bims-simsho 2025-11-09 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–11–09
27 papers selected by
Chun-Chi Chang, Lunds universitet

Evolving our understanding of trained immunity.
Sexually dimorphic responses in androgen metabolism and signalling in the non-human primate placenta to moderate maternal undernutrition.
Exploiting AR-Synergistic Metabolic Vulnerabilities in Prostate Cancer.
Female Sex Hormones Do Not Drive the Sex-Specific Mechanisms of Obesity-Related Hypertension.
Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan.
Enduring prenatal androgen effects on the female brain.
Beyond viral suppression: decoding the mitochondrial-immune axis in HIV-associated inflammation and immune dysfunction.
Crosstalk between decidual natural killer cells and extravillous trophoblasts at the maternal-fetal interface: current status and future perspectives.
Impact of Female Sex Hormones on the Expression of CCR5/CCR8 Co-Receptor Genes and Virus Replication in HIV-1 Infection.
Microbiome alterations in healthy pregnancy and pregnancy disorders in association with autoimmune diseases.
Placental intervillous blood harbors NK cells with distinct tissue-resident characteristics.
Fetal Bovine Serum Modulates Primary Human Cell Phenotypes, Endothelial Barrier Function, Vasculogenesis, and Angiogenesis in a Sex-Specific Manner.
FSH priming and hormonal modulation of oocyte competence in in vitro maturation for infertility treatment: a systematic review and meta-analysis.
Characterizing resistance in prostate cancer at a single cell level with hormonal treatment and epigenetic inhibitors.
Role of oxygen sensing and hypoxia-inducible factors in orchestrating innate immune responses.
Targeted and immunotherapeutic strategies for castration-resistant prostate cancer: emerging strategies, challenges, and future directions.
Characterization of distinct polycystic ovary syndrome subtypes by cluster and principal component analyses.
Sexual dimorphism in the serum metabolome following acute exhaustive exercise.
Differences in associations of follicle-stimulating hormone with lipid profiles according to oral and transdermal hormone replacement therapy in Japanese women during the menopausal transition.
Central SELENOT deficiency impairs gonadotrope axis function, sexual behavior and fertility in male and female mice.
Asian women with PCOS have enhanced ovarian reserve and ART outcomes, even at an advanced maternal age: a model for reproductive longevity?
Relationship of Body Mass Index and Dietary Inflammatory Index With Free Androgen Index and Insulin Resistance in Women With Polycystic Ovary Syndrome.
Impact of endocrine disruptors on female fertility: an update.
Estrogen depletion and immune activation and inflammation in women with HIV.
Deconvoluting the heterogeneities of immune cells at the maternal-fetal interface of mice across pregnancy.
Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer.
Gut microbiome as a potential mediator linking sexual behaviors to immune profiles in HIV-negative men who have sex with men: a multi-omics study.

Elife. 2025 Nov 05. pii: e106029. [Epub ahead of print]14

Evolving our understanding of trained immunity.

Eva Kaufmann, Yahya Sohrabi, Jorge Domínguez-Andrés, Boris Novakovic, Mihai G Netea, Jos W M van der Meer.

  The articles in this focus issue discuss progress towards a more complete understanding of memory in the innate immune system, and efforts to exploit "trained immunity" for the development of new vaccines and therapeutics.

Keywords:  epigenetic changes; immunology; immunotherapy; infectious disease; inflammation; innate immune cells; microbiology; trained immunity

DOI:  https://doi.org/10.7554/eLife.106029
Biol Sex Differ. 2025 Nov 07. 16(1): 93

Sexually dimorphic responses in androgen metabolism and signalling in the non-human primate placenta to moderate maternal undernutrition.

Ashley S Meakin, Peter W Nathanielsz, Cun Li, Vicki L Clifton, Hillary F Huber, Michael D Wiese, Janna L Morrison.

   BACKGROUND: Maternal nutrient restriction (MNR) can increase maternal androgen concentrations during pregnancy and cause placental dysfunction leading to reduced fetal growth, especially in males. Placental androgen metabolism, as well as differential expression and subcellular localisation of androgen receptor (AR) variants, modulates androgen signalling, which may benefit placental function; however, the impact of MNR on these adaptations remains undefined. We characterised the impact of MNR and fetal sex on placental androgen signalling in a non-human primate model of pregnancy.
METHODS: Pregnant baboons (Papio spp.) were randomly assigned to control diet (Ctrl; offspring female n = 5, male n = 6) or MNR diet (70% of global Ctrl; offspring female n = 5, male n = 5) at 0.16 gestation (term = ~ 180 days). Fetuses were delivered by Caesarean section at 0.9 gestation and placenta collected. Molecular measures of sex steroid signalling and placental function were quantified using established LC-MS/MS assays, Western blot, and qRT-PCR. Data were analysed using two-way ANOVA (factors: diet, sex) with Tukey's multiple comparison test.
RESULTS: CYP17A1, SRD5A1, and PGF expression was higher, whereas HSD3B1, CYP19A1, and ANGPT2 was lower in male compared to female placentae, independent of diet. KDR expression and CYP19A1 activity increased in MNR versus Ctrl in females only. Cytoplasmic expression of the antagonistic AR variant, AR-45, was higher in males, whereas MNR increased cytoplasmic and nuclear AR-45 expression independent of sex.
CONCLUSIONS: Differences in placental steroidogenic and angiogenic genes, as well as androgen metabolism and signalling, may explain sex-specific placental responses to MNR. Better understanding of molecular regulators of androgen signalling may lead to novel, targetable therapeutics that improve placental function in complicated pregnancies associated with increased androgen concentrations.

Keywords:  Androgen receptor; Androgen signalling; Baboon; Cytochrome P450; Developmental programming; Nonhuman primate; Placenta; Sex differences

DOI:  https://doi.org/10.1186/s13293-025-00771-y
Cancer Res. 2025 Nov 03. 85(21): 4045-4046

Exploiting AR-Synergistic Metabolic Vulnerabilities in Prostate Cancer.

Jonathan M Anzules, Mark Sayegh, Yun Rose Li.

Resistance to androgen deprivation therapy remains a major clinical challenge in prostate cancer, necessitating alternative therapeutic strategies. The androgen receptor (AR) plays a central role in driving resistance through mechanisms including enhanced AR signaling, DNA repair, and autophagy. In this issue of Cancer Research, Cordova and colleagues identify a metabolic vulnerability in AR protein synthesis, showing that alternate-day fasting (ADF) impairs AR translation by inducing ribosome collisions on AR mRNA. This stress response activates kinases such as p38 MAPK and selectively reduces AR protein levels, independent of transcription or protein stability. Notably, ADF enhances the efficacy of enzalutamide across multiple prostate cancer models. Unlike conventional AR-targeting approaches, ADF reveals a posttranscriptional dependency of AR expression under nutrient stress while sparing most other proteins. These findings highlight a novel translational vulnerability in prostate cancer and support combining dietary interventions with AR-targeted therapies to overcome resistance and improve patient outcomes. See related article by Cordova et al., p. 4182.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-3234
Am J Physiol Heart Circ Physiol. 2025 Nov 04.

Female Sex Hormones Do Not Drive the Sex-Specific Mechanisms of Obesity-Related Hypertension.

