bims-simsho 2025-08-17 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–08–17
twenty-two papers selected by
Chun-Chi Chang, Lunds universitet

Reproductive prognosis factors in women with infertility and polycystic ovary syndrome undergoing in vitro fertilization techniques.
Understanding Sex Differences in Autoimmune Diseases: Immunologic Mechanisms.
Long-term effects of BCG vaccination on telomere length and telomerase activity.
Vaginal microbiota alterations under supraphysiological estradiol state during in vitro fertilization-embryo transfer (IVF-ET) and the association with reproductive outcomes.
Klotho-gonadal hormone crosstalk in male and female reproduction.
Anti-Müllerian hormone, sex steroids, and metabolic profile in cord blood of pregnancies with type 2 diabetes and gestational diabetes.
Effect of Intermittent Fasting on Anthropometric Measurements, Metabolic Profile, and Hormones in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.
The relationship between vaginal and endometrial microbiota and the outcome of Frozen-Thawed embryo transfer during hormone replacement cycles.
H3K27me3-mediated epigenetic regulation of TET1 in the eutopic endometrium of women with endometriosis and infertility.
Effects of Pomegranate Juice on Androgen Levels, Inflammation and Lipid Profile in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.
Targeting epigenetic effects of androgen-androgen receptor signaling in prostate cancer.
From sex hormone decrease to hormonal treatment: impacts on cardiovascular risk with ageing.
Sex and age differences on how testosterone relates to brain activity during working memory among adolescents and young adults.
Mathematical modelling of macrophage and natural killer cell immune response during early stages of peritoneal endometriosis lesion onset.
Androgens drive SLC1A5-dependent metabolic reprogramming in polycystic ovary syndrome.
Differential causal networks highlight sex-based differences in human tissues.
Unraveling mitochondrial dysfunction in polycystic ovary syndrome: Pathophysiological insights.
Epitranscriptomic regulation of immunity: The role of m6A in shaping immune response dynamics.
Menopause as a Critical Turning Point in Lipedema: The Estrogen Receptor Imbalance, Intracrine Estrogen, and Adipose Tissue Dysfunction Model.
Unravelling the molecular landscape of polycystic ovary syndrome (PCOS) and role of inflammation through transcriptomics analysis of human ovarian granulosa cells.
Transcriptome profiling of L. infantum-infected human macrophages reveals sex-specific type I interferon induction.
The relationship between serum estradiol and progesterone levels one day before frozen embryo transfer and pregnancy rates in artificially prepared frozen embryo cycles: are there any threshold serum hormone levels to predict pregnancy in luteal support by the vaginal and subcutaneous route combined?

JBRA Assist Reprod. 2025 Aug 12.

Reproductive prognosis factors in women with infertility and polycystic ovary syndrome undergoing in vitro fertilization techniques.

Margarida Pinto Ribeiro, Carolina Lemos, Carla Leal, Márcia Barreiro, António Tomé, Emídio Vale-Fernandes.

   OBJECTIVE: Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy and is often associated with elevated levels of anti-Müllerian hormone (AMH) and obesity. AMH may influence the reproductive prognosis of women undergoing in vitro fertilization (IVF). This study aims to explore fundamental reproductive characteristics and intra-cycle variables related to IVF and their association with reproductive success in women with PCOS.
METHODS: This retrospective study involved 393 women with PCOS who underwent IVF. It was designed to evaluate the relationship between AMH levels, body mass index (BMI), age, and the luteinizing hormone/follicle-stimulating hormone (LH:FSH) ratio, along with reproductive outcomes. The sample was categorized based on AMH percentiles, BMI classes, age, and LH:FSH ratio.
RESULTS: A negative correlation was observed between AMH levels and age. There were no significant differences in BMI across AMH groups, except in the very high AMH group, where women were found to be overweight. The LH:FSH ratio increased with AMH levels. Notably, women over the age of 35 with elevated AMH levels exhibited lower live birth rates (LBR) and cumulative live birth rates (CLBR) compared to their younger counterparts within the same AMH percentile range. A decrease in the fertilization rate was noted among overweight women.
CONCLUSIONS: While AMH measurement may assist in clinical decision-making, it should not be regarded as a sole predictor of IVF success. Age appears to have a more substantial impact on LBR compared to BMI. In practice, CLBR is the most informative metric to convey reproductive success to couples. Variations in results among studies could be attributed to differences in populations, sample sizes, and inconsistencies in the definitions of LBR and CLBR.

Keywords:  In vitro fertilization/intracytoplasmatic sperm injection; anti-Müllerian hormone; body mass index; infertility; polycystic ovary syndrome

DOI:  https://doi.org/10.5935/1518-0557.20250040
Int J Mol Sci. 2025 Jul 23. pii: 7101. [Epub ahead of print]26(15):

Understanding Sex Differences in Autoimmune Diseases: Immunologic Mechanisms.

Yu Rin Kim, YunJae Jung, Insug Kang, Eui-Ju Yeo.

  Autoimmune diseases such as systemic lupus erythematosus and Sjögren's syndrome show pronounced sex disparities in prevalence, severity, and clinical outcomes, with females disproportionately affected. Emerging evidence highlights sex-based differences in immune and inflammatory responses as key contributors to this bias. Genetic factors-including sex chromosomes, skewed X chromosome inactivation, and sex-biased microRNAs-as well as sex hormones and pregnancy modulate gene expression and immune cell function in a sex-specific manner. Additionally, sex hormone-dependent epigenetic modifications influence the transcription of critical immune regulators. These genetic and hormonal factors collectively shape the activation, differentiation, and effector functions of diverse immune cell types. Environmental factors-including infections, gut microbiota, environmental chemicals and pollutants, and lifestyle behaviors such as diet, smoking, UV exposure, alcohol and caffeine intake, physical activity, and circadian rhythms-further modulate immune function and autoimmune disease pathogenesis in a sex-dependent manner. Together, these mechanisms contribute to the heightened risk and distinct clinical features of autoimmunity in females. A deeper understanding of sex-biased immune regulation will facilitate the identification of novel biomarkers, enable patient stratification, and inform the development of sex-specific diagnostic and therapeutic strategies for autoimmune diseases.

