013
Front Immunol. 2025 ;16 1745168

TAM Plasticity under androgen deprivation therapy and PARP inhibition in prostate cancer: a multi-omics perspective.

Shuangming Chen, Weiwei Cai, Chunlin Liu.

  Androgen deprivation therapy (ADT) and next-generation androgen receptor pathway inhibitors (ARPI) are increasingly combined with PARP inhibitors (PARPi) in metastatic prostate cancer (mPCa). These treatments have improved outcomes, yet responses remain variable and often lack durability. Single-cell and spatial multi-omics studies indicate that tumor-associated macrophages (TAMs) strongly influence therapeutic response and form a treatment-shaped continuum of states enriched for TREM2 and SPP1 programs, lipid metabolic activity, hypoxia adaptation, and phagocytic checkpoint signaling within the osteogenic cancer-associated fibroblast (CAF) niche. Macrophages also possess functional androgen receptor (AR) activity, which supports an AR-driven myeloid circuit that promotes immune exclusion during ADT or ARPI therapy. PARP inhibitors stimulate cGAS-STING and induce senescence-associated secretory phenotypes (SASP), leading to an initial type I interferon (IFN) response that ultimately transitions to an MDSC-like immunosuppressive phenotype. These processes converge on common mechanisms of phagocytic control through CD47-SIRPα, MerTK, Axl, CSF1R, and TREM2 and represent therapeutic targets for combination therapies. This review details the combined impact of ADT and PARPi and introduces a multi-omic framework that integrates TREM2 or SPP1 burden, STING activation status, phagocytic checkpoint expression, and HRR or SPOP genotype into a Myeloid Lymphatic Composite Score (MLCS). The MLCS is a scoring tool to assist in timing and selecting therapeutic combinations of ARPI with TREM2 or CSF1R blockade, PARPi with STING modulation, and ARPI with anti-CD47 therapy. Integrating mechanistic and translational data provides a foundation for biomarker-guided regimens capable of converting prostate cancer from an immune-cold disease to an immune-responsive state.

Keywords:  ADT/AR pathway inhibition; PARP inhibitors; cGAS–STING signaling; multi-omics; prostate cancer

DOI:  https://doi.org/10.3389/fimmu.2025.1745168
Sci Rep. 2026 Jan 06.

Quantitative dissection of sexual dimorphism in mice through Y-linked gene knockouts and multivariate phenotyping.

Nobuhiko Tanaka, Kento Miura, Ai Ozaki, Yasuyo Kozawa, Masaru Tamura, Atsuo Ogura, Shogo Matoba.

Sexual dimorphism (SDM) is regulated by sex chromosomes, yet the specific contribution of individual genes remains unclear. To address this, we conducted a comprehensive phenotyping analysis to investigate the roles of Y chromosome-linked genes in SDM formation in mice. Using C57BL/6J mice, we identified 49 SDM traits across 14 biological systems. To assess gene-specific effects, we generated knockout (KO) mice for 10 unique Y-linked genes using CRISPR/Cas9. As expected, Sry KO resulted in feminization of most SDM traits, including gonadal sex. However, certain body size-related traits remained male-like, suggesting the involvement of additional Y-linked genes. Consistently, KOs of Uty and Usp9y significantly altered traits related to body and organ size. We further applied a dimensionality reduction approach to quantitatively capture SDM variation at the individual level, enabling visualization of phenotypic shifts in each KO mouse. Our findings demonstrate that non-Sry Y-linked genes contribute to SDM and introduce a generalizable framework for quantifying sex differences across individuals and species.

DOI: https://doi.org/10.1038/s41598-025-33814-w
Neurochem Int. 2026 Jan 06. pii: S0197-0186(26)00007-0. [Epub ahead of print] 106116

24-Hydroxycholesterol suppresses steroid 5α-reductase-catalyzed conversion in human glioblastoma cell lines: a novel link between brain cholesterol homeostasis and androgen metabolism.

Kjell Wikvall, Frida Olsson, Erik Wåhlén, Ananya Roy, S J Kumari A Ubhayasekera, Jonas Bergquist, Maria Norlin.

