bims-simsho Biomed News
on Systems immunology and sex hormones
Issue of 2025–07–06
seventeen papers selected by
Chun-Chi Chang, Lunds universitet
  1. The Impact of Microbiota-Mediated Immune Regulation on Recurrent Pregnancy Loss and Intervention Strategies.
  2. Vaginal microbiome and recurrent pregnancy loss.
  3. The Effect of Immunotherapy on Natural Killer Cells Level/Activity in Recurrent Pregnancy Loss (RPL) Patients: A Systematic Review and Meta-Analysis.
  4. Female fertility and pregnancy in autoimmune Addison's disease - a mini review.
  5. Comparative Analysis of Afamin, Asprosin, and Pentraxin 3 Levels in Women with PCOS and Women with Unexplained Infertility.
  6. IL-24 producing regulatory T and B lymphocytes in endometriosis.
  7. Ovarian endometriosis negatively impacts pregnancy outcomes in young infertile women undergoing IVF/ICSI treatment.
  8. Innate Immunity and Tertiary Lymphoid Structures.
  9. Association of hyperuricemia with higher miscarriage rates and lower live birth rates in women undergoing IVF/ICSI.
  10. From glucose to histone modification: sex-specific metabolic responses to ketogenic therapy in VM/Dk mice.
  11. Expression patterns of estrogen and androgen receptors in NSCLC patients according to the PD-L1 profile.
  12. Endometrial stromal Menin supports endometrial receptivity by maintaining homeostasis of WNT signaling pathway through H3K4me3 during WOI.
  13. Advancing prostate cancer treatment: the role of fecal microbiota transplantation as an adjuvant therapy.
  14. Shorter ovarian stimulation is detrimental to fresh embryo transfer outcomes in PCOS women undergoing GnRH antagonist protocol: a retrospective cohort study.
  15. Male sex reversal syndrome: a disorder of sexual differentiation (DSD) with infertility.
  16. Cellular distribution of estrogen receptors alpha in the rabbit ovary during pregnancy and lactation.
  17. Using twin data to examine heritable and intrauterine hormonal influences on transgender and gender diverse identities.
  1. Am J Reprod Immunol. 2025 Jul;94(1): e70121
    The Impact of Microbiota-Mediated Immune Regulation on Recurrent Pregnancy Loss and Intervention Strategies.
    Yao Yao, Yiqing Ye, Caihong Zheng.
      Recurrent pregnancy loss (RPL) significantly affects reproductive health in couples of childbearing age. Its pathogenesis is complex, with nearly 50% of cases remaining unexplained, and immune regulation plays a key role in its development. This review focuses on the relationship between human microbiota (gut, reproductive tract, and endometrial microbiota), immune regulation, and RPL, systematically summarizing related research progress. RPL patients exhibit characteristic changes in the gut, reproductive tract, and endometrial microbiota, such as reduced gut microbial diversity, decreased beneficial bacteria, increased harmful bacteria in the reproductive tract, and an imbalanced endometrial microbiota structure. Dysbiosis can lead to immune regulation abnormalities, increasing the risk of RPL by disrupting immune tolerance, triggering inflammatory responses, and interfering with metabolism. Although microbiota-based interventions, such as probiotics, prebiotics, and fecal microbiota transplantation, show potential, they face challenges related to strain selection, donor screening, and unclear mechanisms. Current research also faces limitations in detection technology and sample size, and the understanding of the microbiota-immune-RPL relationship requires further deepening. Future studies should clarify causal relationships using advanced technologies, develop more effective detection and intervention methods, and create personalized treatment plans based on individual patient characteristics to improve clinical diagnosis and treatment of RPL and safeguard women's reproductive health.
    Keywords:  dysbiosis; endometrial microbiota; gut microbiota; immune regulation; intervention strategies; recurrent pregnancy loss; reproductive tract microbiota
    DOI:  https://doi.org/10.1111/aji.70121
  2. Infect Immun. 2025 Jun 30. e0005325
    Vaginal microbiome and recurrent pregnancy loss.
    Xingxing Yuan, Jiawei Gao, Ousman Bajinka, Xiaoling Feng.
