Reproduction & fertility最新文献

{"title":"Towards microbiome-informed strategies for predicting and preventing pregnancy complications.","authors":"G L Ruschman, J A Bittor, D S Charnock-Jones, P E Day-Walsh","doi":"10.1530/RAF-26-0009","DOIUrl":"10.1530/RAF-26-0009","url":null,"abstract":"<p><strong>Graphical abstract: </strong></p><p><strong>Abstract: </strong>Despite the prevalence of pregnancy complications, including miscarriage, stillbirth, preeclampsia (PE), fetal growth restriction (FGR), and preterm birth (PTB), current predictive tools remain limited. This underscores an urgent need for novel molecular biomarkers and mechanistic insights. The microbiome regulates host physiology, and its disruption correlates with adverse pregnancy outcomes, such as PE, PTB, and gestational diabetes mellitus (GDM), and thus holds promise for predictive insights and therapeutic interventions. However, these associations are largely correlative, based on taxonomic rather than protein- or metabolite-based functional changes. In addition, they are often derived from cross-sectional studies, and the underlying mechanisms remain poorly understood. Given the evidence-based view of a sterile intra-uterine environment, understanding the factors that mediate host-microbe interactions is crucial for improving pregnancy outcomes. Maternal immune and hormonal changes can influence the composition and functional capacity of the microbiome, while the microbiome, in turn, modulates immune, neuroendocrine responses, nutrient bioavailability, and metabolic processes, impacting placental development and pregnancy physiology. We explore direct and indirect mediators of host-microbiome interactions and discuss how these may be targeted to improve pregnancy outcomes. We briefly consider the potential influence of the paternal microbiome and maternal preconception microbial states on pregnancy physiology and outcomes. Finally, we critically evaluate existing methodologies and databases for studying microbial variations in pregnancy-related disorders and propose strategies to better harness microbiome-based research for clinical application. By integrating current evidence and identifying key knowledge gaps, this review aims to highlight microbiome-informed strategies for improving pregnancy outcomes and lifelong health.</p><p><strong>Lay summary: </strong>Understanding how microbes influence pregnancy outcomes is essential. Pregnancy complications, such as miscarriage, stillbirth, preeclampsia (PE), Fetal growth restriction (FGR), and preterm birth (PTB), are common, yet we still lack reliable tools to predict who is at risk. This makes it essential to identify new biological markers and better understand the underlying mechanisms. One promising area is the microbiome, the community of microorganisms that live in and on our bodies, including bacteria, viruses, and fungi. The microbiome plays a major role in regulating health, and changes in its composition have been linked to pregnancy disorders, including PE, PTB, and gestational diabetes mellitus (GDM). However, most of what we know comes from studies that only identify which microbes are present, rather than what these microbes are doing. Many studies are also cross-sectional, capturing only a single time po","PeriodicalId":101312,"journal":{"name":"Reproduction & fertility","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13292987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148221472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined nonoxynol-9 and antimicrobial peptide LL-37 for barrier contraception.","authors":"Murong Xu, Carol Pui Shan Chan, Luping Cong, Jacqueline Pui Wah Chung, Ellis Kin Lam Fok, David Yiu Leung Chan","doi":"10.1530/RAF-25-0123","DOIUrl":"10.1530/RAF-25-0123","url":null,"abstract":"<p><strong>Abstract: </strong>Birth control and sexually transmitted infections are global concerns. Nonoxynol-9 (N-9) is the most commonly used component in spermicides, with controversial safety and efficacy. LL-37 has been considered the most promising antimicrobial peptide for developing spermicides. Thus, we aimed to refine the regime of N-9 through the adjunction of LL-37 with higher spermicidal efficacy, safety, and antimicrobial activity. Processed sperm from density gradient centrifugation were treated with nonoxynol-9, LL-37, or the combination for the spermicidal activity. Acrosome reaction, DNA fragmentation, and hemizona binding were evaluated. Minimal inhibitory concentrations were measured using E. coli. Mouse experiments were conducted to investigate skin and vagina irritations. The spermicidal activities of nonoxynol-9 and LL-37 were dose-dependent. Premature acrosome reactions were shown