Candee T Barris, Taylor C Kress, Galina Antonova, Coleton R Jordan, Austin Newman, Jessica L Faulkner, Muhammad I Saeed, Simone Kennard, Eric J Belin de Chantemèle.

  The global rise in obesity parallels the increasing rates of hypertension and cardiovascular disease (CVD). These trends, and recent clinical and experimental data, have revealed that obesity abolishes the protection from CVD typically conferred by female sex, predisposing young, premenopausal women to vascular dysfunction and hypertension. Findings from our group demonstrated that, in females, obesity induces hypertension via activation of the leptin-aldosterone-mineralocorticoid receptor (MR) axis. However, the origin of this sex-specific mechanism remains unknown. Based on the known effects of estrogen on blood pressure (BP) and vascular function, we tested the contribution of sex hormones. Sham and ovariectomy surgeries (OVX) were conducted in obese female agouti yellow mice to preserve or deplete female sex hormones, respectively. OVX did not significantly alter blood pressure (BP) nor autonomic control of BP or adrenal aldosterone synthase (CYP11B2) expression; however, it impaired endothelial relaxation with no further alterations to vascular function. Chronic leptin receptor blockade decreased BP in both sham and OVX mice and restored endothelium-dependent relaxation, suggesting a lack of contribution of female sex hormones to the mechanism of hypertension. Stimulation of HAC15 and human primary adrenocortical cells with female and male sex steroid hormones did not alter CYP11B2 expression. Furthermore, quantification of CYP11B2 expression in discarded human adrenal glands revealed increases with obesity in women in comparison to men and no alterations with menopause in obese hypertensive women. Collectively, these findings support that female sex hormones do not regulate aldosterone production nor do they drive the sex-specific mechanism underlying obesity-associated hypertension.

Keywords:  Aldosterone synthase; Female sex steroids; Hypertension; Obesity; leptin

DOI:  https://doi.org/10.1152/ajpheart.00630.2025
Front Endocrinol (Lausanne). 2025 ;16 1682231

Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan.

Angel A Lee, Laura J Den Hartigh.

  The aged population, expected to double by 2050, makes up a large proportion of people living with metabolic disease. Obesity rates in the elderly are rapidly increasing, with estimates that nearly 40% of men and women over the age of 60 are classified as obese. White adipose tissue (WAT) is a highly metabolically active organ that undergoes significant changes during both obesity and aging, and metabolic dysfunction in WAT is a major cause for elevated diabetes risk. A marked difference in fat distribution is often reported between men and women. Many studies suggest that pre-menopausal women are protected from the accumulation of visceral adiposity due to gonadal estrogen, which exerts cardiometabolic benefits. Men with obesity harbor a disproportionately higher volume of intra-abdominal fat than premenopausal age-matched women with obesity, an effect that is negated by menopause as women begin to gain intra-abdominal fat. Post-menopausal women are at increased risk of developing diabetes, which can be mitigated by estrogen replacement therapy, suggesting an important role for sex steroids in diabetes risk. In addition to being highly responsive to gonadal estrogens, WAT has the capacity to convert androgens into estrogens, which may similarly impact WAT distribution and metabolism. Estrogens, comprised primarily of estrone (E1) and estradiol (E2) within WAT, are biosynthesized from circulating androgens androstenedione (A4) and testosterone (T) by aromatase (CYP19A1), which is highly expressed in human and mouse adipose tissue. In post-menopausal women, WAT becomes the predominant source of estrogen production, with age-associated increases in WAT aromatase expression that are mirrored by obesity. In contrast to ovarian estrogen production, in which E2 is the predominant estrogen type, E1 tends to be the predominant estrogen post-menopause. To date, little is known about WAT-derived estrogens and their impact on metabolic health, but emerging evidence suggests that increased E1 levels may contribute to metabolic dysfunction in aging. This review will introduce known sex differences in adipose metabolism associated with aging, obesity, and diabetes, and discuss the impact of WAT-derived sex hormones on local and systemic metabolism.

Keywords:  adipocyte; aromatase; estradiol; estrone; menopause; obesity; sex hormones; sex steroids

DOI:  https://doi.org/10.3389/fendo.2025.1682231
Brain Commun. 2025 ;7(6): fcaf396

Enduring prenatal androgen effects on the female brain.

Florian Kurth, Christian Gaser, Debra Spencer, Ajay Thankamony, Ieuan A Hughes, Helen Simpson, Umasuthan Srirangalingam, Helena Gleeson, Melissa Hines, Eileen Luders.

  Structural sex differences in the brain have been reported as early as infancy. Prenatal androgens have been hypothesized to contribute to these sex differences but the available evidence is inconclusive. Congenital adrenal hyperplasia (CAH) is a genetic variant that causes high levels of androgens during gestation in females and more male-typical behaviour after birth, whereas androgen levels and behaviour in males with CAH are largely typical. To assess whether prenatal androgens affect brain anatomy, we studied the largest CAH sample to date, matched pair-wise to a control group for sex, age, education and verbal intelligence. Anatomical sex differences were quantified using T1-weighted brain scans and a relevance-vector machine, which generated a continuous probabilistic brain sex index. Females with CAH exhibited significantly more male-like brain characteristics than control females, whereas no differences were observed between males with CAH and control males. This observed shift towards a male-typical brain anatomy in females with CAH supports the hypothesis that prenatal androgen exposure has formative effects on the human brain that persist into adulthood.

Keywords:  congenital adrenal hyperplasia; development; gender; machine learning; sex

DOI:  https://doi.org/10.1093/braincomms/fcaf396
Front Cell Infect Microbiol. 2025 ;15 1686785

Beyond viral suppression: decoding the mitochondrial-immune axis in HIV-associated inflammation and immune dysfunction.

Tracy Okine, Eleanor Hill, Kate Sheran, Talia H Swartz.

  Antiretroviral therapy (ART) has transformed HIV into a chronic, manageable condition, yet people living with HIV (PLWH) continue to experience persistent immune activation and systemic inflammation that drive long-term comorbidities, including neurocognitive impairment and cardiovascular disease. This residual inflammation requires new mechanistic explanations and targeted therapeutic approaches. Increasing evidence highlights mitochondria as central hubs in the regulation of cellular metabolism and immune responses. In PLWH, both HIV and ART disrupt mitochondrial function, leading to the release of proinflammatory mediators such as reactive oxygen species (ROS) and oxidized mitochondrial DNA (mtDNA). These signals activate the NLRP3 inflammasome, resulting in secretion of IL-1β and other cytokines. In parallel, excess mitochondrial ATP engages purinergic receptors such as P2X1 and P2X7, propagating inflammatory signaling to surrounding immune cells. This review examines the mito-immune axis in HIV, focusing on OxPhos dysregulation, inflammasome activation, and purinergic receptor signaling, and explores potential interventions-including purinergic antagonists-that aim not only to suppress viral replication but also to restore immunometabolic balance. By recognizing mitochondria as dynamic regulators of immune function, we outline a paradigm shift in HIV treatment that addresses the underlying drivers of chronic inflammation.

Keywords:  ATP; HIV; OxPhos; inflammasome; inflammation; mitochondria

DOI:  https://doi.org/10.3389/fcimb.2025.1686785
Front Immunol. 2025 ;16 1703156

Crosstalk between decidual natural killer cells and extravillous trophoblasts at the maternal-fetal interface: current status and future perspectives.