      The joy of every mother is to survive a healthy pregnancy and give birth to a healthy baby. However, until today, many couples are finding it difficult to welcome a baby. Among the factors that cause infertility and recurrent pregnancy loss (RPL) is the microbiome composition that inhabits the vaginal space. These microbiomes occupying the vaginal space play a role in balancing acids, pH, and metabolites to ensure a healthy vaginal environment that can prevent pregnancy loss. What is even more evident is that these microbiomes, when dominated by Lactobacillus spp., prevent the growth of vaginal pathogens and reduce the risk of developing drug resistance. Although there is compelling evidence centered on the vaginal microbiome in promoting a healthy vagina, RPL is attributed to their altered or reduced Lactobacillus spp. While there are discrepancies in the literature, this review aimed to summarize the recent findings on vaginal microbiome and RPL. In addition, this mini review further revealed vaginal microbiota as biomarkers that can predict a healthy vagina and the risk of vaginal microbiome causing RPL. In addition, the immune response and metabolite changes in vaginal microbiome-related RPL, as well as some limitations to this intervention and prospective studies, are summarized.
    Keywords:  immune response; lactobacilli; metabolites; recurrent pregnancy loss; vaginal microbiome
    DOI:  https://doi.org/10.1128/iai.00053-25
  3. Am J Reprod Immunol. 2025 Jul;94(1): e70118
    The Effect of Immunotherapy on Natural Killer Cells Level/Activity in Recurrent Pregnancy Loss (RPL) Patients: A Systematic Review and Meta-Analysis.
    Huan Xiao, Feng Zhang, Yulian Wu, Ruochun Lian, Lianghui Diao, Tailang Yin, Chunyu Huang.
      Some studies have demonstrated that high level of natural killer (NK) cells or NK cytotoxicity was associated with unexplained recurrent pregnancy loss (RPL) and can serve as predictive indicator for subsequent miscarriage in RPL patients. This suggests that reducing the level or activity of NK cells may represent a potential therapeutic strategy. However, there remains controversy regarding the efficacy of current immunotherapies employed in clinical practice for modulating the number and function of NK cells in RPL patients. Consequently, this study aimed to systematically review and assess the impact of various immunotherapies on NK cells in RPL patients, as well as the effectiveness of improving pregnancy outcomes in RPL patients with abnormal NK cells level/activity. This systematic review and meta-analysis was conducted following the PRISMA guidelines and recommendations of the Cochrane Collaboration. A comprehensive search was conducted on PubMed, Web of Science, EMBASE, and the Cochrane Library to identify relevant studies on immunotherapy in patients with RPL up to September 2023. Meta-analyses were used to assess the impact of immunotherapy on NK cells level and activity in RPL patients. Narrative synthesis was conducted to evaluate the effect of immunotherapies on pregnancy outcomes in RPL patients with abnormal NK cells level/activity. Risk-of-bias was assessed using ROBINS-I. A random-effects model or a fixed-effects model was selected according to the heterogeneity test, and standard mean differences (SMDs), risk ratio (RR) and 95% confidence interval (95% CI) were calculated. A total of 17 studies were included in this analysis. The meta-analysis revealed that in the general population of patients with RPL, intravenous immunoglobulin (IVIg) led to a reduction in peripheral natural killer (pNK) cells level (SMD: -0.85, 95% CI: -1.41 to -0.28), lymphocyte immunotherapy (LIT) decreased pNK cell activity, and intralipid reduced both pNK cells level (SMD: -0.32, 95% CI: -0.64 to -0.01) and activity (SMD: -0.74, 95% CI: -1.06 to -0.42). The narrative synthesis illustrated the regulatory impact of immunotherapy on diverse immune cells and cytokines in RPL patients. Furthermore, IVIg and intralipid therapy could potentially enhance live birth rates in RPL patients specifically characterized by elevated pNK cells level. For RPL patients with elevated uterine NK (uNK) levels, cyclosporin A may ameliorate pregnancy outcomes, while prednisolone does not appear to have the same effect. Nevertheless, these findings should be approached with caution given the current insufficiency of evidence. Limited evidence indicated that IVIg, LIT, and intralipid reduce pNK cells level/activity in RPL patients. RPL patients with elevated NK levels may be benefit from immunotherapy, but not all immunotherapies were effective. However, interpretation of these results with caution is strongly advised due to the limited number of high-quality evidence.
    Keywords:  immunotherapy; meta‐analysis; natural killer cell; pregnancy outcomes; recurrent pregnancy loss
    DOI:  https://doi.org/10.1111/aji.70118
  4. Front Endocrinol (Lausanne). 2025 ;16 1510815
    Female fertility and pregnancy in autoimmune Addison's disease - a mini review.
    Liam O'Murchadha, Agnieszka Pazderska.