Keywords:  Sjögren’s syndrome; X chromosome inactivation; autoimmune diseases; epigenetic regulation; estrogens; immune responses; inflammation; systemic lupus erythematosus

DOI:  https://doi.org/10.3390/ijms26157101
iScience. 2025 Aug 15. 28(8): 113159

Long-term effects of BCG vaccination on telomere length and telomerase activity.

Ozlem Bulut, Valerie A C M Koeken, Simone J C F M Moorlag, Charlotte J de Bree, Vera P Mourits, Gizem Kilic, Priya A Debisarun, Marijke P A Baltissen, Joost H A Martens, Jorge Domínguez-Andrés, Leo A B Joosten, Mihai G Netea.

  This study explores the effects of Bacillus Calmette-Guérin (BCG) vaccination on telomere maintenance, an aging-related process, in immune cells. While BCG reduces systemic inflammation and enhances innate immune responsiveness by inducing trained immunity, its effects on other immune aging hallmarks, such as telomere shortening, are not fully understood. We assessed telomere length in two independent human cohorts before and three months after BCG vaccination. Telomere shortening was consistently observed after BCG, but not after placebo vaccination. Trained immunity non-responders were likelier to lose telomere length, but only among males. Higher pre-vaccination testosterone levels were associated with greater telomere loss in males. In vitro, BCG training activated telomerase, particularly in females, and this was partially prevented by exogenous testosterone. These findings suggest BCG vaccination influences telomere dynamics in a sex-specific manner, contributing to understanding BCG's broader effects on aging-related processes.

Keywords:  Age; Cell biology; Immunology

DOI:  https://doi.org/10.1016/j.isci.2025.113159
BMC Microbiol. 2025 Aug 12. 25(1): 500

Vaginal microbiota alterations under supraphysiological estradiol state during in vitro fertilization-embryo transfer (IVF-ET) and the association with reproductive outcomes.

Xijing Chen, Feng Chen, Shufang Wu, Pingping Lv, Ping Li.

   BACKGROUND: The process of in vitro fertilization-embryo transfer (IVF-ET) induces a maternal supraphysiological estradiol environment during embryo implantation and early development. Estrogen is crucial in modulating the colonization of microbiota within the vaginal epithelium. However, the impact of supraphysiological estradiol levels on the vaginal microbiome and the relationship with pregnancy outcomes remains unclear.
RESULTS: The study aimed to characterize the vaginal microbiota under supraphysiological hormonal conditions. A total of 67 patients undergoing fresh embryo transfer were divided into three groups based on their peak estradiol levels: high-estradiol (HE) group (E2 > 11,000 pmol/L), median-estradiol (ME) group (E2 5,000-11,000 pmol/L), and low-estradiol (LE) group (E2 < 5,000 pmol/L). Twenty-five patients undergoing frozen-thawed embryo transfer were categorized into natural cycle (NC) group and hormone replacement cycle (HRT) group according to endometrial preparation protocols. Using 16S rRNA sequencing, we found that the vaginal microbiome exhibited variations with changes in peak estradiol levels. The elevated estradiol levels during ovarian stimulation or exogenous estrogen supplementation, significantly reduced alpha diversity, altered beta diversity within the vaginal microbiome, and shifted the vaginal community state types (CSTs) in Chinese infertile women toward Lactobacillus-dominant profiles, resembling those observed in most Asian women previously. However, the reproductive outcomes were not improved by these variations. The Streptococcus_anginosus and Akkermansia abundance correlated with estradiol levels positively, whereas Escherichia-Shigella showed a negative correlation. The abundance of Streptococcus, Atopobium, and Bifidobacterium on the day of embryo transfer may serve as predictors for adverse pregnancy outcomes, as determined by calculating the area under the curve (AUC) values.
CONCLUSIONS: Supraphysiological estradiol levels induced by IVF-ET significantly alter vaginal microbiota and shift the CSTs in Chinese infertile women toward patterns of most Asian women. The Lactobacillus dominance under supraphysiological estradiol conditions does not help improve assisted reproductive outcomes. The abundance of Streptococcus, Atopobium, and Bifidobacterium on the day of embryo transfer may serve as predictors for adverse pregnancy outcomes. Among them, Streptococcus correlates positively with peak estradiol levels and may act as a microbial mediator impairing reproductive success under hyperestrogenic conditions. However, further larger-scale researches are needed to identify and elucidate the potential mechanisms.

Keywords:  In vitro fertilization-embryo transfer (IVF-ET); Pregnancy outcomes; Supraphysiological estradiol (E2) level; Vaginal microbiome

DOI:  https://doi.org/10.1186/s12866-025-04242-7
Biol Reprod. 2025 Aug 07. pii: ioaf181. [Epub ahead of print]

Klotho-gonadal hormone crosstalk in male and female reproduction.

Farzaneh Rostamzadeh, Mahboobeh Yeganeh-Hajahmadi, Yasmin Moosavi-Saeed.

  Fertility and sexual performance are directly related to the amounts of gonadal hormones. Gonadal hormones, fertility, and sexual function decrease with age. Klotho, an age-related protein, plays a role in reproduction and sex hormone-related diseases by regulating the amount and function of gonadal hormones. Klotho is a regulator of testosterone and estrogen at both the gene expression level and posttranslational modifications. Klotho is also involved in regulating spermatogenesis, oocyte development, fertilization, and fertility by participating in FGFs pathways and FGF receptors. On the other hand, gonadal hormones regulate the expression of this protein, and disruption of the related signaling pathways causes infertility, sexual dysfunction, and other sex hormone-related diseases. Gonadal hormones also interact with Klotho in maintaining the function of different body systems and can contribute to diseases like cancer and preeclampsia. Thus, the interaction between gonadal hormones and Klotho is strong, but the areas where the mechanism remains unclear.