  Glioblastoma is the most aggressive primary brain tumor in adults. Androgens are reported to influence the development of glioblastoma. Dihydrotestosterone (DHT) is formed from testosterone by action of the enzyme steroid 5α-reductase and is the most potent growth-inducing androgen metabolite. 24-Hydroxycholesterol, another steroid in the brain, is pivotal for brain cholesterol homeostasis and has been suggested to influence glioblastoma cells. However, a connection between 24-hydroxycholesterol and androgen metabolism related to glioblastoma has not previously been reported. The present study reports that human T98G glioblastoma cells metabolize testosterone into DHT, 3α-androstanediol and androstenedione. The 5α-reductase pathway converted testosterone to DHT and further to 3α-androstanediol. The 17β-hydroxysteroid dehydrogenase pathway metabolized testosterone to androstenedione. Results indicated that the 5α-reductase pathway is the major pathway for testosterone metabolism in this cell line. 24-Hydroxycholesterol significantly suppressed the conversion of testosterone to DHT and 3α-androstanediol, to a similar degree as the synthetic 5α-reductase inhibitor finasteride. Suppression of DHT formation resulted in increased metabolism to androstenedione. Similar effects on DHT formation were observed with the LXR agonist T0901317 as with 24-hydroxycholesterol. In addition, 24-hydroxycholesterol suppressed DHT formation in patient-derived primary GB cell lines U3009 and U3013, indicating that the observed connection between 24-hydroxycholesterol and androgen metabolism is not unique for T98G cells. Furthermore, 24-hydroxycholesterol-mediated suppression of DHT formation was also observed in human neuroblastoma SH-SY5Y cells. To summarize, the present data provide information on androgen metabolism in glioblastoma cells and indicate a previously unknown link between cholesterol homeostasis and growth-inducing androgens in glioblastoma and potentially other cell types.

Keywords:  5α-reductase; androgen metabolism; cholesterol homeostasis; dihydrotestosterone; glioblastoma; oxysterol

DOI:  https://doi.org/10.1016/j.neuint.2026.106116
bioRxiv. 2026 Jan 04. pii: 2026.01.03.697507. [Epub ahead of print]

Single-cell map of the female brain across reproductive transitions.

Luisa Demarchi, Maria Tickerhoof, Ayyappa Kumar Sista Kameshwar, Devin Rocks, Laila Ouldibbat, Ana Milosevic, Masako Suzuki, Marija Kundakovic.

Ovarian hormone shifts enable reproduction and are associated with substantial brain plasticity and disease risks. While imaging studies provide (micro)structural insights into brain changes across the ovarian cycle and pregnancy, the high resolution, single-cell map of the brain across reproductive transitions is missing. Here, we performed multiome (gene expression and chromatin accessibility) analysis of the mouse ventral hippocampus (vHIP) across sex, estrous cycle, and peripartum period at single cell resolution. We identify dynamic changes in vHIP cellular composition across the estrous cycle and pregnancy, including in the neural stem cells of the dentate gyrus (DG), enabling hormone-driven neurogenesis. Major gene expression changes are neuronal function-relevant, cell type-specific, and found in excitatory neurons of CA1, CA3, and DG subfields, across sex and reproductive transitions. In contrast, chromatin accessibility changes are more extensive and found across cell types, likely driven by estrogen level shifts in both within-female and between-sex comparisons. We show that chromatin remodeling during the estrous cycle primes the genome for gene expression changes during pregnancy and is also enriched for brain disease-relevant genes. Finally, we reveal a thyroid hormone transporter (Transthyretin, Ttr ) gene as the major candidate gene that drives structural and behavioral changes across the estrous cycle and pregnancy. Our study provides an extensive cellular and molecular view of how reproductive transitions shape the brain and opens the possibility to target downstream targets of estrogen, including thyroid hormone signaling, as a treatment option for hormone-sensitive periods in women.

DOI: https://doi.org/10.64898/2026.01.03.697507
J Appl Physiol (1985). 2026 Jan 07.

Neonatal inflammation induces lasting sex- and region-dependent microglia activation and sex-dependent impairments in chemoreflexes.

Sarah A Beyeler, Deanna L M Plunkett, Jyoti J Watters, Adrianne G Huxtable.