      Autoimmune Addison's Disease (AAD) is by far the most common cause of primary adrenal insufficiency in developed countries, occurring more commonly in women compared with men. The condition is associated with a spectrum of disorders affecting fertility and reproductive health. Premature ovarian insufficiency (POI) is a clinical condition defined by cessation of menstrual cycles and menopausal range gonadotrophins before the age of 40 years. This occurs with a prevalence of 1-2% in the general population, but has been estimated at 6-10% for women with AAD. One registry study demonstrated that one-third of those with AAD who develop POI, do so before the age of thirty. The onset of POI precedes or is contemporaneous with the diagnosis of AAD in the majority. It has also been demonstrated that women with AAD are more likely to use hormone replacement therapy. The pathophysiology of POI in this cohort is thought to be primarily through autoimmune mediated inflammation of the ovarian theca cells. In particular, cross-reacting autoantibodies to steroid-producing cells (StCA) have been identified which are present in AAD and POI. That said, when women with POI are excluded, fertility remains significantly reduced. Impaired adrenal androgenesis and resulting sex-hormone deficiency have also been implicated in subfertility in AAD. These lead to suboptimal follicular development. This, in turn, may also affect libido. Despite physiological glucocorticoid replacement therapy, patients with AAD consistently report reduced quality of life compared to matched controls. These factors may affect fecundity and likelihood of conception. Other autoimmune conditions such as hypothyroidism and type 1 diabetes occur with increased prevalence in those with AAD. These conditions have been shown to independently affect reproductive health. This review focuses on the current understanding of the factors and mechanisms impacting fertility in women with autoimmune Addison's disease.
    Keywords:  Addison disease; STCA; autoimmune diseases; fertility; pregnancy; premature ovarian insufficiency
    DOI:  https://doi.org/10.3389/fendo.2025.1510815
  5. Med Sci Monit. 2025 Jul 04. 31 e947895
    Comparative Analysis of Afamin, Asprosin, and Pentraxin 3 Levels in Women with PCOS and Women with Unexplained Infertility.
    Mehmet Kursat Derici, Engin Yıldırım.
      BACKGROUND Infertility is defined as the absence of pregnancy despite unprotected, regular sexual intercourse of couples of reproductive age for at least 1 year. Infertility may be unexplained or linked to anovulation/polycystic ovary syndrome (PCOS). PCOS can involve the processes of inflammation, insulin resistance, and metabolic syndrome. This study compared serum levels of afamin, asprosin, and pentraxin3 (PTX3) between women with PCOS and women with unexplained infertility to elucidate underlying pathophysiological mechanisms. MATERIAL AND METHODS Our study included 106 women: 55 with unexplained infertility and 51 with PCOS. Using the electrochemiluminescence immunoassay method, we assessed the levels of estradiol, follicle-stimulating hormone, luteinizing hormone, and anti-Mullerian hormone. Afamin, asprosin, and PTX3 levels were measured by ELISA. RESULTS Age, fasting glucose levels, and body mass index (BMI) of the groups were statistically similar. Anti-Mullerian hormone, antral follicle count, and LH levels were higher (P<0.05) in the PCOS group. Afamin and PTX3 levels were higher in the PCOS group (P<0.05), while asprosin levels were similar. CONCLUSIONS Our study demonstrates the importance of afamin associated with oxidative stress and the PTX3, which plays a role in the regulation of humoral immune responses, in the etiology of infertility cases. Afamin and PTX3 should be evaluated in ovulatory and non-ovulatory PCOS cycles to facilitate treatment and to elucidate the ovulation and implantation processes in PCOS. These recommendations specifically include dividing PCOS patients into subgroups such as diabetogenic, obese, and hirsute, and re-examining biochemical markers accordingly.
    DOI:  https://doi.org/10.12659/MSM.947895
  6. Front Immunol. 2025 ;16 1582762
    IL-24 producing regulatory T and B lymphocytes in endometriosis.
    Anna Ewa Kedzierska, Daria Lorek, Anna Slawek, Mikolaj Karmowski, Aleksandra Kalota, Jaroslaw Pajak, Agnieszka Chrobak, Krzysztof Grzymajlo, Anna Chelmonska-Soyta.
       Problem: Unbalanced production of pro- and anti-inflammatory cytokines by immune cells is a hallmark of endometriosis. IL-24, a member of the IL-10 family, is a pleiotropic cytokine produced by both non-immune cells like astrocytes, keratinocytes, pancreatic myofibroblasts, and endothelial cells and immune cells such as monocytes, macrophages, dendritic cells, NK cells, T cells (including Th2 and Th17), and B cells. However, its expression in regulatory T (Tregs) and B lymphocytes (Bregs) has not been explored. In this study, we determined the expression of IL-24 in Tregs and selected Breg subpopulations in women with endometriosis compared with healthy women.
    Methods: Percentages of Tregs, B10 cells, immature B cells, and plasmablasts that produce IL-24 were measured in the peripheral blood of women with endometriosis (n=24) and healthy women (n=24) using flow cytometry.