Yeqi Qiu, Mingye Chen, Rong Lin, Xiaoyan Chen, Lichun He, Hui Yin, Xian Chen.

  The immune tolerance microenvironment is essential for the establishment and maintenance of pregnancy at the maternal-fetal interface. The maternal-fetal interface is a complex system containing various cells, including decidual stromal cells, lymphocytes, and trophoblasts. Decidual natural killer cells (dNKs) are the largest leukocytes and play a critical role in maintaining maternal-fetal immune tolerance and regulating the biological behaviors of extravillous trophoblasts (EVTs). Numerous studies have investigated the crosstalk between dNKs and EVTs at the maternal-fetal interface. On the one hand, dNKs can affect the invasion and migration of EVTs. On the other hand, EVTs can influence the immunological function of dNKs and the state of the maternal-fetal immune microenvironment. This review aims to summarize the most recent advancements in comprehending the phenotypes and functions of dNKs and EVTs, as well as their dynamic interactions that are crucial for the establishment and maintenance of pregnancy. Further developments in this area will greatly enhance both basic research and clinical applications in the field of reproductive medicine.

Keywords:  decidual NK cells; extravillous trophoblasts; invasion; maternal-fetal interface; pregnancy

DOI:  https://doi.org/10.3389/fimmu.2025.1703156
Bull Exp Biol Med. 2025 Nov 04.

Impact of Female Sex Hormones on the Expression of CCR5/CCR8 Co-Receptor Genes and Virus Replication in HIV-1 Infection.

M N Nosik, E P Bystritskaya, K A Ryzhov, E V Berezhnaya, O A Lobach, I A Kiseleva, D E Kireev, A V Kuzina, E P Kostyuchenko, V E Vasileva, A A Zimina, O A Svitich.

  We studied the effects of female sex hormones estradiol and progesterone on the expression of CCR5 and CCR8 co-receptor genes (that play an important role in the HIV-1 entry into the cell) in human peripheral blood mononuclear cells (PBMC) isolated from different female donors and infected with HIV-1 subtype G. Female sex hormones produced a dose-dependent effect on the replication of HIV-1 subtype G: low doses of estradiol and high doses of progesterone significantly induced CCR8 expression in PBMC of all donors, which correlated with an increase in viral load by 1.5-1.7 times on average. The exception was one donor, in whom a high dose of estradiol also induced an increase in CCR8 expression. High concentrations of progesterone also enhanced the expression of the CCR5 co-receptor. The detected differences in the co-receptor expression in infected PBMC from different donors indicates that the host genetics may also play an important role in PBMC susceptibility to HIV infection.

Keywords:  CCR5 co-receptor; CCR8 co-receptor; HIV-1; estradiol; progesterone

DOI:  https://doi.org/10.1007/s10517-025-06512-w
Folia Microbiol (Praha). 2025 Nov 03.

Microbiome alterations in healthy pregnancy and pregnancy disorders in association with autoimmune diseases.

Fatma El-Saeed El-Demerdash, Osama A Mohammed, Hend H Mohamed, Ahmed S Doghish.

  Pregnancy induces significant alterations in the maternal microbiome, which are critical for fetal development and maternal health. Gynecological diseases, along with infertility, have increased due to excessive personal care product usage, which contains endocrine-disrupting chemicals (EDCs). Mammalian immune systems develop during pregnancy and after birth owing to crucial inputs from the environment. The growing incidence of autoimmune diseases (AIMDs) emphasizes the need to understand the environmental elements that play a role in their development, with the microbiome emerging as a key player. Exposure to EDCs with oxidative stress (OS) induces microbiome disruptions to promote AIMDs and negatively impacts female reproductive health and fetuses. Because the body changes in a number of ways to provide ideal conditions for fetal growth, pregnancy is a special moment in a woman's life. All microorganisms undergo changes, and their quantity and composition vary over the three trimesters of pregnancy. Recent research suggests a connection between pregnancy issues and the microorganisms present during pregnancy. This review explores the pivotal role of the human microbiome in pregnancy health, emphasizing how microbiome dynamics influence immune development and long-term immunity in offspring. It examines the impact of environmental factors, particularly EDCs, on maternal microbiota and their association with pregnancy complications such as hypertensive disorders and autoimmune diseases. The manuscript highlights current research findings and discusses potential microbiome-targeted interventions to promote maternal and fetal well-being.

Keywords:  Autoimmune diseases; Endocrine-disrupting chemicals (EDCs); Fetal health; Healthy pregnancy; Microbiome; Pregnancy disorders

DOI:  https://doi.org/10.1007/s12223-025-01369-y
Mucosal Immunol. 2025 Nov 04. pii: S1933-0219(25)00117-5. [Epub ahead of print]

Placental intervillous blood harbors NK cells with distinct tissue-resident characteristics.

Sara Vikberg, Robert Lindau, Arwen Stikvoort, Martin Solders, Laia Gorchs, Jessica Oudshoorn, Martin A Ivarsson, Johan Henriksson, Eleonor Tiblad, Sebastian Gidlöf, Helen Kaipe.

  The placental intervillous space is a unique immunological niche where circulating maternal immune cells come into direct contact with the fetal syncytiotrophoblast. While adaptations in immune cell composition are known to occur in the maternal decidua throughout pregnancy, it remains unclear whether similar changes take place in the intervillous space. Here, we demonstrate that the intervillous immune cell composition undergoes dynamic changes during pregnancy, with a decreased proportion of NK cells and an increased proportion of T cells from second trimester to term pregnancy. Interestingly, second-trimester intervillous NK cells were predominantly CD56brightCD16- with high expression of CD49a, CD103, and CD69. This phenotype more closely resembled tissue-resident decidual NK (dNK) cells than peripheral NK cells. Conditioned medium from fetal villous tissue did not induce changes in peripheral NK cell phenotype, suggesting that the observed phenotypic alterations are not driven by soluble factors from the villous microenvironment. Analysis of predicted ligand-receptor complexes suggested that NK cells may provide important growth signals to the syncytiotrophoblast. In conclusion, immunological adaptations occur in the intervillous space throughout pregnancy and the presence of dNK-like cells in the intervillous space underscores a potential role for these cells in maintaining a balanced immune environment at the maternal-fetal interface.

Keywords:  NK cells; decidua; intervillous space; maternal-fetal interface; placenta; tissue immunology

DOI:  https://doi.org/10.1016/j.mucimm.2025.11.001
Cell Mol Bioeng. 2025 Oct;18(5): 433-449

Fetal Bovine Serum Modulates Primary Human Cell Phenotypes, Endothelial Barrier Function, Vasculogenesis, and Angiogenesis in a Sex-Specific Manner.

Ashley Martier, G Wills Kpeli, Keefer Boone, Isabella R Posey, Mark J Mondrinos.