  Neonatal inflammation is common and has lasting detrimental consequences for the health of the adult nervous system, including on the neural control of breathing. Our previous work demonstrated neonatal inflammation abolished adult respiratory motor plasticity; yet, the mechanisms underlying this impairment or the broader impact of neonatal inflammation on control of breathing were unknown. Since microglia are key immune cells in the brain and contribute to lasting sex-specific disruptions in non-respiratory behaviors, we hypothesized that neonatal inflammation would induce lasting sex-dependent activation of adult microglia in respiratory control regions and contribute to broader breathing impairments. In support of this hypothesis, neonatal inflammation increased adult male medullary microglia number and TNFα gene expression. In adult females, microglia number was unchanged, but neonatal inflammation increased female medullary microglial IL-6 gene expression. Surprisingly, changes in adult microglia were confined to the medulla and cortex, with no changes in ventral cervical spinal microglia, suggesting the origins of impaired respiratory motor plasticity after neonatal inflammation are likely outside the spinal cord. Neonatal inflammation also augmented adult male hypercapnic ventilatory responses (HCVR) and hypoxic ventilatory responses (HVR), and decreased sighs in females, consistent with neonatal inflammation increasing adult risks for ventilatory control disorders. Thus, lasting increases in microglia number and inflammatory gene expression likely contribute to abolished adult respiratory motor plasticity after neonatal inflammation, with distinct inflammatory mechanisms likely underlying abolishment in males and females.

Keywords:  chemoreflexes; microglia; neonatal inflammation; respiratory control; sex differences

DOI:  https://doi.org/10.1152/japplphysiol.00669.2025
Biosci Microbiota Food Health. 2026 ;45(1): 42-50

Effect of probiotic Limosilactobacillus reuteri on a serum sex-hormone- and metabolic-syndrome-related health evaluation: a single-arm open-label pilot study.

Masafumi Noda, Narandalai Danshiitsoodol, Keishi Kanno, Sayaka Yonezawa, Ryoko Ishida, Masanori Sugiyama.

  The oral administration of living Limosilactobacillus reuteri (formerly Lactobacillus reuteri) ATCC PTA 6475 cells has been shown preliminarily to prevent obesity in diet-derived obese mice and to act to ameliorate the decline in serum testosterone in old male mice. Through a clinical trial comprising a single-arm open-label pilot study in which all subjects received the same intervention, the present study aimed to evaluate whether L. reuteri ATCC PTA 6475 cells can also ameliorate the decline in serum testosterone levels in senior citizens and explore how the strain changes the intestinal microbiota. The trial was conducted with 10 eligible subjects (aged 50-69) at Hiroshima University from January to April 2024. They were instructed to take two capsules that contained a total of 1.0 × 1010 living lyophilized cells of ATCC PTA 6475 strain every day. After the 12 weeks, although remarkable changes in sex hormones were not observed, significant decreases were observed in body fat percentage, blood pressure, and some inflammation-related parameters. In addition, analysis of the fecal microbiota indicated that intake of ATCC PTA 6475 cells significantly increased the relative abundance of the genera Butyricimonas, Holdemania, and Odoribacter, which have been reported to contribute to the amelioration of obesity phenotypes. In conclusion, although the present study was carried out as a pilot study with only 10 subjects, making a placebo-controlled study necessary in the future, it demonstrates the probiotic potential of the ATCC PTA 6475 strain.

Keywords:  clinical trial; estradiol; lactic acid bacteria; microbiota; testosterone

DOI:  https://doi.org/10.12938/bmfh.2025-020
Life Sci. 2026 Jan 03. pii: S0024-3205(25)00820-3. [Epub ahead of print]387 124184

Early-life sex hormone deficiency promotes beneficial remodeling in white adipose tissue and whole-body metabolism.

Ignacio Miguel, Ana Alzamendi, Alejandro Ezequiel Harnichar, Alejandra Paula Giordano, Carolina Carla Garraza, Eduardo Julio Spinedi, Andrés Giovambattista.