    Results: We observed an increased percentage of IL-24-producing Tregs in the total pool of women with endometriosis and in women with stages III and IV of endometriosis compared to controls. Within the Breg subpopulations, the percentages of IL-24-producing plasmablasts were higher in the overall endometriosis cohort as well as in women with stage IV endometriosis compared with healthy women. In contrast, the percentages of IL-24-producing immature B cells were lower in the endometriosis group than that in the control group.
    Conclusions: We have shown, for the first time, that Tregs and Bregs secrete IL-24 and that their percentages are altered in endometriosis. The significance of this cytokine secretion by regulatory cells is unclear, but we speculated that IL-24 may enhance the improper immunosuppressive activity of Tregs and plasmablasts in endometriosis, which enables the implantation and growth of endometrial lesions outside the uterus.
    Keywords:  B10; Bregs; IL-24; Tregs; endometriosis; immature B cells; plasmablasts
    DOI:  https://doi.org/10.3389/fimmu.2025.1582762
  7. Eur J Med Res. 2025 Jul 02. 30(1): 555
    Ovarian endometriosis negatively impacts pregnancy outcomes in young infertile women undergoing IVF/ICSI treatment.
    Ruihui Lu, Wenxiong Jiao, Xin Li, Cheng Zeng, Jing Shang, Qing Xue.
       BACKGROUND: This study aimed to investigate the effect of ovarian endometriosis (OE) on ovarian reserve, as well as on cumulative clinical pregnancy rates (cCPR) and cumulative live birth rates (cLBR) in groups of younger women (those under 35 years) and older women (those aged 35 years and above) who are experiencing infertility and receiving treatment through in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI).
    METHODS: This retrospective analysis included a sample of 300 women diagnosed with OE and 2956 women without the condition, all of whom initiated their first IVF or ICSI cycle between January 2016 and December 2021. Participants were divided into two age categories: younger women (under 35 years) and older women (35 years and older). To establish a comparable baseline, a propensity score matching technique was utilized in a 1:1 ratio, considering age, body mass index, and duration of infertility to align women with OE against those without it. Both univariate and multivariate logistic regression analyses were applied to identify factors that influence cLBR. Furthermore, the ability of anti-Müllerian hormone (AMH) levels to predict cLBR was evaluated through receiver operating characteristic (ROC) curve analysis. Spearman's correlation was employed to examine the associations between age and AMH levels, as well as the relationship between cyst size and AMH levels.
    RESULTS: Women diagnosed with OE exhibited a significantly lower ovarian reserve, as indicated by reduced levels of AMH and a decreased antral follicle count, compared to those without the condition (P < 0.05). Within the younger age group, women with OE showed substantially lower cCPR and cLBR than their counterparts without OE (62.8% vs. 75.4%, P = 0.010; 56.1% vs. 67.6%, P = 0.025). In contrast, among older women, no significant differences in cCPR and cLBR were noted between those with OE and those without. Among younger women with OE, logistic regression analysis identified age, AMH levels, and the number of top-quality embryos as independent predictors of cLBR. ROC curve analysis determined an optimal AMH threshold of 1.835 ng/ml for predicting cLBR, with a sensitivity of 50.6% and specificity of 82.2%. AMH levels showed no correlation with age, but exhibited a negative correlation with cyst size. In contrast, among older women (≥ 35 years) with OE, AMH levels displayed a negative correlation with age but no significant association with cyst size.
    CONCLUSIONS: OE negatively impacts pregnancy outcomes in younger women, with AMH serving as an independent factor influencing cLBR.
    Keywords:  Age; Anti-Mullerian hormone; Cumulative live birth rate; Cumulative pregnancy rate; Endometriosis
    DOI:  https://doi.org/10.1186/s40001-025-02816-9
  8. Immunol Rev. 2025 Jul;332(1): e70052
    Innate Immunity and Tertiary Lymphoid Structures.
    Ruibo Zhao, Daxing Gao.
      Tertiary lymphoid structures (TLSs) are ectopic lymphoid tissues that form in response to chronic inflammation, such as in autoimmune diseases or cancer. Their presence has been increasingly recognized as a significant factor in determining patient prognosis and response to cancer treatments. The formation and development of TLSs are intricately linked to inflammatory cytokines and chemokines, which can be induced by the innate immune system. The innate immune system serves as the body's first line of defense against pathogens by producing cytokines and chemokines upon the detection of foreign invaders. The interplay between innate immunity and TLSs is multifaceted and involves various components and mechanisms. Here, we focus on three key aspects. First, the involvement of specific innate immune cell types in TLS dynamics; second, the role of innate immune receptors in TLS formation; lastly, the contributions of innate immune effectors to TLS formation and maintenance. By examining these interconnected aspects, we can gain a comprehensive understanding of how innate immunity regulates the formation and function of TLSs in the context of chronic inflammation and cancer. This knowledge not only enhances our understanding of immune responses but also holds potential for developing novel therapeutic strategies targeting TLSs in various pathological conditions.