in both groups by increasing acrosome-reacted sperm at around 9 and 21% significantly, and interestingly, the combined group showed a synergistic effect by raising over 60%. In the DNA fragmentation, although there were no significant changes in the nonoxynol-9 or LL-37 groups, the combined group showed a 3% increase at a significant level. Both nonoxynol-9 and LL-37 showed reduced binding capacity with the hemizona-binding indexes at 43.2 and 8.0, and the combined group showed the lowest capacity at 5.6. In animal experiments, the addition of LL-37 to the nonoxynol-9 could alleviate the disruptions caused by nonoxynol-9 in reducing skin epidermal hyperplasia and vaginal irritation. However, the presence of nonoxynol-9 would reduce the antibacterial activity of LL-37. This refined regime showed enhanced spermicidal effects and reduced irritations, but only limited antimicrobial activity.</p><p><strong>Lay summary: </strong>Birth control and sexually transmitted infections are global concerns. One of the most common components used in spermicides to kill sperm is nonoxynol-9, but there have been questions about safety and efficacy. LL-37 has been considered a promising component, together with its function in killing microbes. We aimed to design a spermicide using N-9 and LL-37 together, with potentially higher efficacy and safety. This refined regime showed improvements in killing sperm and improved effects on sperm functions. It also reduced the irritation to the skin and vagina, but only showed limited activity in killing the microbes.</p>","PeriodicalId":101312,"journal":{"name":"Reproduction & fertility","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13292980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148166437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Higher BMI is associated with vaginal microbiome alterations in women with PCOS.","authors":"Marta Spochacz-Santoro, Anna Szeliga, Magdalena Durda-Masny, Katarzyna Morańska, Monika Englert-Golon, Wawrzyniec Sadowski, Maria Bocheńska, Swapnil Doijad, Bas E Dutilh, Rose Brouns, Marlena Grabowska, Stefan Sajdak, Błażej Męczekalski, Anita Szwed","doi":"10.1530/RAF-26-0051","DOIUrl":"10.1530/RAF-26-0051","url":null,"abstract":"<p><strong>Abstract: </strong>Polycystic ovary syndrome (PCOS) is commonly associated with obesity and metabolic disturbances. Although gut and vaginal microbiome changes have been linked to PCOS, the independent role of body mass index in these alterations remains unclear. This study aimed to compare gut and vaginal microbiomes in women with PCOS and healthy controls, emphasizing the impact of body mass index. Seventy-five women were enrolled, including 55 with PCOS and 20 healthy controls. Participants were stratified into normal-weight (<25) and overweight (≥25) groups. Vaginal and anorectal swabs were analyzed using full-length 16S rRNA nanopore sequencing. Microbial diversity and composition were assessed with alpha diversity indices, principal component analysis, analysis of composition of microbes, PERMANOVA, and vaginal community state type classification. Without body mass index stratification, women with PCOS showed differences in several vaginal taxa compared with healthy controls. Within the PCOS cohort, overweight women exhibited higher vaginal alpha diversity, reduced Lactobacillus dominance, and enrichment of anaerobic taxa compared with normal-weight women with PCOS. Differences in vaginal microbial composition were also observed between healthy and PCOS women with normal body mass index. In contrast, gut microbiome alterations were limited and less consistent across analytical approaches. Vaginal community state type analysis revealed predominance of class IV communities in both healthy women and women with PCOS. These findings suggest that higher body mass index is associated with vaginal microbiome alterations in women with PCOS, although PCOS-related factors independent of body weight may also contribute to the observed microbial differences.</p><p><strong>Lay summary: </strong>Polycystic ovary syndrome is a common condition that affects hormones, fertility, and metabolism in women. Many women with this condition are also overweight, but it is not fully understood how body weight influences the bacteria living in the body. In this study, we compared bacteria present in vaginal and anorectal samples from women with and without polycystic ovary syndrome, while also considering body weight. We found that women with higher body weight had more noticeable changes in vaginal bacterial composition, including lower amounts of protective Lactobacillus bacteria and higher diversity of anaerobic bacteria. At the same time, some bacterial differences were also observed in women with polycystic ovary syndrome who had normal body weight. Changes in gut bacteria were smaller and less consistent. These findings suggest that both body weight and polycystic ovary syndrome may influence vaginal bacterial composition and should be considered in future studies of women's reproductive health.