   AIMS: This study investigates the impact of female sex hormone deficiency (FSHD) on white adipose tissue (WAT) development, focusing on two distinct depots: retroperitoneal adipose tissue (RPAT) and inguinal adipose tissue (IAT).
MATERIALS AND METHODS: Prepubertal ovariectomy was performed, and animals were pair-fed (FSHD-PF) to account for hyperphagia.
KEY FINDINGS: FSHD-PF animals exhibited reduced plasma triglyceride and insulin levels, with improved glucose handling. A redistribution of adipose tissue was observed, with increased IAT mass and decreased RPAT mass, accompanied by a reduction in adipocyte size in RPAT. Expression markers of inflammation, such as ob and tnf-α, were significantly decreased in RPAT of FSHD-PF, suggesting a potential reduction in the inflammatory state. Likewise, we found that prepubertal ovariectomy also modulated adipocyte precursor cells (APCs), leading to increased cd34 expression in both depots, indicative of greater competency. However, RPAT showed elevated pparγ-2 levels, while IAT exhibited increased wnt10b, suggesting a depot-specific regulation. Notably, IAT-derived APCs from FSHD-PF animals display enhanced differentiation capacity in vitro. Cold exposure further modulated WAT browning, with a notable increase in UCP-1 protein expression although observed in IAT from FSHD-PF rats only.
SIGNIFICANCE: This study is the first to examine FSHD in the context of WAT development, identifying early-life ovarian hormone loss as a critical and previously underexplored determinant of metabolic regulation. Accordingly, the consequences of early FSHD, together with its association with non-shivering thermogenesis, emerge as promising areas for further investigation with potential therapeutic relevance.

Keywords:  Adipocyte precursor cells; Adipogenesis; Female sexual hormone deficiency; Thermogenic programming; White adipose tissue

DOI:  https://doi.org/10.1016/j.lfs.2025.124184
J Anal Toxicol. 2026 Jan 06. pii: bkag002. [Epub ahead of print]

Aldehyde dehydrogenase 2 and sex influence blood acetaldehyde levels in mice, but not ethanol levels.

Mostofa Jamal, Sella Takei, Takanori Miki, Ikuko Tsukamoto, Hiroshi Kinoshita, Murase Takehiko.

  This study measured the concentrations of blood ethanol (EtOH) and acetaldehyde (AcH) in mice to examine the roles of aldehyde dehydrogenase 2 (ALDH2) and sex following intragastric administration of EtOH. The experiment utilized males and females of two mouse strains: C57BL/6N (wild-type, WT) and Aldh2-knockout (Aldh2-KO) mice. Aldh2-KO mice lack the ALDH2 enzyme, leading to the accumulation of high levels of AcH in the blood. The mice were fasted for approximately six hours before EtOH administration. EtOH (1.0, 2.0, and 3.0 g/kg) was administered intragastrically, and blood samples were collected at 30, 60, 120, 180, 240, and 300 minutes post-EtOH administration through retro-orbital puncture. The samples were then analyzed using headspace gas chromatography. The results for both male and female WT mice showed that EtOH and AcH levels increased in a dose-dependent manner, peaked at 60 min post-ingestion, and then gradually decreased. While there were no significant differences in blood EtOH concentrations between males and females, the concentrations of AcH were significantly higher in female mice than in male mice, indicating potential sex-related differences in EtOH metabolism. In Aldh2-KO mice, the EtOH and AcH levels increased initially and peaked at 30-60 minutes post-ingestion, with no significant differences in EtOH or AcH concentrations between the sexes. While the concentrations of EtOH in both male and female Aldh2-KO mice gradually decreased, the concentration of AcH remained elevated until six hours post-ingestion due to the ALDH2 deficiency inhibiting AcH oxidation. Our findings emphasize the importance of considering the influences of sex and ALDH2 when researching the effects of alcohol, particularly in relation to the EtOH byproduct AcH.

Keywords:  Acetaldehyde; EtOH; Sex; aldehyde dehydrogenase

DOI:  https://doi.org/10.1093/jat/bkag002
JACC Heart Fail. 2026 Jan;pii: S2213-1779(25)00329-4. [Epub ahead of print]14(1): 102460

"Arising" Above Heart Failure: Sex Differences in Diabetic Cardiomyopathy.

Ersilia M DeFilippis, Eileen O'Meara.



Keywords:  diabetic cardiomyopathy; heart failure; obesity; sex differences

DOI:  https://doi.org/10.1016/j.jchf.2025.03.021
Turk J Med Sci. 2025 ;55(7): 1641-1647

The effects of endocrine disruptors on the female reproductive system.

Rıza Gökhan Baykal, Reyhan Ersoy.