    Keywords:  chemokines; cytokines; inflammation; innate immunity; pattern recognition receptors; tertiary lymphoid structures
    DOI:  https://doi.org/10.1111/imr.70052
  9. J Ovarian Res. 2025 Jul 03. 18(1): 142
    Association of hyperuricemia with higher miscarriage rates and lower live birth rates in women undergoing IVF/ICSI.
    Ling Zhou, Jiahuan Luo, Shuhua Zhao, Longda Wang, Meng Rao, Huawei Wang, Li Tang.
       BACKGROUND: Hyperuricemia (HUA) has become popular globally, being an important risk factor for various metabolic diseases. Elevated serum uric acid (UA) levels cause adverse reproductive outcomes in women with polycystic ovary syndrome undergoing assisted reproductive technology (ART). However, its impact on reproductive outcomes in the general population is unknown.
    METHOD: This retrospective study was conducted on a general population of infertility patients at a single center (March 2016-April 2023). Overall, 2189 first transfer cycles were screened for inclusion. HUA was defined as serum UA ≥ 360 µmol/L. Variables identified by LASSO regression analysis were entered into logistic regression models to calculate odds ratios. Generalized additive models were employed to examine the nonlinear relationship between serum UA as a continuous variable with outcomes. The primary outcome was live birth rate (LBR).
    RESULTS: Baseline characteristics revealed that HUA patients presented with significantly elevated metabolic parameters, including higher BMI, fasting glucose, lipid profiles, and greater prevalence of polycystic ovarian syndrome. Patients with HUA demonstrated significantly lower LBR and fertilization rates, along with higher miscarriage rates, while no significant differences were observed in oocyte retrieval numbers, embryo utilization rates, high-quality cleavage embryo formation, blastocyst formation rates, or clinical pregnancy rates (CPR). After adjusting for confounding variables, HUA remained a significant factor affecting LBR and miscarriage rate. Notably, the detrimental effects of HUA exhibited modality-specific patterns, with frozen-thawed embryo transfer (FET) cycles demonstrating greater vulnerability to HUA than fresh transfers. Among younger women, HUA independently predicted reduced LBR and increased miscarriage risk, with no significant association observed in those ≥ 35 years. And this effect remained significant in normal-weight (< 24 kg/m2) women but not in overweight individuals.
    CONCLUSION: Elevated UA levels are linked to lower LBR and higher miscarriage risk in ART, especially in younger, non-obese women where HUA is an independent risk factor. Though not affecting embryo quality or implantation, HUA may impair pregnancy maintenance. Even in older or overweight patients, UA monitoring remains important. Routine assessment and tailored management-particularly greater attention to pregnancy loss and cautious use of programmed FET in poorly controlled cases-may help improve ART outcomes.
    Keywords:  Assisted reproduction technology; Hyperuricemia; Live birth; Miscarriage
    DOI:  https://doi.org/10.1186/s13048-025-01720-4
  10. Front Nutr. 2025 ;12 1554743
    From glucose to histone modification: sex-specific metabolic responses to ketogenic therapy in VM/Dk mice.
    Sara E Moss, Angela M Poff, Apryl Moss, Janine M DeBlasi, Dominic P D'Agostino.
       Introduction: The assessment of sex-specific effects in pre-clinical models is critical for improving the translatability of findings to clinical applications. However, preclinical studies often combine sexes or focus exclusively on one sex, including research utilizing syngeneic cancer models. Considering sex differences is particularly important in metabolic studies, as males and females exhibit distinct body compositions, hormone profiles, and metabolic demands.
    Methods: This study evaluates sex-specific metabolic responses to ketogenic therapies in VM/Dk mice, including assessments of glucose metabolism, ketone metabolism, and histone modifications linked to metabolism.
    Results: Our findings reveal significant sex differences in body weight, circulating metabolites, blood insulin levels, and histone modification profiles.
    Discussion: We demonstrate that male and female VM/Dk mice respond differently to ketogenic therapies, with responses varying based on the specific type of therapy applied.
    Keywords:  epigenetic; exogenous ketones; insulin; ketone metabolic therapy; metabolic therapy
    DOI:  https://doi.org/10.3389/fnut.2025.1554743
  11. Front Immunol. 2025 ;16 1602579
    Expression patterns of estrogen and androgen receptors in NSCLC patients according to the PD-L1 profile.