</p>","PeriodicalId":101312,"journal":{"name":"Reproduction & fertility","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13292985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148213985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peripheral cytokines as candidate biomarkers for recurrent pregnancy loss.","authors":"Danai Bagkou Dimakou, Jennifer Tamblyn, David Lissauer, Alex Richter","doi":"10.1530/RAF-25-0152","DOIUrl":"10.1530/RAF-25-0152","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Graphical abstract: &lt;/strong&gt;&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Abstract: &lt;/strong&gt;A current working hypothesis in recurrent pregnancy loss (RPL) suggests immune dysregulation, underlain by a pro-inflammatory cytokine shift in TH cells. NK cells, which are primary immune effectors throughout pregnancy, also orchestrate immune activity via cytokine secretion, which appears aberrant in women with RPL. Experimental findings remain contentious, hindering clinical adoption of cytokine testing, despite increasing pressure from clinicians and couples affected. This study aims to identify peripheral cytokine biomarkers that could be utilized for the stratification of women with RPL displaying underlying immune dysregulation. Peripheral blood samples from non-pregnant women with RPL (n = 99) and controls (n = 80) were assessed for TH and NK cell cytokine production via flow cytometry. Cytokine secretion by peripheral blood mononuclear cells was examined via ELISA. Elevated pro-/anti-inflammatory cytokine-producing TH cell ratios were detected in RPL (P &lt; 0.0001). This was, however, accompanied by reduced pro-/anti-inflammatory cytokine expression within individual cells (IL-2/IL-10: P &lt; 0.0001, IFN-γ/IL-10: P &lt; 0.0001, TNF-α/IL-10: P = 0.0136, IL-17A/IL-10: P &lt; 0.0001). NK cell cytokine production appeared deficient overall in women with RPL (TNF-α+ NKs: P &lt; 0.0001, IL-10+ NKs: P = 0.0006). Interestingly, a pro-inflammatory shift was evident when cytokine secretion was investigated (TNF-α/IL-5: P = 0.0120, IL-2/IL-13: P = 0.0105, IFN-γ/IL-13: P = 0.0040, TNF-α/IL-13: P &lt; 0.0001). A pro-inflammatory shift in cytokine secretion was identified in women with RPL, indicating systemic cytokine dysregulation. Peripheral cytokine levels emerged as discriminatory and, thus, upon validation, may present valuable biomarkers in the identification of immune-associated RPL. Further research on the functional effects of cytokine imbalance in utero is required to strengthen the pathogenic relevance of these findings.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Lay summary: &lt;/strong&gt;Pregnancy losses (miscarriages) that happen repeatedly may be linked to an overactive immune system. We studied proteins that are used as signals to/from immune cells, called 'cytokines', in blood from women with repeated miscarriages and women without this history. We measured the production of these molecules by two immune cell types that are key in pregnancy: T helper cells and natural killer cells and their total levels in blood. In women with miscarriages, more T helper cells produced immune-activating over immune-suppressing cytokines. Natural killer cells made fewer cytokines overall. When we looked at their total levels in the blood, more immune-activating cytokines were seen. Our findings point to a change towards more immune activation in women with multiple miscarriages. After examining this further, cytokines could be used as a test to identify women who are more likely to benefit from treatments that help balance the i","PeriodicalId":101312,"journal":{"name":"Reproduction & fertility","volume":"7 2","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13292982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148285084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of prolonged embryo cryopreservation after fertility treatment in Denmark.","authors":"Emilie Høyer Preisler, Morten Rønn Petersen, Marie Louise Grøndahl, Anette Gabrielsen, Stine Ravn Hansen, Tilde Veng Eskildsen, Betina Boel Povlsen, Bettina Troest, Dea Frøding Skipper, Emilie Steentoft Dahlberg, Henriette Svarre Nielsen, Nina la Cour Freiesleben, Anne Zedeler","doi":"10.1530/RAF-25-0185","DOIUrl":"10.1530/RAF-25-0185","url":null,"abstract":"<p><strong>Abstract: </strong>This retrospective cohort study