   Purpose: Sex differences in cellular biology significantly influence cell responses in culture. Yet, the sex-specific effects of culture reagents such as fetal bovine serum (FBS) remain understudied. Increased adoption of cell-based models such as microphysiological systems (MPS) as replacements for animal models demands a greater understanding sex-specific responses to common media formulations. This study examined the effects of FBS and hormone-free charcoal-stripped serum (CSS) on male (XY) and female (XX) cells in 2D and 3D MPS culture models to demonstrate profound sex-specificity in bioassays and inform the development of future sex-specific cell culture protocols and methods.
Methods: Primary human endothelial cells and fibroblasts from multiple organ sources were cultured in 2D and in 3D MPS models. Cells were cultured with either FBS or CSS. Endothelial specific gene expression, cytoskeletal spreading, and cell cycle status were analyzed in 2D culture. Vascular network formation, macromolecular leakage, and directional angiogenic sprouting were assessed in 3D MPS models.
Results: FBS promoted significant upregulation of genes associated with endothelial function in XX endothelial cells, but the same gene clusters were downregulated in XY cells. FBS increased cytoskeletal spreading and cell cycle participation of XX endothelial cells and fibroblasts relative to culture with CSS. Conversely, culture with CSS increased these 2D metrics in XY cells. Measurement of 40 kDa FITC-dextran leakage in a single vessel MPS model revealed that culture with FBS significantly decreased XX endothelial barrier permeability relative to culture with CSS. In line with 2D assays, CSS conversely enhanced XY endothelial barrier permeability relative to culture with FBS. Culture with FBS increased metrics of vasculogenesis in XX tissues relative to CSS cultures, whereas prolonged cultured in CSS supported vasculogenesis in XY models. MPS angiogenesis assays revealed increased sprouting in XX tissues cultured with FBS, while only minimal sprouting was observed in all other conditions.
Conclusions: FBS imparted significant sex-specific effects on the gene expression patterns, morphology, and cell cycle status of human endothelial cells and fibroblasts in 2D culture. Sex-specific effects measured in 2D culture assays carried over to 3D MPS assays of endothelial barrier function, vasculogenesis, and angiogenesis. Notably, FBS significantly enhanced XX cell functions relative to XY cells in all 2D and 3D MPS assays. Thus, accounting for the sex-specific effects of culture media components will be imperative to improve reproducibility and translational relevance of MPS in preclinical research.
Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-025-00860-3.

Keywords:  Endothelial cells; Fetal bovine serum; Microphysiological systems; Sex differences; Sex hormones; Tissue engineering

DOI:  https://doi.org/10.1007/s12195-025-00860-3
Front Endocrinol (Lausanne). 2025 ;16 1682277

FSH priming and hormonal modulation of oocyte competence in in vitro maturation for infertility treatment: a systematic review and meta-analysis.

Krystal Baysan Lin, Yungchen Chien, Jung-Hsiu Hou, Yen-Chen Wu, Ping Lun Lin, Li-Ting Chien, Chi-Huang Chen.

   Background: Does follicle-stimulating hormone priming improve reproductive outcomes in women undergoing in vitro maturation treatment for infertility?Follicle-stimulating hormone (FSH) is a key endocrine regulator of oocyte folliculogenesis and is crucial for granulosa-oocyte communication and cytoplasmic maturation. In vitro maturation (IVM) offers a lower risk when compared with conventional in vitro fertilization ovarian stimulation; however, widespread clinical adoption is limited by variable success rates and protocol heterogeneity. In regard to optimization strategies, FSH priming has been proposed to enhance oocyte competence, but its impact remains debatable.
Objective: To evaluate the effects of FSH priming on oocyte maturation and reproductive potential in IVM cycles for infertile women.
Methods: Employing PRISMA guidelines, we systematically searched PubMed, Cochrane Library, Embase, and Web of Science for randomized controlled trials comparing FSH-primed versus non-primed IVM cycles in infertile women. The primary outcome was oocyte maturation rate, whereas secondary outcomes included fertilization rate, cleavage rate, pregnancy rate, and implantation rate. Data pooled used random-effects models, with heterogeneity assessed by I2 statistic.
Results: Six randomized controlled trials comprising of 497 women were analyzed. FSH priming was associated with a statistically significant increase in oocyte maturation rate [OR 1.24(95% CI, 1.05-1.45)] when compared with the non-stimulated group. However, pooled analysis showed no significant differences in fertilization rate or clinical pregnancy rate between groups.
Conclusion: FSH priming has been shown to enhance oocyte maturation rate in in vitro maturation cycles. However, current evidence shows that gonadotropin does not significantly improve fertilization or pregnancy outcomes.

Keywords:  ART; FSH; IVM; gonadotropin; priming

DOI:  https://doi.org/10.3389/fendo.2025.1682277
J Pharm Pharmacol. 2025 Nov 03. pii: rgaf100. [Epub ahead of print]

Characterizing resistance in prostate cancer at a single cell level with hormonal treatment and epigenetic inhibitors.

Morgan Howells, Priyadarsini Gangadharannambiar, Calum McMullen, Francesco Crea, Wendi Bacon, Colette Christiansen.

   BACKGROUND: Late-stage prostate cancer is treated with hormonal therapy. While initially effective, development of drug resistance is common. Hypoxia, a local-environmental occurrence in tumours, is known to trigger hormone-independence and concurrent drug resistance in cancer cells.
METHODS: Here we analyse single-cell transcriptomes of LNCaP cells throughout drug treatment. These cells were exposed to chronic hypoxia and treated with Enzalutamide, a hormonal drug which inhibits the androgen receptor, both with and without Tazemetostat, an epigenetic drug that inhibits EZH2 catalytic activity, which renders Enzalutamide-resistant clones partially sensitive to hormonal therapies. We identify genes characterizing the resistant clone and assess clinical relevance.
RESULTS: We characterize a resistant cluster present with Enzalutamide treatment but not with combination therapy. The top 10 upregulated genes in this cluster included genes previously linked to resistance: DDIT3, MDM2, and CDKN1A, and one previously proposed as a pan-cancer hallmark (HSP90B1). Analysis of clinical databases showed expression of CDKN1A, POLH, and GADD54 to be significantly upregulated in association with neuroendocrine prostate cancer.
CONCLUSION: This work characterizes at a single-cell level the Enzalutamide resistant clone and the impact of epigenetic inhibitors on resistance development. This characterization may enable the identification of resistant and non-resistant cells by their gene expression profile.

Keywords:  cancer; drugs; epigenetic; genes; hormonal; resistance

DOI:  https://doi.org/10.1093/jpp/rgaf100
Nat Immunol. 2025 Nov 07.

Role of oxygen sensing and hypoxia-inducible factors in orchestrating innate immune responses.

Jie Ting Low, Youngjun Kim, Mai Matsushita, Ping-Chih Ho.

Oxygen availability and fluctuation are common changes in tissues and organs undergoing infection and damage. While acute hypoxia can rapidly alter immune cell metabolism and activity, chronic hypoxia can induce long-lasting changes in immune responses via oxygen-guided adaptation in signaling cascades and epitranscriptomic programs. These adaptations are orchestrated mainly by oxygen-sensing hydroxylases and oxygen-sensing epigenetic modifiers that regulate downstream hypoxia-inducible factor pathways and epigenetic reprogramming. In this Review, we summarize how acute and chronic hypoxia influence innate immune cell function and metabolism, thereby tailoring immune cell behavior within the tissue microenvironment. We further highlight the dual roles of hypoxia in regulating innate immune cell function in different (patho)physiological contexts and evaluate therapeutic strategies that target oxygen-sensing pathways to restore immune competence and tissue homeostasis.