Keywords:  FGFs; Klotho; estrogen; progesterone; sex hormone-related diseases; testosterone

DOI:  https://doi.org/10.1093/biolre/ioaf181
Front Endocrinol (Lausanne). 2025 ;16 1589541

Anti-Müllerian hormone, sex steroids, and metabolic profile in cord blood of pregnancies with type 2 diabetes and gestational diabetes.

Claudio Villarroel, Patricia López, Soledad Henriquez, Paulina Kohen, Ethel Codner.

   Context: The prevalence of type 2 diabetes (T2D) and gestational diabetes (GD)among women of reproductive age has increased in recent decades, making it the most common pregnancy complication. Many studies have examined pregnancy complications in women with diabetes; however, the impact of diabetes on the intrauterine environment, specifically ovarian markers and metabolic profiles in very preterm infants at birth, has not been studied. This study aimed to investigate AMH, sex steroid levels, and the metabolic profile in venous cord blood (VCB) in gestations affected by type 2 diabetes (T2D) and gestational diabetes (GD).
Material and methods: Hormonal profile was evaluated in VCB of pregnancies with T2D (n=24), GD (n=26), and pregnancies without diabetes (C, n=25). Only pregnancies carrying a female offspring were included. AMH, sex steroids, and metabolic function biomarkers, including glucose, insulin, IGF-1, and adiponectin (APN) were measured. Clinical and anthropometric data were assessed in the mothers and offspring.
Results: AMH VCB levels were significantly higher in T2D than in GD and C pregnancies (P<0.01 and P<0.005, respectively). Dehydroepiandrosterone sulfate (DHEAS) and sex hormone-binding globulin (SHBG) VCB levels were lower in T2D pregnancies than in GD and C (P < 0.01, P < 0.0001, respectively). APN levels were lower in T2D pregnancies than in C (P < 0.05). Additionally, higher insulin and IGF-1 VCB levels and HOMA-IR index were observed in T2D than in C and GD (P < 0.001, P<0.05, and P<0.05, respectively). No significant correlations were observed between maternal and AMH, insulin, IGF-1, and androgen VCB levels.
Discussion: T2D disrupts the intrauterine environment, leading to increased insulin, IGF-1, HOMA-IR, and AMH concentrations and decreased adiponectin levels in VCB. These findings describe the impact that maternal T2D may have on the health and development of their offspring.

Keywords:  androgens; anti-Müllerian hormone; diabetes in pregnancy; fetal programming; insulin resistance; ovary

DOI:  https://doi.org/10.3389/fendo.2025.1589541
Nutrients. 2025 Jul 25. pii: 2436. [Epub ahead of print]17(15):

Effect of Intermittent Fasting on Anthropometric Measurements, Metabolic Profile, and Hormones in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

Yazan Ranneh, Mohammed Hamsho, Wijdan Shkorfu, Merve Terzi, Abdulmannan Fadel.

   BACKGROUND: Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder characterized by excess body weight, hyperandrogenism, hyperglycemia, and insulin resistance often resulting in hirsutism and infertility. Dietary strategies have been shown to ameliorate metabolic disturbances, hormonal imbalances, and inflammation associated with PCOS. Recent evidence indicates that intermittent fasting (IF) could effectively enhance health outcomes and regulate circadian rhythm; however, its impact on PCOS remain unclear.
OBJECTIVE: Therefore, this systematic review and meta-analysis aims to examine the effect of IF on women diagnosed with PCOS.
METHODS: Comprehensive research was conducted across three major databases including PubMed, Scopus, and Web of Science without date restrictions. Meta-analysis was performed using Cochrane Review Manager Version 5.4 software.
RESULTS: Five studies fulfilled the inclusion criteria. IF significantly reduced body weight (MD = -4.25 kg, 95% CI: -7.71, -0.79; p = 0.02), BMI (MD = -2.05 kg/m2, 95% CI: -3.26, -0.85; p = 0.0008), fasting blood glucose (FBG; MD = -2.86 mg/dL, 95% CI: -4.83, -0.89; p = 0.004), fasting blood insulin (FBI; MD = -3.17 μU/mL, 95% CI: -5.18, -1.16; p = 0.002), insulin resistance (HOMA-IR; MD = -0.94, 95% CI: -1.39, -0.50; p < 0.0001), triglycerides (TG; MD = -40.71 mg/dL, 95% CI: -61.53, -19.90; p = 0.0001), dehydroepiandrosterone sulfate (DHEA-S; MD = -33.21 μg/dL, 95% CI: -57.29, -9.13; p = 0.007), free androgen index (FAI; MD = -1.61%, 95% CI: -2.76, -0.45; p = 0.006), and C-reactive protein (CRP; MD = -2.00 mg/L, 95% CI: -3.15, -0.85; p = 0.006), while increasing sex hormone-binding globulin (SHBG; SMD = 0.50, 95% CI: 0.22, 0.77; p = 0.004). No significant changes were observed in waist-to-hip ratio (WHR), total cholesterol (TC), LDL, HDL, total testosterone (TT), or anti-Mullerian hormone (AMH).
CONCLUSIONS: IF represents a promising strategy for improving weight and metabolic, hormonal, and inflammatory profiles in women with PCOS. However, the existing evidence remains preliminary, necessitating further robust studies to substantiate these findings.

Keywords:  PCOS; hormonal profile; intermittent fasting; meta-analysis; metabolic profile; polycystic ovary syndrome; time-restricted eating

DOI:  https://doi.org/10.3390/nu17152436
BMC Microbiol. 2025 Aug 11. 25(1): 494

The relationship between vaginal and endometrial microbiota and the outcome of Frozen-Thawed embryo transfer during hormone replacement cycles.

Lili Chen, Yi Ke, Huanhuan Guo, Bingping Wu, Lan Liu.