    Vianey Rodriguez-Lara, Gala Cortés-Ramírez, Itzel Amayrani Angeles-Torres, Jeronimo Rodriguez-Cid, Sally María Luisa Pedraza-Reyes, Maria Rosa Avila-Costa, José Luis Ordoñez-Librado, Marco Cerbón.
       Background: Lung cancer is the leading cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) being the most common type. Immunotherapy targeting programmed death ligand-1 (PD-L1) blockade has significantly improved survival, but differences in responses by sex have been reported, suggesting a possible role of sex hormones. Estrogens and androgens, through their receptors support lung carcinogenesis, but their role in immune evasion via the PD-1/PD-L1 pathway remains poorly understood.
    Materials and Methods: We analyzed by immunohistochemistry the expression patterns of estrogen receptors (ERα and ERβ) and androgen receptor (AR) in 95 PD-L1-positive (PD-L1+) and 72 PD-L1 negative (PD-L1-) NSCLC patients by sex and hormonal status. We also investigated associations between hormonal receptors, PD-L1 profile, PD-L1 tumor proportion score (TPS), and clinical features (cancer stage according to the TNM stage of cancer, smoking history, wood smoke exposure, and asbestos exposure).
    Results: ERβ was the predominant form of estrogen receptor in PD-L1- patients, while ERα expression was significantly higher in PD-L1+ patients and strongly associated with the PD-L1+ profile, regardless of sex or hormonal status. AR expression was low across all groups and showed no association with PD-L1. Among PD-L1+ patients, ERα expression levels were highest in premenopausal women, followed by men and postmenopausal women. ERα levels in the PD-L1+ group, were not associated with PD-L1 TPS or with clinical features.
    Conclusion: The estrogen pathway, particularly via ERα, plays a key role in PD-L1 expression and may contribute to tumor immune evasion. Antiestrogen therapy could represent a promising strategy to enhance immunotherapy efficacy in patients expressing ERs.
    Keywords:  NSCLC; PD-L1; androgen receptor; estrogen receptor; immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2025.1602579
  12. Commun Biol. 2025 Jul 04. 8(1): 995
    Endometrial stromal Menin supports endometrial receptivity by maintaining homeostasis of WNT signaling pathway through H3K4me3 during WOI.
    Xin Xu, Yichen Han, Keer Jin, Weina Xu, Huanyu Zhang, Yana Ma, Xiangjuan Li, Haibin Wang, Mengying Liu, Xiaona Lin.
      Dysregulated endometrial receptivity is a well-established critical factor that contributes to recurrent implantation failure (RIF). Decidualization of stromal cells and differentiation of epithelial cells in the endometrium are crucial processes for achieving endometrial receptivity. Menin, the unique subunit of the H3K4 methyltransferase complex, exhibits cell-specific effects on gene expression through chromatin modification by histone 3 lysine 4 trimethylation (H3K4me3). We have previously reported the significant role of Menin-regulated modifications in H3K4me3 in the maintenance of early pregnancy in mice. However, the physiological function of Menin and its interaction with H3K4me3 in regulating human endometrial receptivity remain poorly understood. Here, we report that Menin expression is reduced in the endometrial stroma of RIF patients. Stromal Menin deficiency not only impairs the decidualization of stromal cells but also negatively impacts the differentiation of epithelial cells through HAND2-FGFs-FGFR axis. Transcriptome analysis reveals that MEN1 knockdown in stromal cells induces the aberrant activation of the WNT signaling pathway, and in vivo experiments show it is associated with a significant reduction in the weight of implantation sites. Mechanistically, Menin deficiency suppresses the expression of SFRP2 and DKK1, which are negative regulators of the WNT signaling pathway, through H3K4me3. In summary, our study identifies Menin as a critical regulator of endometrium receptivity, advances our understanding of its molecular mechanisms, and highlights its potential role in the pathogenesis of RIF.
    DOI:  https://doi.org/10.1038/s42003-025-08434-9
  13. Curr Res Microb Sci. 2025 ;9 100420
    Advancing prostate cancer treatment: the role of fecal microbiota transplantation as an adjuvant therapy.
    Rasoul Ebrahimi, Shahrzad Shahrokhi Nejad, Mehra Fekri, Seyed Aria Nejadghaderi.