examined the effects of the Danish legislative amendment extending the permitted duration of embryo cryopreservation from five years until the woman reaches 46 years on frozen embryo transfer (FET) during assisted reproductive technology. The number of embryos discarded across the eight public fertility clinics due to the five-year storage limit was quantified between January 1, 2017, and December 31, 2019, with an average annual destruction of 1,399 embryos. As of March 2024, 29,591 embryos were cryopreserved in the public fertility clinics. FET cycles from the public clinics between October 2020 and March 2024 were included in the outcome analysis (n = 14,677), of which 1.9% (n = 284) involved embryos cryopreserved >5 years. Ongoing pregnancy rate (OPR) and live birth rate (LBR) were assessed by parity and cryopreservation duration (≤5 years vs >5 years). OPR and LBR increased significantly with parity (36.7 and 31.3% for first, 42.6 and 35.6% for second, and 48.8 and 39.0% for third/fourth child), although the increase in LBR for first vs third/fourth child was not statistically significant. OPR and LBR in FET cycles with embryos cryopreserved >5 years were not significantly different from cycles with embryos cryopreserved ≤5 years (OPR: 36.4 vs 38.0%; LBR: 30.9 vs 32.2%). During the study period, 84 children were born from embryos cryopreserved >5 years that previously would have been destroyed. The findings suggest that the amendment has enabled patients to use surplus embryos for family expansion and prevented the disposal of many good embryos.</p><p><strong>Lay summary: </strong>In fertility treatment, cryopreservation is the process of freezing fertilized eggs called embryos. Embryos can be warmed and transferred to the uterus in a future treatment cycle, giving patients another chance at pregnancy without repeating egg retrieval and fertilization. In Denmark, a recent legislative amendment extended the storage limit for embryos from five years to the woman's 46th birthday. This study investigated how this amendment affected the use of cryopreserved embryos as well as pregnancy and live birth outcomes after FET. Few transfers involved embryos cryopreserved over five years. Pregnancy and live birth rates were similar whether embryos had been frozen under or over five years, and 84 children were born from embryos stored over five years that previously would have been destroyed. The findings suggest that the amendment has enabled patients to use embryos from previous treatments for family expansion and reduced unnecessary destruction of good embryos.</p>","PeriodicalId":101312,"journal":{"name":"Reproduction & fertility","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13280622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148152898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic benefits of gonadotropins in male hypogonadotropic hypogonadism: a focus on spermatogenesis and fertility.","authors":"M Huijben, A M A Prinsen, C E de Keyser, S M van der Leij, E F H I Peeters, A M E Stades, S J Tanahatoe, L M O de Kort, H M K van Breda","doi":"10.1530/RAF-25-0100","DOIUrl":"10.1530/RAF-25-0100","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Graphical abstract: &lt;/strong&gt;&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Abstract: &lt;/strong&gt;Male hypogonadotropic hypogonadism is characterized by deficient secretion of luteinizing hormone and follicle-stimulating hormone, leading to low testosterone levels, impaired spermatogenesis, and often infertility. Treatment aims to normalize testosterone and induce spermatogenesis, with gonadotropin therapy as standard. Factors affecting treatment success and optimal duration remain unclear. This single-center retrospective cohort study assessed the outcomes of gonadotropin therapy in men with hypogonadotropic hypogonadism and azoospermia. Men ≥ 18 years were included. The primary outcome was the successful induction of spermatogenesis. Data on demographics, treatment regimens, semen parameters, pregnancy outcomes, and side effects were collected. Regression analyses identified factors associated with treatment success. Thirty-five men were included. Spermatogenesis was achieved in 74% of patients, with higher success rates in those receiving combined human chorionic gonadotropin and follicle-stimulating hormone therapy (78%) versus human chorionic gonadotropin monotherapy (33%). Of those producing sperm, 69% upgraded to a higher WHO semen category, with 29% reaching normospermia. The median maximum sperm concentration achieved during treatment was 8.3 million/mL (IQR: 1.9-36.3). A larger baseline testicular volume was associated with a higher success rate of spermatogenesis and a shorter time to pregnancy. Pregnancy was achieved in 68% of patients, with 39% through spontaneous conception. The median time to first spermatogenesis was 7 months and to pregnancy was 21 months. Mild side effects occurred in 16% of patients. Gonadotropin therapy is effective and well tolerated in inducing spermatogenesis and achieving pregnancy in azoospermic men with HH. These findings, based on a contemporary Western cohort, provide updated evidence that supports personalized counseling and underscore the importance of long-term treatment adherence for successful fertility restoration.