   OBJECTIVE: To investigate whether vaginal and endometrial microbiota impact pregnancy outcomes in frozen embryo transfers (FET) during hormone replacement cycles.
METHODS: This retrospective cohort study analyzed 51 first-time FET patients from January 2021 to December 2022. Using 16 S rRNA sequencing, patients were stratified based on uterine microbiota composition into Lactobacillus-dominant (LD, 20 cases) and non-Lactobacillus-dominant (NLD, 31 cases) groups based on uterine microbiota. Vaginal (A1, A2) and uterine (B1, B2) microbiota were compared, along with pregnancy outcomes.
RESULTS: Sequencing yielded 5,753,727 valid sequences and 1,545 OTUs. Alpha diversity showed lower Shannon index (P=0.034) and higher Simpson index in B1 vs. B2 (P=0.017), indicating reduced diversity in B1. Beta diversity analysis revealed more concentrated and similar microbial composition in B1, with significant differences between B1 and B2 (Anosim R = 0.3812, P = 0.001). B1 had higher abundance of Firmicutes and Lactobacillus, while B2 had more Proteobacteria and potential pathogens. Clinical pregnancy rate (75.00%) and live birth rate (65.00%) were higher in LD compared to NLD (45.16% and 29.03%, respectively, P = 0.036 and P = 0.011).
CONCLUSION: Vaginal microbiota do not fully reflect uterine microbiota. Dominance of Lactobacillus in the uterine microbiome is beneficial for favorable FET outcomes, while the presence of non-Lactobacillus dominant species may negatively impact FET results.

Keywords:  Frozen-Thawed embryo transfer; Hormone replacement cycle; Microbiota

DOI:  https://doi.org/10.1186/s12866-025-04167-1
Sci Rep. 2025 Aug 10. 15(1): 29282

H3K27me3-mediated epigenetic regulation of TET1 in the eutopic endometrium of women with endometriosis and infertility.

Magdalena Adamczyk, Agnieszka Rawłuszko-Wieczorek, Przemysław Wirstlein, Marta Nowacka, Michał Nowicki, Paweł Piotr Jagodziński, Ewa Wender-Ożegowska, Małgorzata Kędzia.

  Endometriosis is a common gynecological condition associated with chronic inflammation, epigenetic dysregulation, and infertility. The TET1 gene, involved in DNA demethylation, may be regulated by repressive histone modifications such as H3K27me3, but its role in endometriosis remains poorly understood. This study aimed to assess H3K27me3 enrichment in the promoter region of TET1 in eutopic endometrium of infertile and fertile women with endometriosis compared to fertile controls. Endometrial biopsies were collected during laparoscopy from 25 women (18 with endometriosis, 7 controls). Chromatin immunoprecipitation (ChIP) was performed to quantify H3K27me3 levels in three promoter regions of TET1. Analyses included stratification based on ChIP efficiency and subgroup comparisons according to fertility status and menstrual cycle phase. In overall comparisons, no significant differences in H3K27me3 levels were observed between endometriosis and control groups. However, after stratification by ChIP efficiency, region 2 showed a significant difference, indicating higher H3K27me3 enrichment in endometriosis samples (p = 0.04), confirmed after correction for multiple comparisons. Analyses by fertility status and cycle phase did not reveal additional significant differences. These findings suggest potential region-specific epigenetic alterations of TET1 in endometriosis. Due to the modest sample size and inconsistent subgroup effects, results should be interpreted with caution. Larger, cell-type-specific studies are warranted to clarify the relevance of H3K27me3-mediated TET1 regulation in endometriosis-related infertility.

Keywords:  Endometriosis; Eutopic endometrium; H3K27me3; Histone modification; Infertility; TET protein

DOI:  https://doi.org/10.1038/s41598-025-13618-8
J Clin Med. 2025 Aug 03. pii: 5458. [Epub ahead of print]14(15):

Effects of Pomegranate Juice on Androgen Levels, Inflammation and Lipid Profile in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

Vitória Silveira, Pamela Braz, Antonio Jose Grande, Tamy Colonetti, Maria Laura Rodrigues Uggioni, Gabriele da Silveira Prestes, Leonardo Roever, Valdemira Santina Dagostin, Maria Inês da Rosa.

  Background/Objectives: Polycystic ovary syndrome (PCOS) is a multifactorial endocrine disorder frequently associated with metabolic and inflammatory disturbances. Due to its antioxidant and anti-inflammatory properties, pomegranate juice has been proposed as a potential adjunctive therapy in managing PCOS. To evaluate the effects of pomegranate juice on hormonal, inflammatory, and lipid parameters and body mass index (BMI) in women with PCOS. Methods: A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted following PRISMA guidelines. Comprehensive searches were performed in electronic databases including Medline, Scopus, Web of Science, Cochrane CENTRAL, and Embase from inception to July 2025, using keywords and MeSH terms related to "polycystic ovary syndrome" and "pomegranate juice" without language restrictions. The primary outcomes were changes in serum testosterone, luteinizing hormone (LH), high-sensitivity C-reactive protein (hs-CRP), lipid profile parameters (HDL, LDL, triglycerides, and total cholesterol), and body mass index (BMI). Results: Four RCTs published between 2020 and 2023, encompassing 128 women with PCOS, were included. The meta-analysis revealed significant reductions in testosterone (MD: -0.05; 95% CI: -0.07 to -0.03; p < 0.0001; I2 = 0%, two studies, 85 participants) and hs-CRP (SMD: -0.85; 95% CI: -1.35 to -0.35; p = 0.0009; I2 = 20%, two studies, 85 participants), along with increases in HDL (MD: 6.21; 95% CI: 2.43 to 10.00; p = 0.001; I2 = 0%, two studies, 85 participants) and reductions in triglycerides (MD: -23.30; 95% CI: -45.19 to -1.42; p = 0.04; I2 = 0%, two studies, 85 participants). No significant changes were observed in LH, LDL, total cholesterol, or BMI. Conclusions: Pomegranate juice demonstrates promising effects as an adjunctive intervention in women with PCOS, improving androgen levels, inflammatory markers, and certain lipid parameters. Further long-term studies are needed to confirm these findings.