DOI: https://doi.org/10.1038/s41590-025-02317-1
Front Immunol. 2025 ;16 1668188

Targeted and immunotherapeutic strategies for castration-resistant prostate cancer: emerging strategies, challenges, and future directions.

Bo Wang, Yuchu Xiang, Zitong Fang, Junjun Le, Yu Jian, ShuLian Chen, Daobing Li, Guobiao Liang, Xiaoting Pan.

  Castration-resistant prostate cancer (CRPC) represents an advanced stage of prostate cancer progression. Although the combination of androgen deprivation therapy (ADT) with chemotherapy and first generation hormone therapy is initially effective, patients ultimately develop resistance. In recent years, breakthroughs in targeted therapies and immunotherapies, along with the emergence of novel combination strategies, have provided new hope for patients with CRPC. This article systematically reviews the latest advancements in targeted and immunotherapeutic approaches for CRPC, integrating clinical data and mechanistic studies to analyze the efficacy and challenges of novel agents (e.g., second-generation AR inhibitors, PARP inhibitors, PSMA-targeted therapies) and combination regimens. It also provides insights for exploring future optimization directions.

Keywords:  castration-resistant prostate cancer; challenges; emerging strategies; future directions; immunotherapy; targetedtherapy

DOI:  https://doi.org/10.3389/fimmu.2025.1668188
Front Endocrinol (Lausanne). 2025 ;16 1572427

Characterization of distinct polycystic ovary syndrome subtypes by cluster and principal component analyses.

Kharis A Burns, Alexander W Stuckey, Scott G Wilson, Gerald F Watts, Bronwyn G A Stuckey.

   Introduction: Polycystic ovary syndrome (PCOS) is a common, but clinically heterogeneous, condition. This study explores PCOS subtypes using two orthogonal statistical analyses of biochemical and anthropometric data.
Methods: Unsupervised hierarchical cluster analysis and principal component analysis (PCA) of hormonal and metabolic parameters were performed in a cohort of PCOS-affected women, diagnosed based on the NIH criteria. Data collected included body mass index (BMI), blood pressure (BP), fasting insulin and glucose (HOMA-IR), gonadotropins, androgens, and lipids. Subtypes were explored using unsupervised hierarchical cluster analysis, grouping both phenotypic variables and patients into clusters. PCA resolved correlated variables (excluding BMI) into independent factors, and the influence of BMI on the components was then explored.
Results: One thousand and thirty-five women with PCOS were included in the study, with 975 assessed using cluster analysis and PCA. Two main clusters of variables were evident: one characterized by BP, BMI, HOMA-IR, and lipids (triglycerides/cholesterol/LDL) and the second by LH: FSH, androgens, SHBG, and HDL. Three separate patient clusters emerged: cluster A (29.6% of women) showed higher BP, BMI, HOMA-IR, and lipids (triglycerides/cholesterol/LDL) and lower LH: FSH, SHBG, and HDL. Cluster C (43.3%) showed lower BP, BMI, HOMA-IR, triglycerides, testosterone, and FAI and higher LH: FSH, DHEAS, androstenedione, 17-hydroxyprogesterone, SHBG, and HDL. Cluster B (27.1%) was intermediate. Two components aligned with the cluster analysis: principal component (PC) 1, including HOMA-IR, systolic and diastolic BP, triglycerides, LDL, FAI, and SHBG, was positively correlated with BMI (R 2= 0.32, p-value < 0.0001) and aligned with cluster A. PC2, influenced by testosterone, LH: FSH, FAI, DHEAS, androstenedione, and 17-hydroxyprogesterone, with loadings in the opposite direction from LDL and cholesterol, aligned with cluster C, with little relationship with BMI (R 2= 0.0067, p-value = 0.0107).
Discussion: Different metabolic and reproductive PCOS subtypes are evident. Androstenedione and 17-hydroxyprogesterone are important in the reproductive phenotype, highlighting the importance of these hormones in diagnosis and subtype identification and emphasizing their significance in understanding PCOS biology as a predominantly hyperandrogenic disorder. BMI influences and exacerbates the metabolic subtype; in the reproductive group and in lean/normal BMI patients, there is little relationship between weight and other PCOS-related characteristics. Accordingly, traditional treatment paradigms cannot be generalized to all women, and these subtypes may ultimately be viewed as separate disorders.

Keywords:  PCOS subtypes; body mass index; cluster analysis; insulin resistance; metabolic; polycystic ovary syndrome; principal component analysis

DOI:  https://doi.org/10.3389/fendo.2025.1572427
Biol Sex Differ. 2025 Nov 06. 16(1): 91

Sexual dimorphism in the serum metabolome following acute exhaustive exercise.

Baile Wu, Chunxue Tang, Zhongxun Ren, Jiayu Qian, Yuxiao Deng, Zihan Fan, YanYan Zhang, Lijun Shi.

BACKGROUND: Sex differences in exercise metabolism have been recognized for decades, but the molecular metabolic landscape in which men and women reach standardized physiological exhaustion criteria remains unexplored.
OBJECTIVE: We systematically characterized serum metabolic sexual dimorphism following acute exhaustive exercise using standardized termination criteria.
METHODS: In a cross-sectional study (ChiCTR2400089036), forty healthy adults (20 males, 20 females; aged 22.4 ± 3.4 years, BMI 22.4 ± 2.1 kg/m2; V̇O2peak 40.92 ± 5.69 ml/kg/min) underwent cardiopulmonary exercise testing via objective termination criteria, with female participants tested during the mid-luteal phase. Serum samples were collected at baseline, immediately post-exercise, and at 15 and 30 min post-exercise for comprehensive metabolomics and targeted triacylglycerol (TAG) analysis via mass spectrometry.
RESULTS: All participants achieved standardized exhaustion endpoints. Despite equivalent fat-free mass-normalized V̇O2peak, males expended 20% more energy per unit fat-free mass (P = 0.015). While both sexes showed similar numbers of altered metabolites (290-308), their molecular compositions differed markedly. Lipids comprised the largest fraction of sex-specific responses, with hypoxanthine, sarcosine, and lysophospholipids as key discriminators. Females showed sustained lipid downregulation while males demonstrated recoverable patterns. Notably, 37 TAGs showed sexually antagonistic regulation, and 41.7% of fitness-correlated metabolites exhibited opposite associations between sexes.
CONCLUSIONS: This study reveals distinct metabolic response patterns between males and females when standardized exhaustion endpoints are reached. Key exercise-induced sex-discriminating metabolites were identified and opposing metabolic-fitness associations were observed between sexes. These findings emphasize the necessity of sex-stratified analysis in exercise metabolism research and metabolic biomarker interpretation. While men and women respond differently to exercise, molecular differences at complete exhaustion have never been studied. We studied 20 men and 20 women who exercised to exhaustion using standardized criteria, then analyzed hundreds of blood molecules before, during, and after exercise. Although both sexes showed similar numbers of changed molecules, the specific types were remarkably different, with fat-related molecules showing the largest differences. We identified molecular markers that distinguished male from female responses, found certain fat storage molecules responded in opposite directions between sexes, and discovered that molecules like kynurenine and androsterone sulfate showed opposite fitness relationships in men versus women. These findings reveal that even at identical exhaustion levels, men and women use fundamentally different molecular strategies. By understanding these biological differences, we could develop personalized exercise and nutrition plans that work better for everyone's biology, potentially improving health outcomes and athletic performance.
HIGHLIGHTS: 1. Males and females exhibit distinct serum metabolomic profiles when they reach standardized physiological exhaustion endpoints, with similar numbers of altered metabolites but different molecular compositions. 2. Lipid species composed the largest fraction of sex-differential responses, including LPLs, bile acids, and fatty acids, showing female-dominant sustained downregulation and male-dominant recoverable downregulation patterns. 3. Targeted analysis revealed the sexually antagonistic regulation of 37 triacylglycerol species. These species are characterized primarily by C50‒C52 carbon chain lengths and enrichment with monounsaturated fatty acids, particularly those containing palmitoleic acid. 4. Key metabolites showing sex-related differential characteristics, including hypoxanthine, sarcosine, and LPLs, were identified, providing molecular markers for sex differences in exercise responses. 5. Among the 115 metabolites correlated with V̇O2peak, 41.7% exhibited opposing correlations between sexes, with L-kynurenine and androsterone sulfate as key examples, highlighting the necessity of sex-stratified analysis and the limitations of pooled approaches.