      Prostate cancer (PCa) is a major cause of cancer-related deaths worldwide. While current treatments such as surveillance, surgery, and radiation are effective, they have their limitations. These can include patient incompliance due to side effects or resistance to hormonal changes, highlighting the need for alternative approaches. Human microbiota, a complex and dynamic host, plays a significant role in the homeostasis and is associated with several diseases or cancers in cases of dysregulation and dysbiosis. Research on fecal microbiota profiling and its association with certain cancers has opened new possibilities for preventing and managing tumor progression. One such possibility is fecal microbial transplantation (FMT). Studies show that different composition of urinary microbiota is found in various urinary tract diseases. Gut microbiota can regulate immune response against tumors; therefore, FMT may help modulate gut microbiota in a way that potentially enhances responses to immune checkpoint inhibitors, as suggested by emerging evidence in other cancers, though this needs further validation in PCa. Nevertheless, long-term complications and the safety of FMT are still questioned. We reviewed the roles of gut microbiota in PCa and suggested FMT as a potential tool in the treatment of PCa, which needs further investigations.
    Keywords:  Dysbiosis; Fecal microbiota transplantation; Gastrointestinal microbiome; Microbiota; Prostatic neoplasms
    DOI:  https://doi.org/10.1016/j.crmicr.2025.100420
  14. Sci Rep. 2025 Jul 01. 15(1): 21002
    Shorter ovarian stimulation is detrimental to fresh embryo transfer outcomes in PCOS women undergoing GnRH antagonist protocol: a retrospective cohort study.
    Shan Xiao, Su Liu, Ling Hong, Zhiqiang Liu, Rui Jia, Hongzhan Zhang, Meilan Mo, TuRui Yang.
      Polycystic ovary syndrome (PCOS) is a common endocrine disorder with dysfunctional ovulation affecting female fertility. The purpose of this study was to determine the association between gonadotropin (Gn) duration and in vitro fertilization (IVF) outcomes in PCOS women undergoing GnRH antagonist treatment. Retrospective cohort study at a large private fertility practice. Patients with PCOS undergoing the GnRHantagonist treatment between January 1, 2017, and July 31, 2021 were included. Patients were classified into two groups depending on their Gn duration, ≤ 8 days (n = 501) and >8 days (n = 1326). After propensity score matching (PSM), there were 87 PCOS women with Gn duration ≤ 8 days and 137 PCOS women with Gn duration >8 days in the fresh embryo transfer cycle. The primary outcomes measures included the clinical pregnancy, ongoing pregnancy, early miscarriage and live birth rate between the two groups after fresh embryo transfer. In addition, the embryo quality was also evaluated. There was no significant difference in baseline characteristics between groups. However, the total Gn dosage was lower in PCOS women in the ≤ 8 days group. In addition, the oocytes retrieved and D3 high quality embryos were compared between groups. However, the number of 2PN embryos was decreased in the group with Gn duration ≤ 8 days. The clinical pregnancy and live birth rate were significantly decreased in the ≤ 8 days group in fresh embryo transfer (52.87% vs. % 68.61%, 43.68% vs. 59.12%). After logistic regression, PCOS women with Gn duration ≤ 8 days were associated with poor clinical pregnancy and live birth rate. PCOS women with shorter Gn duration (≤ 8 days) were not associated with impaired embryo outcomes except for 2PN embryos in GnRH antagonist protocol. However, the shorter Gn stimulation was detrimental to clinical pregnancy outcomes in fresh embryo transfer cycle.
    Keywords:  GnRHantagonist; In vitro fertilization; Ovarian stimulation; PCOS; Pregnancy outcomes
    DOI:  https://doi.org/10.1038/s41598-025-06217-0
  15. BMJ Case Rep. 2025 Jul 03. pii: e265767. [Epub ahead of print]18(7):
    Male sex reversal syndrome: a disorder of sexual differentiation (DSD) with infertility.
    Namita Bellad, Radha Vembu, Monna Pandurangi, N Sanjeeva Reddy.
      46,XX male sex reversal syndrome is a rare genetic disorder where individuals with a 46,XX karyotype present with male phenotypic characteristics despite the absence of an Y chromosome. We report a case of a male in his early 30s, presenting with infertility and azoospermia, with bilateral small testes, but no other sexual dysfunction or any signs of hypovirulisation. His hormonal evaluation revealed hypogonadism with normal gonadotropin levels. Genetic testing showed a 46,XX karyotype with the presence of the sex-determining region on the Y chromosome (SRY) gene and microdeletions in the azoospermia factor region, confirming the diagnosis of SRY-positive 46,XX male sex reversal syndrome. As sperm retrieval was not recommended, the couple pursued donor insemination, resulting in conception during the first cycle. The female partner is now in her third trimester of pregnancy. Testosterone replacement therapy was initiated for hypogonadism, and long-term follow-up was recommended for monitoring therapy and neoplastic risk. This case intends to provide an overview focused on improving diagnostic and management strategies for 46,XX male sex reversal syndrome, emphasising the necessity of genetic evaluation for all patients with hypogonadism and azoospermia presenting with infertility, not limited to those with hypergonadotropic hypogonadism. It also highlights the critical role of a multidisciplinary approach in the effective management of this condition.