Keywords:  hyperandrogenism; meta-analysis; polycystic ovary syndrome; pomegranate juice; systematic review

DOI:  https://doi.org/10.3390/jcm14155458
Vitam Horm. 2025 ;pii: S0083-6729(25)00028-7. [Epub ahead of print]129 143-183

Targeting epigenetic effects of androgen-androgen receptor signaling in prostate cancer.

Anjali Pal, Kainat, Nuzhat Bano, Pradeep Kumar Sharma.

  Prostate cancer (PCa) is a multifaceted and heterogeneous disease that affects men globally. PCa incidences and related deaths in men are a major clinical challenge that needs immediate attention to prevent, manage, or treat the disease to improve overall health in patients. Activation of androgen receptor (AR) signaling and subsequent transactivation of downstream genes play a predominant role in PCa development, progression, and metastasis. Over the last few decades, the role of epigenetics has been much appreciated in the pathogenesis of PCa. There is widespread involvement of several epigenetic changes (such as DNA modifications by methylation, histone modifications by acetylation, chromatin remodellers, and non-coding RNAs, etc.) in the regulation of PCa initiation, progression, as well as the emergence of androgen-insensitive castration-resistant PCa (CRPC) phenotype, which has improved our understanding of disease etiology. Moreover, targeting selective epigenetic marks has raised immense opportunities to target PCa, owing to the possibilities of reversal of epigenetic changes involved in the disease progression. Several epigenetic inhibitors (e.g., DNMT inhibitors, HDAC inhibitors) have been investigated in preclinical studies as well as in clinical trials to establish effective epigenetic-based therapies against PCa, and indeed, few of them have already made their way to the clinic. Epigenetics also plays a role in the reactivation of AR signaling in CRPC; though hormonal therapies are ineffective in these tumors, epigenetic inhibitors combined with other therapies are considered important in targeting CRPC. Here, we have summarized epigenetics in the regulation of AR signaling, progress in understanding epigenetics' role in etiology, and the importance of designing effective therapies for PCa, including CRPC. We have also discussed the limitations and challenges in epigenetics therapies and strategies to overcome obstacles in improving existing therapies to better manage PCa disease in clinics.

Keywords:  Androgen receptor; Androgens; Castration-resistant prostate cancer; DNA methylation; Epigenetics; Histone modifications; Prostate cancer

DOI:  https://doi.org/10.1016/bs.vh.2025.04.001
Cardiovasc Res. 2025 Aug 14. pii: cvaf086. [Epub ahead of print]

From sex hormone decrease to hormonal treatment: impacts on cardiovascular risk with ageing.

Coralie Fontaine, Anna Gosset, Morgane Davezac, Mélissa Buscato, Virginie Grouthier, Marie-Ange Renault, Daniel Henrion, Florence Trémollières, Michael Schumacher, Françoise Lenfant, Jean-François Arnal.

  Ageing plays a critical role in the deterioration of artery function and structure, and clearly represents the first cardiovascular (CV) risk factor in men but also in women. Coronary and cerebral arteries are particularly prone to atheroma, and the tissues they perfuse are particularly vulnerable to ischaemia. In both sexes, the age-related decrease in sex hormones (menopause and andropause) has deleterious effects on CV health. The extent to which hormonal supplementation can limit the CV risks increased by ageing remains controversial. The Women Health Initiative study, the main clinical intervention designed to evaluate the benefit/risk ratio of hormone treatment after menopause, revealed in 2002 an unexpected increase in CV events in aged women (>70 years) given estrogens plus a peculiar synthetic progestin medroxyprogesterone acetate, whereas estrogens alone were not harmful but even protective in younger women (<60 years). This pointed out the double problem of the progestin (now natural progesterone is preferred) and of the age. The clinical situation is not yet clear for testosterone and CV disease in men. Related to these questions, we will analyse and summarize: (i) the importance of the doses and concentrations of estrogens and testosterone, both in humans and in experimental models, allowing to define relevant/physiological or pharmacological actions of sex hormones in respect to their medical modulations in practice; (ii) the main clinical studies conducted with estrogens or androgens, in terms of CV protection and the impact of age on these effects; (iii) the mechanisms underlying these actions; (iv) the gender-affirming hormone therapy, as these sex hormones are the cornerstone of gender transition care management.

Keywords:  Ageing; Androgens; Cardiovascular disease; Estrogens; Menopause; Sex hormone

DOI:  https://doi.org/10.1093/cvr/cvaf086
Cereb Cortex. 2025 Aug 01. pii: bhaf218. [Epub ahead of print]35(8):

Sex and age differences on how testosterone relates to brain activity during working memory among adolescents and young adults.

Attakias T Mertens, Katrina Myers, Delaney Sherman, Cecile D Ladouceur, Gaelle E Doucet.

  Working memory is an important cognitive process that develops throughout early life. During adolescence, there is marked improvement in this process that is associated with structural and functional brain changes. These changes have been linked to age; however, endogenous testosterone is thought to regulate structural and functional changes in the brain during puberty, with differential influences across adolescence into early adulthood. Thus, testosterone may have a direct impact on brain activity that is modulated by age. The current study aimed to examine this using a working memory functional magnetic resonance imaging (fMRI) task in adolescents and young adults. Saliva samples collected prior to scanning were assayed for endogenous testosterone levels. One hundred and forty-five typically developing participants (74 female), aged 12-25 yr, completed a working memory fMRI task. Results showed that, for the most difficult versus the 0back conditions, younger female participants (≤19) only had more deactivation in the anterior cingulate cortex with higher level of testosterone. In contrast, male participants showed increased activation in the precentral gyrus with higher testosterone, regardless of age. These findings indicate sex differences in how endogenous testosterone relates to the activity of different brain regions recruited during working memory. Furthermore, these associations vary across typical adolescent development.