DOI: https://doi.org/10.1186/s13293-025-00780-x
J Med Invest. 2025 ;72(3.4): 290-297

Differences in associations of follicle-stimulating hormone with lipid profiles according to oral and transdermal hormone replacement therapy in Japanese women during the menopausal transition.

Takako Kawakita, Toshiyuki Yasui, Sumika Matsui, Takeshi Iwasa.

   BACKGROUND AND AIM: The associations between follicle-stimulating hormone (FSH) levels and lipid profiles have been controversial. The aim of this study was to examine the associations between FSH levels and lipid profiles before and during hormone replacement therapy (HRT) in Japanese women.
SUBJECTS AND METHODS: We recruited 117 women who were receiving HRT and examined serum levels of FSH, LH, estradiol, triglycerides (TG), LDL-C and HDL-C. In addition, the associations of reduction rate of FSH and increase in estradiol level with changes in lipid parameters before and during HRT were examined.
RESULTS: FSH showed a significant negative correlation with TG and LDL-C and a significant positive correlation with LH and HDL-C. In women receiving oral estrogen, the rate of increase in HDL-C and TG was significantly greater in the group with a large decrease in FSH. In women receiving oral estrogen, LDL-C was significantly decreased and TG was significantly increased in the group with a large increase in estradiol.
CONCLUSION: We demonstrated associations between FSH level and favorable lipid profiles in this study. During HRT, the action of reduction of FSH on lipid parameters did not exceed the direct action of estrogen. J. Med. Invest. 72 : 290-297, August, 2025.

Keywords:  HDL-C; LDL-C; follicle-stimulating hormone; hormone replacement therapy; triglycerides

DOI:  https://doi.org/10.2152/jmi.72.290
JCI Insight. 2025 Nov 06. pii: e189775. [Epub ahead of print]

Central SELENOT deficiency impairs gonadotrope axis function, sexual behavior and fertility in male and female mice.

Ben Yamine Mallouki, Loubna Boukhzar, Ludovic Dumont, Azénor Abgrall, Marjorie Gras, Agathe Prieur, David Alexandre, David Godefroy, Yves Tillet, Luca Grumolato, Nathalie Rives, Fatiha Chigr, Youssef Anouar.

  Reproductive disorders can result from a defective action of the neuropeptide gonadotropin-releasing hormone (GnRH), the master regulator of reproduction. We have previously shown that SELENOT, a newly-described thioredoxin-like selenoprotein highly expressed in endocrine and neuroendocrine cells, plays a role in hormone secretion and neuroprotection. However, whether SELENOT is involved in neuro-endocrine regulations in vivo is totally unknown. We found that SELENOT deficiency in the brain impaired sexual behavior, leading to a decline in fertility in both male and female mice. Biochemical and histological analyses of the gonadotrope axis of these mice revealed a higher expression of GnRH, which is associated with circulating luteinizing hormone (LH) excess, and elevated steroid hormones in males and a polycystic ovary syndrome (PCOS)-like phenotype in females. In addition, SELENOT deficiency impaired LH pulse secretion in both male and female mice. These alterations are reverted after administration of a GnRH antagonist. Together, our data demonstrate for the first time the role of a selenoprotein in the central control of sexual behavior and reproduction, and identify a new redox effector of GnRH neuron activity impacting both male and female reproductive function.

Keywords:  Behavior; Endocrinology; Fertility; Neuroendocrine regulation; Reproductive biology

DOI:  https://doi.org/10.1172/jci.insight.189775
Hum Reprod Open. 2025 ;2025(4): hoaf062

Asian women with PCOS have enhanced ovarian reserve and ART outcomes, even at an advanced maternal age: a model for reproductive longevity?

Qian Yang, Paula Benny, Jovin Jie Ning Lee, Devi Natalie Nadjaja, Shaili P Sashidharan, Eu-Leong Yong, Mahesh Choolani, Stephen Chew, Ling-Jun Li, Peng Cheang Wong, Zhongwei Huang.

   STUDY QUESTION: Does polycystic ovary syndrome (PCOS) represent a human model for reproductive longevity?
SUMMARY ANSWER: Asian women with PCOS have enhanced ovarian reserve and ART outcomes, even at an advanced maternal age.
WHAT IS KNOWN ALREADY: PCOS afflicts 4-20% of women at reproductive age and is associated with anovulation, hyperandrogenism, and polycystic ovarian morphology. However, there remains a paucity in research into the PCOS-related reproductive outcomes in Asian women following ART. This study addresses a critical gap in elucidating the Asian PCOS phenotype and reproductive longevity associated with PCOS, within the context of a multi-ethnic Asian population.
STUDY DESIGN SIZE DURATION: A retrospective observational cohort with a total of 3092 women from a tertiary-care centre in Singapore was analysed in this study.
PARTICIPANTS/MATERIALS SETTING METHODS: PCOS was diagnosed according to the 2003 Rotterdam Criteria. After exclusions, 1249 women were grouped into the PCOS (n = 212) or normo-ovulatory (n = 1037) groups. Clinical demographics, ART protocols, reproductive outcomes, and hormone levels were evaluated in the study. Modified Poisson Regression analyses were used to compare the ART outcomes between PCOS and normo-ovulatory groups.
MAIN RESULTS AND THE ROLE OF CHANCE: Women with PCOS exhibit elevated levels of anti-Müllerian hormone (AMH) in comparison to normo-ovulatory women. While AMH levels typically decreased with age, the decline was observed to be significantly slower in women with PCOS when compared to their normo-ovulatory counterparts. Even after the age of 36 years, women with PCOS maintained relatively higher AMH levels (PCOS vs normo-ovulatory: 44.4 vs 19.3 pmol/l). The cumulative pregnancy rate following one ovarian stimulation cycle of ART decreased with age in normo-ovulatory women after 30 years old: 46.0% for ages 31-35 and 28.6% for ages 36 and older (P < 0.001). Conversely, for women with PCOS following ART, cumulative pregnancy rates remained stable in advanced maternal age, namely 56.7% for ages 31-35 and 55.9% for ages 36 and older. Compared with the normo-ovulatory group, the adjusted relative risk (aRR) of cumulative pregnancy rates in the PCOS group was significantly higher for women aged 36 years and older undergoing ART (aRR: 1.78; 95% CI: 1.24-2.54), especially for those undergoing IVF (2.01; 1.40-3.14).
LIMITATIONS REASONS FOR CAUTION: This retrospective study included only Asian women, and hence this may not be applicable to other non-Asian populations.
WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide strong support for our hypothesis that women with PCOS may exhibit an extended reproductive life span and could attain successful pregnancy outcomes through ART, even at advanced maternal ages. These results demonstrate that women with PCOS are likely to have an enhanced reproductive lifespan and warrant further prospective longitudinal studies to unravel the mechanisms underlying the reproductive longevity observed in women with PCOS.
STUDY FUNDING/COMPETING INTERESTS: This work was funded in part by the NUS Bia-Echo Asia Centre for Reproductive Longevity and Equality. All authors declare that no competing interests exist.
TRIAL REGISTRATION NUMBER: NA.