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Lay summary: &lt;/strong&gt;Some men are infertile because their brain does not produce the hormones needed to make sperm. This condition is called hypogonadotropic hypogonadism. These men often have low testosterone and no sperm in their semen. In this study, we looked at whether hormone treatment could help these men produce sperm and have children. We studied 35 men who were given hormone injections at a Dutch university hospital. After treatment, 74% of them started producing sperm. Those who received a combination of two hormones had better results than those who received only one. Almost 70% of men with sperm had better sperm quality, and over a quarter reached normal sperm levels. Two-thirds of men who wanted children became fathers, mostly through natural conception. Our findings show that hormone treatment is safe and often successful. This can offer hope to men with this condition who want t","PeriodicalId":101312,"journal":{"name":"Reproduction & fertility","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13280620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148038925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A bridge between infertility and anxiety: a novel role for genes.","authors":"Raminta Bausyte, Brigita Vaigauskaite-Mazeikiene, Giedre Skliute, Elvina Valatkaite, Evelina Sabaityte, Edita Kazenaite, Diana Ramasauskaite, Ruta Navakauskiene","doi":"10.1530/RAF-25-0165","DOIUrl":"10.1530/RAF-25-0165","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Graphical abstract: &lt;/strong&gt;&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Abstract: &lt;/strong&gt;Psychological imbalance is hypothesized to negatively affect reproductive function and vice versa; however, the underlying mechanisms of this relationship remain poorly understood. Therefore, this study aimed to investigate the association between infertility and anxiety and/or depression by examining underlying genetic factors. The study was conducted in several stages: i) psychological assessment of women undergoing assisted reproductive technology (ART) due to couple infertility using the Hospital Anxiety and Depression Scale (HADS), ii) collection of endometrial samples before ART procedures, iii) isolation and cultivation of human endometrial-derived mesenchymal stromal cells (EnSCs), iv) analysis of 26 EnSC genes using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and v) statistical analysis. A total of 32 women were included in the study. Twelve participants reported considerable symptoms of anxiety, and one showed symptoms of depression. Nineteen women conceived after ART. Gene expression analysis suggested altered expression of genes involved in cell cycle regulation, transcription and translation, immune response, signal transduction, cell differentiation, secretion, angiogenesis, and hemostasis according to anxiety status. These mechanisms may influence, or at least reflect, pregnancy outcomes following ART. The findings suggest a potential relationship between anxiety symptoms and gene activity in the endometrium of women undergoing ART. However, the relatively small sample size limits the strength of the conclusions; therefore, the results should be interpreted as preliminary. Further studies with larger cohorts are required to confirm these observations and to better understand the interaction between psychological well-being and molecular mechanisms involved in fertility.