Keywords:  adolescence; development; fMRI; testosterone; working memory

DOI:  https://doi.org/10.1093/cercor/bhaf218
J R Soc Interface. 2025 Aug;22(229): 20250076

Mathematical modelling of macrophage and natural killer cell immune response during early stages of peritoneal endometriosis lesion onset.

Claire M Miller, Domenic P J Germano, Alicia M Chenoweth, Sarah Holdsworth-Carson.

  The immune system is hypothesized to contribute to the onset of endometriosis lesions. However, the precise mechanisms underlying its role are not yet known. We introduce a novel compartmental model that describes the interactions between innate immune cells, specifically macrophages and natural killer cells, and endometrial cells, occurring within the peritoneal fluid during the early stages of (superficial peritoneal) endometriosis lesion onset. Our study focuses on retrograde influx, immune detection and immune clearance. Results show an increased influx of endometrial cells into peritoneal fluid correlates with heightened pro-inflammatory macrophage activation, but does not lead to an increase in disease. We compare the system's response to changes in immune cytotoxicity and ability to detect ectopic endometrial cells. We predict that reduced cytotoxicity is a key driver of disease. These findings align with the increased immune activation observed clinically. Finally, we predict that an individual can transition to a diseased state following a reduction in immune system cytotoxicity and/or reduced ability to detect ectopic cells. Due to hysteresis, a significant improvement is then required to restore an individual to the disease-free state. This work provides a valuable framework to explore hypotheses of endometriosis lesion onset and assist in understanding of the disease.

Keywords:  computational biology; endometriosis; immune system; macrophages; mathematical biology; natural killer cells

DOI:  https://doi.org/10.1098/rsif.2025.0076
Nat Commun. 2025 Aug 15. 16(1): 7611

Androgens drive SLC1A5-dependent metabolic reprogramming in polycystic ovary syndrome.

Yishu Wang, Jiaying Wu, Gaochen Zhang, Yan Shi, Yicong Meng, Pingping Lv, Weiwei Huang, Yunfei Su, Zhiyang Zhou, Bo Wang, Xiaojun Chen, Chengliang Zhou, Jiexue Pan, Li Jin, Xiaotao Wang, Yanting Wu, Jianzhong Sheng, Xinmei Liu, Yu Zhang, Guolian Ding, Chuanjin Yu, Hefeng Huang.

Polycystic ovary syndrome is the primary cause of female infertility. Growing evidence suggests that dysregulation of amino acid metabolism plays a significant role in the onset and progression. However, the underlying mechanism remains unclear. In this study, we conduct targeted metabolite profiling of human follicular fluid and granulosa cells. A significant increase in glutamine uptake is observed in patients with hyperandrogenic polycystic ovary syndrome, mediated by the upregulation of SLC1A5, a specific glutamine transporter. We find that androgen excess primarily activates SLC1A5 expression. Furthermore, SLC1A5 overexpression in female mice induces polycystic ovary syndrome-like phenotypes, including hyperandrogenism and abnormal follicle development. Additionally, the pharmacological blockade of SLC1A5 provides reproductive benefits to mice exhibiting polycystic ovary syndrome-like symptoms. Mechanistically, we show that elevated flux of Gln-derived α-ketoglutarate enhances HDAC5 expression and suppresses acetylation on histone 3 lysine residue 14 and lysine residue 56. The reduction in acetylation level is associated with the downregulation of several genes related to folliculogenesis, including CYP19A1, thereby exacerbating androgenic homeostasis imbalance. These findings indicate that androgen-induced aberrant glutamine uptake via SLC1A5 is crucial for the development and progression of polycystic ovary syndrome, suggesting pharmacological blockade of SLC1A5 as a potential therapeutic strategy.

DOI: https://doi.org/10.1038/s41467-025-62951-z
Brief Bioinform. 2025 Jul 02. pii: bbaf407. [Epub ahead of print]26(4):

Differential causal networks highlight sex-based differences in human tissues.

Annamaria Defilippo, Kimberly Glass, Federico M Giorgi, Tamer Kahveci, Pierangelo Veltri, Pietro Hiram Guzzi.

  Sex differences appear in healthy and pathological conditions and may influence sex-specific therapeutic responses. Understanding such differences is a key activity for developing precision medicine strategies. This study investigates sex differences in gene expression across 40 human tissues by applying a Differential Causal Network (DCN) analysis using data from the Genotype-Tissue Expression project. We identified sex-based DCNs that highlight distinct molecular mechanisms influencing both health and disease in men and women. For example, in pancreas tissue, genes associated with immune system show significant differences in their regulatory patterns between sexes, demonstrating a possible different response to diseases such as diabetes mellitus and cancer. Our findings provide valuable information on the biological underpinnings of sex differences, offering potential pathways for the development of precision medicine strategies.

Keywords:  differential causal networks; gene differentiation; human tissues; sex differences

DOI:  https://doi.org/10.1093/bib/bbaf407
J Chin Med Assoc. 2025 Aug 15.

Unraveling mitochondrial dysfunction in polycystic ovary syndrome: Pathophysiological insights.

Chia-Jung Li, Li-Te Lin, Pei-Hsuan Lin, Yu-Chen Chen, Po-Wen Lin, Zhi-Hong Wen, Kuan-Hao Tsui.

  Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder that affects women of reproductive age. It is characterized by problems with ovulation, excessive levels of androgens, and the presence of multiple cysts in the ovaries. Although the exact cause of PCOS remains uncertain, recent studies have identified mitochondrial dysfunction as a key contributing factor. Mitochondria, often described as the energy centers of the cell, are essential for producing ATP, generating reactive oxygen species (ROS), and regulating cell death pathways. A growing body of evidence shows that mitochondrial dysfunction occurs in the ovaries, skeletal muscle, and fat tissue of individuals with PCOS. This dysfunction may play a central role in the development of the disorder by increasing oxidative stress and chronic inflammation, worsening insulin resistance, and interfering with the growth and quality of eggs. This review summarizes recent progress in understanding how mitochondrial dysfunction contributes to the underlying biology of PCOS. It also explores emerging treatment strategies that aim to restore mitochondrial health, such as the use of antioxidants, therapies that specifically target mitochondria, and mitochondrial replacement techniques. These approaches hold promise for reducing the symptoms and long-term complications associated with PCOS.