  Endocrine-disrupting chemicals (EDCs) are a diverse, comprehensive group of mostly synthetic chemicals that disrupt many physiological functions in humans and animals. EDCs are particularly disruptive to the female reproductive system. Reproductive function in women is a dynamic process regulated by the hypothalamic-pituitary-ovarian axis. EDCs show their effects on the reproductive system through estrogenic, antiestrogenic, androgenic, and antiandrogenic effects or by directly affecting gonadotropin-releasing hormone secretion. Disruption in the menstrual cycle, decrease in fertility, infertility, increased risk of miscarriage, polycystic ovary syndrome, endometriosis, early or delayed puberty, and hormone-sensitive cancers can be listed as the main negative effects of endocrine disruptors on the female reproductive system. In this review, findings on the effects of the most studied EDCs, bisphenol A, phthalates, methoxychlor ethane, tetrachlorodibenzo-p-dioxin, atrazine, per- and polyfluoroalkyl substances, and micro- and nanoplastics on the female reproductive system are summarized.

Keywords:  Endocrine disruptors; bisphenol A; female reproductive system; infertility; microplastics; nanoplastics

DOI:  https://doi.org/10.55730/1300-0144.6125
BMJ Open. 2026 Jan 05. 16(1): e112257

Sex-specific differences in obesity among adults in Bangladesh: a nationally representative cross-sectional study.

Md Abdur Rafi, Urby Saraf Anika, Md Golam Hossain.

   BACKGROUND: Bangladesh is facing a growing obesity epidemic; however, evidence on sex-specific patterns and socioeconomic determinants is limited.
OBJECTIVE: We aimed to investigate sex differences in obesity prevalence and to assess how socioeconomic and demographic factors influence obesity risk among adult men and women.
METHODS: We analysed data from the Bangladesh Demographic and Health Survey 2022. Prevalence of obesity (body mass index ≥25.0 kg/m²) among men and women was estimated by sociodemographic characteristics. Two multinomial logistic regression models were fitted: first, to quantify sex-specific odds of obesity with socio-demographic variables as interaction terms for effect modification; and second, adjusted sex-stratified models to assess determinants of obesity separately in men and women.
RESULTS: Overall, 30% of our participants had obesity, with women more affected than men (36% vs 20%; adjusted OR (aOR) 2.75, 95% CI 2.53 to 3.00). Interaction analyses showed attenuation of the female-male difference among those with higher education (interaction aOR 0.57, 95% CI 0.43 to 0.74), richest quintile (interaction aOR 0.63, 95% CI 0.47 to 0.83) and urban residence (interaction aOR 0.81, 95% CI 0.68 to 0.96). Obesity was positively associated with age, education, wealth and urban residence, with stronger effects in men, except for higher education (interaction aOR 0.65, 95% CI 0.47 to 0.89), richest quintile (interaction aOR 0.72, 95% CI 0.54 to 0.98) and urban residence (interaction aOR 0.84, 95% CI 0.70 to 0.98).
CONCLUSIONS: Obesity disproportionately affected women, although association with socio-demographic factors was stronger in men. Targeted sex-specific interventions that address socioeconomic and contextual determinants are needed to mitigate obesity burden in Bangladesh.

Keywords:  Body Mass Index; EPIDEMIOLOGIC STUDIES; Obesity

DOI:  https://doi.org/10.1136/bmjopen-2025-112257
Gut Microbes. 2026 Dec 31. 18(1): 2609405

The maternal microbiome influence on pregnancy success: breeding comparison of germ-free and conventionalized mice.

Chudan Xu, Simona Antonacci, Francine Z Marques.

  Germ-free (GF) animals, which are entirely devoid of all microorganisms, are one of the most powerful tools for studying the role of the microbiome in a phenotype, moving the microbiome field from association to causation. They allow the introduction of specific microbes or microbial communities to interrogate the causality of microbiomes in protecting against or contributing to a phenotype. Here, we report critical and underappreciated challenges in using GF models to investigate the intergenerational effects of maternal diet and microbiota on offspring health. Using 57 GF and littermate conventionalized GF dams, we observed unexpectedly high maternal (odds ratio 11.5, p < 0.0001) and offspring (odds ratio 4.12, p < 0.0001) mortality in GF animals. Remarkably, GF dams had an extremely low pregnancy and parturition (pmicrobiome < 0.0001) and a high incidence of cecal torsion (18.2%) compared to the conventionalized group, underscoring the indispensable role of the maternal microbiome in reproductive success and early development. Notably, even conventionalized GF mothers on high-fiber diets exhibited poor fertility, suggesting that microbial colonization timing and maternal microbial capacity to metabolize fiber are crucial. These findings not only reveal significant limitations in GF breeding protocols but also indicate that the maternal microbiota might influence offspring health far earlier than previously recognized, with implications for the developmental origins of health and disease research.