Keywords:  ART; Asian women; anti-Müllerian hormone; human reproduction; polycystic ovary syndrome; reproductive longevity

DOI:  https://doi.org/10.1093/hropen/hoaf062
Int J Vitam Nutr Res. 2025 Oct 16. 95(5): 38965

Relationship of Body Mass Index and Dietary Inflammatory Index With Free Androgen Index and Insulin Resistance in Women With Polycystic Ovary Syndrome.

Niloufar Ghanbarzadeh, Khadije Hajizadeh, Azizeh Farshbaf-Khalili, Mahdi Mahdipour, Mahnaz Shahnazi.

   BACKGROUND: Polycystic ovary syndrome (PCOS) is a leading endocrine disorder in reproductive-aged women. While dietary interventions are widely advocated, the distinct roles of adiposity and dietary inflammation in driving PCOS phenotypes remain unclear. Therefore, this study aimed to dissect the contributions of body mass index (BMI) and dietary inflammatory index (DII) to hyperandrogenism and insulin resistance (IR) in PCOS.
METHODS: This cross-sectional study included 115 women with PCOS who visited gynecology and infertility clinics affiliated with Tabriz University of Medical Sciences. Data from the DII were computed using a validated 168-item semi-quantitative food frequency questionnaire. The free androgen index (FAI) was calculated as follows: (total testosterone (nmol/L)/SHBG (nmol/L)) × 100. The relationships between the BMI and DII and FAI, the Homeostasis model assessment of insulin resistance (HOMA-IR), the Homeostasis model assessment of β-cell function (HOMA-β), the quantitative insulin sensitivity check index (QUICKI), sex hormone binding globulin (SHBG), testosterone, fasting insulin (FI), and fasting blood sugar (FBS) were assessed using descriptive and analytical statistics. The general linear model was applied to adjust for confounders.
RESULTS: The mean (standard deviation, SD) BMI and FAI among subjects were 26.27 (3.82) kg/m2 and 1.5 ± 1.5%, respectively. The median DII (range: -3.66 (most anti-inflammatory) to 4.31 (most pro-inflammatory)) was 0.75. Significant direct relationships were observed between the BMI and FAI (p < 0.001), HOMA-IR (p = 0.008), QUICKI (p = 0.002), testosterone (p < 0.001), FI (p = 0.017), FBS (p = 0.004), and Ferriman Gallwey score (p < 0.001). No significant associations were found between DII and the aforementioned biomarkers (p > 0.05). A normal BMI was associated with a significantly lower hirsutism score (β = -3.94, p = 0.003), fasting blood sugar (β = -10.02, p < 0.001), fasting insulin (β = -4.05, p = 0.042), HOMA-β (β = -1.20, p = 0.012), QUICKI (β = -0.19, p = 0.015), testosterone (β = -0.34, p < 0.001), and free androgen index (β = -0.96, p = 0.025) compared to an obese BMI after adjusting for confounders. No significant associations were observed for DII categories (median split) across any biomarkers or hirsutism.
CONCLUSION: Adiposity (measured by BMI)-not dietary inflammation-was independently associated with key PCOS manifestations, demonstrating significant positive relationships with hyperandrogenism markers (FAI, testosterone), insulin resistance (HOMA-IR), and clinical hirsutism. A normal BMI was correlated with clinically meaningful reductions in metabolic-androgen parameters compared to obesity. Thus, weight loss and a generally healthy diet may need to be combined to impact PCOS features significantly.

Keywords:  body mass index; dietary inflammatory index; hormonal disorders; insulin resistance; life style; polycystic ovary syndrome

DOI:  https://doi.org/10.31083/IJVNR38965
Ann Med Surg (Lond). 2025 Nov;87(11): 6915-6917

Impact of endocrine disruptors on female fertility: an update.

Christian Tague, Dujardin Makeda, Hermann Yokolo, Joshua Ekouo, Léopoldine Sybile Tatsadjieu Ngoune, Jones Onesime, Styves Banga, Alimasi Kashafali, Aymar Akilimali.

  Endocrine disruptors (EDs) are a heterogeneous group of natural or synthetic chemicals capable of interfering with hormonal regulation. Widely present in plastics, cosmetics, pesticides, food packaging, and household products, they contribute to constant human exposure. Compounds such as bisphenol A, phthalates, parabens, dioxins, and certain pesticides are among the most studied. Their mechanisms of action include interaction with hormone receptors, modulation of gene expression through epigenetic changes, disruption of steroidogenesis, and interference with the hypothalamic-pituitary-gonadal axis. Evidence from animal and human studies suggests that EDs may reduce ovarian reserve, impair oocyte maturation, alter ovulation and implantation, and contribute to infertility. Associations have also been observed with polycystic ovary syndrome, endometriosis, and poorer outcomes of assisted reproductive techniques. Despite these findings, human data remain largely observational, with methodological limitations such as variable exposure assessment, lack of standardized biomarkers, and the unaddressed "cocktail effect." Strengthening preventive strategies, regulatory measures, and further research is essential to better understand and mitigate the risks EDs pose to female reproductive health.

Keywords:  endocrine disruptors; female fertility; reproduction

DOI:  https://doi.org/10.1097/MS9.0000000000003977
Curr Opin HIV AIDS. 2025 Oct 30.

Estrogen depletion and immune activation and inflammation in women with HIV.

Sarah A LaMere, Ashley F George, Nadia R Roan, Nancie M Archin, Elizabeth Hastie, Eileen Scully, Sara Gianella.