Keywords:  Dysfunction; Mitochondria; Pathogenesis; Polycystic ovary syndrome; Reactive oxygen species

DOI:  https://doi.org/10.1097/JCMA.0000000000001281
Cytokine. 2025 Aug 08. pii: S1043-4666(25)00158-9. [Epub ahead of print]194 157011

Epitranscriptomic regulation of immunity: The role of m6A in shaping immune response dynamics.

Devesh Srivastava, Vinayak Nayak, Srijoni Pahari, Gopu Sandeep, Ashish Misra.

  N6-methyladenosine (m6A) is the most prevalent internal modification found in eukaryotic mRNAs and plays a critical role in shaping immune response. It acts as a dynamic regulatory step modulating the splicing, stability, degradation and translation of target mRNAs involved in regulating immune outcome. These effects are mediated by the dynamic interplay of m6A methyltransferases ("writers"), demethylases ("erasers"), and binding proteins ("readers") which work in concert to fine-tune immune activation and suppression. m6A modifications modulate both innate and adaptive immune responses by regulating chemokine signaling, inflammation, and guiding the lineage commitment and function of various cells involved in immune regulation. For example, m6A-modified mRNAs encoding interferons and pro-inflammatory cytokines are translated more efficiently, facilitating a swift response to infection, while m6A-mediated degradation of pro-inflammatory transcripts offers a counterbalance, allowing immune cells to fine-tune responses and limit overactivation. In T cells, m6A readers influence antigen responsiveness and immune tolerance, while in regulatory T cells, m6A plays a key role in maintaining immune equilibrium. In this review, we present an in-depth overview of how m6A methylation shapes immune function and outline its potential as a therapeutic target. A detailed understanding of the interplay between m6A and immune regulation may provide valuable insights for developing novel therapies for immune-related diseases.

Keywords:  Adaptive immune system; Epitranscriptomics; Immune regulation; Innate immune system; m6A modification

DOI:  https://doi.org/10.1016/j.cyto.2025.157011
Int J Mol Sci. 2025 Jul 23. pii: 7074. [Epub ahead of print]26(15):

Menopause as a Critical Turning Point in Lipedema: The Estrogen Receptor Imbalance, Intracrine Estrogen, and Adipose Tissue Dysfunction Model.

Diogo Pinto da Costa Viana, Lucas Caseri Câmara, Robinson Borges Palau.

  Lipedema is a chronic, estrogen-sensitive adipose tissue disorder characterized by disproportionate subcutaneous fat accumulation, fibrosis, inflammation, and resistance to fat mobilization. Despite its high prevalence, lipedema remains poorly understood and frequently misdiagnosed. This narrative review proposes a novel pathophysiological model in which menopause acts as a critical turning point in the progression of lipedema, driven by estrogen receptor imbalance (ERβ predominance over ERα), intracrine estrogen excess, and adipose tissue dysfunction. We demonstrate how menopause amplifies adipose tissue dysfunction by suppressing ERα signaling; enhancing ERβ activity; and disrupting mitochondrial function, insulin sensitivity, and lipid oxidation. Concurrently, the upregulation of aromatase and 17β-HSD1, combined with the suppression of 17β-HSD2, sustains localized estradiol excess, perpetuating inflammation, fibrosis, and immune dysregulation. The molecular signature observed in lipedema closely mirrors that of other estrogen-driven gynecological disorders, such as endometriosis, adenomyosis, and uterine fibroids. Understanding these molecular mechanisms highlights the pivotal role of menopause as a catalyst for disease progression and provides a rationale for targeted therapeutic strategies, including hormonal modulation and metabolic interventions. This review reframes lipedema as an estrogen receptor-driven gynecological disorder, offering a new perspective to improve clinical recognition, diagnosis, and management of this neglected condition.

Keywords:  17β-hydroxysteroid dehydrogenase; ERα and Erβ; adipose tissue dysfunction; aromatase; estrogen receptors; intracrine estrogen; lipedema; menopause

DOI:  https://doi.org/10.3390/ijms26157074
Genomics Inform. 2025 Aug 11. 23(1): 18

Unravelling the molecular landscape of polycystic ovary syndrome (PCOS) and role of inflammation through transcriptomics analysis of human ovarian granulosa cells.

Kanika Mahra, Vineet Singh, Jae-Ho Shin.

   BACKGROUND: Polycystic ovary syndrome (PCOS) is a common metabolic problem in women of reproductive age that can lead to infertility and other metabolic disorders. Recent evidence indicates that inflammation might be one of the contributing factors in PCOS progression. However, there is a lack of information on the regulation of inflammatory genes in PCOS. Therefore, the aim of the study is to investigate the role of inflammation-associated genes and pathways in relation to PCOS.
METHOD: The bulk RNA-seq data of granulosa cells of human ovaries of PCOS-affected and healthy women were analyzed to evaluate the inflammatory regulation in PCOS. After quality trimming, the raw RNA-seq data were aligned to the human genome, and gene expression was quantified using featureCounts with Ensembl annotation. Further, downstream analyses of the resulting count matrix were performed in R Studio, where differentially expressed genes (DEG) were identified and CO-DEG analysis was performed.
RESULTS: The study identifies the various differentially expressed inflammatory genes in the case of PCOS such as SPI1, HSPB1, MNDA, and ITGA. These DEG are closely associated with the activation of inflammatory responses, i.e., activation of lymphocytes and leukocytes, leukocyte migration and mononuclear cell proliferation, stimulating binding of various cytokines, immunoglobulins, and chemokines. PCOS group also exhibited an increased expression of androgen-mediated genes (SPI1 and ETS transcription factors) and genes associated with hyperlipidemia and insulin resistance (TNFRSF1B). Further, KEGG pathway enrichment analysis revealed significant upregulation of various pathways (autophagy, endocytosis) in the PCOS group. In addition, network analysis (cnetplot) of the top 10 KEGG GSEA pathways also highlights the key pathways in the PCOS group such as SNARE complex assembly pathway, SNAP-25, nucleophagy, and regulation of mast cell activation.
CONCLUSION: Therefore, the study highlights that inflammation is a major effector in PCOS, which also fuels obesity, an independent effector that further worsens the PCOS condition. In addition, the genes related to hyperandrogenism, hyperlipidemia, and insulin resistance were also overexpressed in PCOS, exacerbating the condition.