    Keywords:  Genetic screening / counselling; Reproductive medicine
    DOI:  https://doi.org/10.1136/bcr-2025-265767
  16. Sci Rep. 2025 Jul 02. 15(1): 23159
    Cellular distribution of estrogen receptors alpha in the rabbit ovary during pregnancy and lactation.
    Mahmoud Abd-Elkareem, Sulaiman Mohammed Alnasser, Alotaibi Meshal, Mohsen A Khormi, Mohammed A Alfattah.
      Pregnancy and lactation is a critical period for rabbit production. Estrogen (E2) and estrogen receptors alpha (ERA) are essential during pregnancy and lactation and their importance stems from their role in ovarian activities. Despite extensive research into the roles of E2 and its receptors in the ovary, cellular distribution of ERA in the rabbit ovary during pregnancy, after parturition and during lactation remained unexpectedly elusive. To achieve this aim, eighteen healthy sexually mature New Zealand white rabbit does (2.97 ± 0.2 kg) were raised in the animal house, faculty of medicine, Assiut University. The females rabbit were mated by fertile bucks; the day of mating as was considered Day 0 of pregnancy. Ovaries were collected at 12 h, 3, 7, 14 days post-mating, at parturition and at 10 days of lactation and fixed then processed for immunohistochemistry of ERA. In the present study, the cellular distribution of ERA in the rabbit ovary during pregnancy, postpartum and during lactation revealed moderate ERA immunolocalization in the ovarian surface epithelial cells, stroma cells, fibroblast cells of the tunica albuginea, and follicular cells of the primordial and primary follicles. The growing and small antral follicles showed strong cytoplasmic and nuclear ERA immunolocalization in the granulosa cells and theca folliculi cells. The large antral (graafian) and pre-ovulatory follicles showed moderate to strong ERA immunolocalization in the granulosa cells, corona radiata cells, cumulus oopherous cells, oocyte, theca interna cells and theca externa cells. The atretic antral follicle showed strong cytoplasmic and negative nuclear ERA immunolocalization in the apoptotic granulosa cells and strong cytoplasmic and nuclear ERA immunolocalization in the proliferated theca interna cells. The endothelial cells of the ovarian blood vessels, the interstitial gland cells and telocytes showed strong cytoplasmic and nuclear ERA immunolocalization. The corpus luteum (CL) during pregnancy till parturition showed moderate to strong ERA immunolocalization in the large lutein cells, small lutein cells and luteal endothelial cells. The regressed CL in the rabbit ovary 10 days of lactation showed weak ERA immunolocalization in the regressed large lutein cells and moderate cytoplasmic and negative nuclear ERA immunolocalization in the small lutein cells. Interestingly, the rabbit ovary during lactation showed abundant interstitial gland with strong ERA immunolocalization in the interstitial gland cells. This work highlights the role of ERA in the ovulation, folliculogenesis, lutenization and luteal regression in the rabbit during pregnancy and lactation which contribute to enhancing this animal's reproductive success.
    Keywords:  CL; ERA; Follicles; Immunolocalization; Ovary; Rabbit
    DOI:  https://doi.org/10.1038/s41598-025-99582-9
  17. Sci Rep. 2025 Jul 01. 15(1): 21680
    Using twin data to examine heritable and intrauterine hormonal influences on transgender and gender diverse identities.
    Will Conabere, Anja Ravine, Sue Malta, Louise Bourchier, Fintan Harte, John L Hopper, Ken C Pang.
      Previous reports have suggested genetic and prenatal hormonal contributions to gender diversity, albeit using small datasets. To further examine this issue, we recruited 27 twin pairs from two Australian specialist gender clinics, and obtained details of zygosity and self-reported gender identity. To increase the power of our analysis, we pooled our observations with previously published twin data that used comparable methods to ours. The pooled sample of 463 twin pairs comprised 47/222 (21.2%) MZ and 21/241 (8.7%) DZ concordant pairs. Based on a 1% population prevalence estimate, the estimated relative risk ratios for transgender concordance were 21.2 for MZ pairs (95%CI 16.4-27.3), and 8.7 for DZ pairs (95%CI 5.8-13.1). These findings suggest a substantial genetic contribution to gender diversity. In contrast, the combined results for concordance among same and opposite sex DZ pairs were 12/131 (9.2%) and 9/110 (8.2%) respectively, and did not support a role for prenatal sex hormones in the occurrence of gender diversity.
    DOI:  https://doi.org/10.1038/s41598-025-06265-6
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