   PURPOSE OF REVIEW: As more women with HIV survive into older age, the menopausal transition has emerged as a critical yet underexplored determinant in HIV pathogenesis. Declining exposure to estrogens during menopause alters innate and adaptive immunity, driving inflammation, comorbidities, and viral persistence.
RECENT FINDINGS: Estrogen influences both innate and adaptive immune responses. Estradiol enhances plasmacytoid dendritic cell type I interferon (IFN) production through Toll-like Receptor 7 (TLR7), promotes natural killer (NK) cell activity, and tempers monocyte/macrophage activation. Menopause reverses these effects, contributing to elevated inflammatory mediators. On the adaptive side, estrogen loss increases T-cell activation and exhaustion, impairs B-cell responses, and removes estrogen receptor (ER)-mediated suppression of HIV transcription. Together, these shifts may promote stabilization or expansion of the HIV reservoir in perimenopausal women with HIV, in contrast to the gradual decay often observed in men on antiretroviral therapy (ART).
SUMMARY: Estrogen depletion during menopause reshapes immunity in women with HIV, fueling chronic inflammation, comorbidity risk, and HIV reservoir persistence. Integrating reproductive aging into HIV cure and comorbidity research, and testing hormone-based and anti-inflammatory interventions, will be essential to improve health outcomes for aging women with HIV.

Keywords:  HIV reservoir persistence; estrogen depletion; immune activation and inflammation; innate and adaptive immunity (pDCs, natural killer cells, TLR7); menopause; women with HIV

DOI:  https://doi.org/10.1097/COH.0000000000000989
Reproduction. 2025 Dec 01. pii: e250090. [Epub ahead of print]170(6):

Deconvoluting the heterogeneities of immune cells at the maternal-fetal interface of mice across pregnancy.

Jingjing Su, Yue Wang, Qian Li, Ziwei Yin, Qingbao Liu, Liangliang Yang, Xiangxiang Jiang.

   In brief: Mice often serve as valuable surrogate models for studying human reproduction. This study provides a single-cell transcriptomic profile of mouse immune cells at the maternal-fetal interface throughout pregnancy and assesses the similarities and differences between these immune cells and human decidual immune cells.
Abstract: Homeostasis of the immune microenvironment at the maternal-fetal interface is essential for pregnancy. Immune cell heterogeneity at the maternal-fetal interface in pregnant mice remains understudied. Here, we perform in-depth single-cell transcriptomic analysis with 120,238 maternal-fetal single cells of mice from embryonic day 7.5 (E7.5) to E18.5 and in vitro experiments to establish an immune cell atlas. Macrophages constitute the largest population, with some subsets resembling human counterparts, and the number of Ccr2 + macrophages in the decidua increases as pregnancy progresses. Neutrophils constitute the second largest population, and Ifit1 + N2 neutrophils are localized close to the implantation site during early pregnancy. Three NK cell subsets were identified, including the previously reported NK1.1 - subset. In combination with in vitro experiments, the presence of T and B cells within the decidua was validated. Our work profiles a comprehensive immune cell atlas of the mouse maternal-fetal interface, offering a valuable reference for further investigations.

Keywords:  NK cell; immune cell atlas; macrophage; single-cell RNA sequencing; the maternal–fetal interface of mice

DOI:  https://doi.org/10.1530/REP-25-0090
Nat Genet. 2025 Nov 05.

Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer.

Haolong Li, James E Melnyk, Becky Xu Hua Fu, Raunak Shrestha, Meng Zhang, Martin Sjöström, Siyu Feng, Jasmine A Anderson, Wanting Han, Lisa N Chesner, Hyun Jin Shin, Tatyanah Farsh, Humberto J Suarez, Seema Nath, Jonathan Chou, Rajdeep Das, Emily A Egusa, Marsha Calvert, Audrey Kishishita, Abhilash Barpanda, Jun Zhu, Ashutosh Maheshwari, William S Chen, Mohammed Alshalalfa, Aidan Winters, Junjie T Hua, Tianyi Liu, Elai Davicioni, Arun P Wiita, Bradley A Stohr, Javed Siddiqui, Bo Huang, Eric J Small, Kevan M Shokat, Peter S Nelson, David A Quigley, Elizabeth V Wasmuth, Luke A Gilbert, Felix Y Feng.

The androgen receptor (AR) is a critical driver of prostate cancer (PCa). Here, to study regulators of AR protein levels and oncogenic activity, we developed a live-cell quantitative endogenous AR fluorescent reporter. Leveraging this AR reporter, we performed genome-scale CRISPRi flow cytometry sorting screens to systematically identify genes that modulate AR protein levels. We identified and validated known AR protein regulators, including HOXB13 and GATA2, and also unexpected top hits including PTGES3-a poorly characterized gene in PCa. PTGES3 repression resulted in loss of AR protein, cell-cycle arrest and cell death in AR-driven PCa models. Clinically, analysis of PCa data demonstrates that PTGES3 expression is associated with AR-directed therapy resistance. Mechanistically, we show PTGES3 binds directly to AR, regulates AR protein stability and is necessary for AR function in the nucleus at AR target genes. PTGES3 represents a potential therapeutic target for overcoming known mechanisms of resistance to existing AR-directed therapies in PCa.

DOI: https://doi.org/10.1038/s41588-025-02388-8
Front Immunol. 2025 ;16 1659556

Gut microbiome as a potential mediator linking sexual behaviors to immune profiles in HIV-negative men who have sex with men: a multi-omics study.

Kangjie Li, Haijiao Zeng, Tian Liu, Siyan Huo, Cong Zhang, Wenlong Li, Jielian Deng, Xiaohua Zhong, Yi Tao, Bing Lin, Jiaxiu Liu, Biao Xie, Xiaoni Zhong.

   Introduction: The effects of sexual behaviors on the gut microbiome and immune system in men who have sex with men (MSM) remain unclear. Here, we conducted a multi-omics study in MSM to investigate how sexual behaviors shape gut microbiome composition and immune profiles in this population. The interplay among high-risk sexual behaviors, gut microbiome, and systemic immune activation was also explored.
Methods: HIV-negative MSM were enrolled in this study. Fecal samples were collected and subjected to 16S rRNA gene sequencing. Bulk and single-cell transcriptome sequencing of peripheral blood mononuclear cells (PBMCs) were performed to investigate the systemic immune profiles. Primary component analysis and spearman correlation analysis were used to assess the associations between gut microbiome and immune signatures. BayesPrism algorithm was applied to predict cellular composition and gene expression in individual cell types by integrating bulk RNA sequencing and sc-RNA sequencing. Causal mediation analysis evaluated the contribution of gut microbiome in linking sexual behaviors to immune outcomes.
Results: The gut microbiome of HIV-negative MSM was dominated by Segatella. Receptive anal intercourse had the most significant impact on the gut microbiome, characterized by increased diversity, depletion of Xylanibacter, and enrichment of Holdemania. We also identified altered immune gene expression, an elevated CD8:CD4 ratio, distinctive CD4+ T cell communications, and higher expression of CXCR4 in CD4+ T cells in MSM engaged in receptive anal intercourse. Mediation analysis indicated that Bilophila potentially mediated the effects of receptive anal intercourse on CD4+ T cell proportions (P = 0.026). MSM exposed to group sex and illicit drug had elevated HIV susceptibility index, possibly mediated by Bifidobacterium (P = 0.012, P = 0.02 respectively).
Conclusion: Our study indicates that gut microbiome partially mediates the immunomodulatory effects of sexual behaviors, providing mechanistic insights into HIV susceptibility. These findings underscore the gut-immune axis as a potential target for HIV prevention strategies in high-risk MSM.

Keywords:  causal mediation analysis; gut microbiome; immunology; men who have sex with men; sexual behaviors

DOI:  https://doi.org/10.3389/fimmu.2025.1659556