Keywords:  DOHaD; Microbiome; breeding; germ-free; intergenerational; microbiota; offspring; pregnancy

DOI:  https://doi.org/10.1080/19490976.2025.2609405
J Anim Sci. 2026 Jan 06. pii: skaf462. [Epub ahead of print]

Cooperation of luteinizing hormone and estradiol in the promotion of goat oocyte maturation via regulation and activation of the GPR30 and EGFR signaling pathways.

Baijuan Yue, Jie Liu, Sihai Lu, Meini Yu, Lele Zhu, Yaju Tang, Xiaoe Zhao, Sha Peng, Menghao Pan, Qiang Wei, Baohua Ma.

  The luteinizing hormone (LH) is well established to trigger oocyte maturation and cumulus expansion in preovulatory follicles, primarily through activating the epidermal growth factor (EGF) signaling network. While previous studies have demonstrated that activation of the G protein-coupled estrogen receptor (GPR30) accelerates meiotic resumption and first polar body extrusion in oocytes, the molecular mechanisms underlying GPR30 function in this process remain poorly defined. Here, cumulus-oocyte complexes (COCs) of goat follicles were used to investigate the interaction between the EGF network and GPR30 during oocyte maturation and ovulation. Our results showed that: LH signal was found to increase GPR30 protein levels via the EGF receptor signaling pathway (P＜0.05); Estradiol (E2) acts via GPR30 to promote ERK1/2 phosphorylation, cyclic adenosine monophosphate (cAMP) production, first polar body extrusion, and the expression of cumulus expansion-related genes in COCs (P＜0.05), and E2 further enhances these functional outcomes by increasing EGFR protein levels in cumulus cells. Collectively, these findings reveal a synergistic interaction between LH and E2 in regulating goat oocyte maturation: E2, via GPR30-mediated upregulation of EGFR, enhances COCs' responsiveness to LH-induced EGF signaling-thereby amplifying oocyte maturation efficiency and cumulus expansion. This study provides new insights into the integrated signaling network governing mammalian oocyte maturation and offers a potential molecular target for optimizing in vitro maturation (IVM) protocols for goat.

Keywords:  Epidermal growth factor receptor; Estradiol; G protein-coupled receptor 30; Goat; Luteinizing hormone; Oocyte maturation

DOI:  https://doi.org/10.1093/jas/skaf462
Med Sci Monit. 2026 Jan 08. 32 e949643

Eutopic Endometrium Immune Changes Involved in Development and Progression of Endometriosis: A Review.

Izabela Dymanowska, Karolina Frankowska, Katarzyna Cencelewicz, Aleksandra Kusaj, Patrycja Bździuch, Piotr Stachurski, Grzegorz Polak.

Numerous abnormalities of the endometriosis eutopic endometrium contribute to the initiation and development of ectopic lesions. It is also believed that among the complex causes of the disease, systemic immunological disorders play a significant role. Therefore, this literature review aims to summarize the current knowledge on immunological alterations in the endometriosis eutopic endometrium and the impact of these changes on the progression of this disease. The reviewed studies mostly indicated a pro-inflammatory immunological profile within this tissue. This was evidenced by a predominance of M1 macrophages, which have a pro-inflammatory character and elevated levels of pro-inflammatory cytokines such as interleukin-1 (IL-1) or IL-6. Additionally, an increased number of cytotoxic T lymphocytes and a positive correlation between B lymphocyte levels and the presence of endometriosis have been observed. Some changes in T cells and natural killer (NK) cells receptors, which possibly determine endometriosis development, have been described. Several studies have also revealed that patients with endometriosis exhibit reduced presence of dendritic cells in the eutopic endometrium of affected individuals, which may impair uterine cavity clearance during menstruation and contribute to ectopic lesion formation. In summary, current data indicate a pivotal role of the endometrial immune environment in disease progression, but further research is needed to drive development of immunological treatment in endometriosis management.

DOI: https://doi.org/10.12659/MSM.949643