Keywords:  Granulosa cells; Inflammation; Obesity; PCOS; RNA-seq

DOI:  https://doi.org/10.1186/s44342-025-00051-6
PLoS Pathog. 2025 Aug 12. 21(8): e1013427

Transcriptome profiling of L. infantum-infected human macrophages reveals sex-specific type I interferon induction.

Annika Bea, Helena Fehling, Fabian Hausmann, Fahten Margot Habib, Melanie Lütkemeyer, Lara Buer, Carola Schäfer, Charlotte Sophie Hansen, Barbara Honecker, Stefan Bonn, Bianca Elisabeth Schneider, Joachim Clos, Hanna Lotter.

Sex-based differences in the immune system influence the clinical course of infectious diseases, including many parasitic infections. Field studies of human infections and controlled experimental rodent models have shown that certain clinical forms of leishmaniasis occur more frequently in males. Leishmania parasites infect and proliferate in innate immune cells, particularly macrophages, and modulate early immune responses that constrain their survival and replication. In this study, we used a high-throughput in vitro system to assess sex differences in human macrophage-specific immunity to Leishmania (L.) infantum infection. Quantification of infection showed significantly higher infection rates and parasite loads in macrophages derived from men compared to those from women up to 76 hours post-infection (hpi). Evaluation of the macrophage phenotype during L. infantum infection revealed only minor changes in the proportions of primarily proinflammatory M1-like macrophages, whereas a reduction in the anti-inflammatory M2-like phenotype was observed in both sexes. Cytokine profiling revealed elevated levels of TNF, IL-8, IL-10, and reduced levels of IL-18 and CCL2 in culture supernatants over the time of infection. Transcriptomic analysis showed the highest adaptation of gene expression at 6 hpi, which was more pronounced in female-derived macrophages (1428 down-regulated/2145 up-regulated genes) compared to male-derived macrophages (972 down-regulated/1637 up-regulated genes), and gradually decreased over time in both sexes. Genes associated with type I interferon responses (e.g., IFIT2, IFIT3, IFIT5, OASL, JAK1), specific cytokine response (IL-15, IL-1R1), and the matrix metalloproteinase MMP9 were up-regulated in female macrophages, while genes encoding proinflammatory chemokines involved in immune cell recruitment (CXCL1, CXCL3, CCL20, CCL7) were up-regulated in male macrophages. Treatment of infected macrophages with estradiol conferred marginal resistance to infection in female-derived macrophages, whereas testosterone treatment had no effect. In summary, our findings reveal immune mediators and underscore a biological sex difference that may explain females' superior ability to combat Leishmania infections.

DOI: https://doi.org/10.1371/journal.ppat.1013427
J Turk Ger Gynecol Assoc. 2025 Aug 13.

The relationship between serum estradiol and progesterone levels one day before frozen embryo transfer and pregnancy rates in artificially prepared frozen embryo cycles: are there any threshold serum hormone levels to predict pregnancy in luteal support by the vaginal and subcutaneous route combined?

Levent Dikbaş, Michael H Dahan.

   Objective: To investigate the potential influence of serum estradiol (E2) and progesterone (P4) levels, measured one day before artificially prepared frozen embryo transfer (FET), on pregnancy rates in women who received combined vaginal and injectable P4.
Material and Methods: This retrospective cohort study analyzed the association between serum E2 and P4 levels on the day before FET in 167 cases prepared with hormone replacement therapy between February 2022 and October 2023. The primary outcomes assessed were the pregnancy and live birth rates. We modeled a cut-off serum value based on luteal support for pregnancy. Luteal support was through a combination of vaginal suppositories and subcutaneous injections. Multivariate logistic regression was used to test relationships between pregnancy outcomes and independent variables. Cut-off values were evaluated using receiver operating characteristic (ROC) analysis and percentile analysis.
Results: No significant relationships were found between serum E2 or P4 levels on the day before FET and pregnancy rates. The mean E2 level was 169.0±51.9 pg/mL for individuals who achieved conception and 177.7±56.9 pg/mL for individuals who did not conceive (p=0.45). The corresponding values for P4 were 28.1±18.4 ng/mL and 31.2±25.4 ng/mL, respectively (p=0.73). No differences were observed in body mass index (BMI) or endometrial thickness between the groups. Cut-off values for predicting pregnancy using E2 and P4 could not be determined using ROCs. However, no one in the lowest 10th percentile of serum P4 levels conceived (range 10.0-15.6 ng/mL). When multivariate logistic regression was used, this finding lost significance suggesting that low serum levels are related to age, BMI, and/or other factors.
Conclusion: In artificially prepared FET cycles, the serum E2 and P4 levels one day before embryo transfer do not significantly affect pregnancy rates in women with serum E2 levels between 150-300 pg/mL and P4 between 10-40 ng/mL when ROC was used for evaluation. However, percentile analysis suggests that serum P4 levels should be more than 15.6 ng/mL when combined injectable and vaginal P4 is used for programed FET. Although this finding may be due to the confounding effects of age, BMI, and other factors affecting steroid metabolism, when controlled for in the multivariate logistic regression.

Keywords:  Estradiol; frozen embryo transfer; pregnancy; progesterone

DOI:  https://doi.org/10.4274/jtgga.galenos.2025.2025-1-13