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Lay summary: &lt;/strong&gt;Infertility affects many couples worldwide and can be emotionally challenging. People undergoing fertility treatment often experience stress or anxiety, but it is still unclear how emotional well-being may influence reproductive health. In this study, we explored whether anxiety might be linked to biological processes involved in fertility. Women undergoing assisted reproductive treatment completed a questionnaire about anxiety and depression symptoms. We also analyzed small tissue samples from the lining of the uterus, which is important for embryo implantation and pregnancy. Our findings suggested that women who reported higher anxiety levels showed differences in some biological processes compared with women who reported lower anxiety levels. Some of these differences were also observed in women who did not become pregnant after treatment. Although the study involved a small number of participants, the results suggest that emotional well-being may be connected to reproduction and highlight the importance of psychological suppor","PeriodicalId":101312,"journal":{"name":"Reproduction & fertility","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13261345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147944519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunological dynamics of the epididymis: from experimental insights to clinical translation.","authors":"Christiane Pleuger, Erick J R Silva, Daniela Fietz, Maria Carolina Avenatti, Maria Agustina Battistone, Rukmali Wijayarathna","doi":"10.1530/RAF-26-0007","DOIUrl":"10.1530/RAF-26-0007","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Graphical abstract: &lt;/strong&gt;&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Abstract: &lt;/strong&gt;The epididymal immune environment is crucial to male fertility as it delicately balances defense against pathogens with tolerance to antigenic spermatozoa. This review synthesizes current knowledge on the epididymal immune landscape under homeostatic and pathological conditions, focusing on the dynamics of resident immune cells and immunomodulatory factors. Distinct immune populations occupy the epididymal epithelium and interstitium, with pronounced regional specialization along the duct. CX3CR1hi intraepithelial mononuclear phagocytes form an extensive surveillance network in the proximal epididymis, supporting epithelial integrity, antigen handling, and controlled immune activation. In the distal regions, heterogeneous interstitial macrophages and conventional dendritic cells coordinate antimicrobial defense and adaptive immune responses. These populations are shaped by a local cytokine milieu enriched in immunomodulatory factors, including TGF-β, activins, and indoleamine 2,3-dioxygenase (IDO), which collectively promote tolerance while restraining inflammation. Regulatory T cells further reinforce cytokine-driven control and prevent antisperm antibody formation. Experimental animal models of epididymitis reveal that disruption of these networks triggers leukocytosis, loss of peripheral tolerance, and tertiary lymphoid structures, sustaining chronic inflammation and autoantibody production, which, in turn, may cause infertility. Both infectious and autoimmune models highlight the cauda epididymis as particularly vulnerable to immune-mediated tissue damage and fibrotic obstruction. Current clinical strategies for the management of epididymitis are reviewed, while postulating possible new therapeutic avenues to target immune and inflammatory pathways that could support existing treatments. In conclusion, this review positions epididymal immune regulation as a central determinant of male fertility and reproductive health while highlighting promising avenues for immunomodulatory interventions to preserve fertility.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Lay summary: &lt;/strong&gt;The epididymis is the organ in which sperm mature and acquire the ability to fertilize an egg. The epididymis has a unique immune system that must protect sperm against infections while avoiding attacks on sperm, which the body recognizes as foreign. This review summarizes how the epididymal immune environment works in both health and disease. Different immune cells populate distinct regions of the epididymis, with specialized roles: some monitor and maintain the tissue, while others combat infections and guide immune responses. Signals from certain molecules help keep the immune system balanced, preventing harmful inflammation or antisperm immune attacks. Studies in animals show that when this balance is disrupted, male fertility can be impaired. Understanding these immune networks could lead to new treatments for diseases suc","PeriodicalId":101312,"journal":{"name":"Reproduction & fertility","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13261346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148038936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repeat cesarean delivery with hysterectomy: a sheep model to examine uterine scars.","authors":"Alexander Paping, Elise Elsenmüller, Rebecca Mirbach, Julia Sommer, Alma Franziska Mackert, Loreen Ehrlich, Kerstin Melchior, Thomas Ziska, Lilli Bittner-Schwerda, Alexander Starke, Karin Heinichen, Wolfgang Henrich, Thorsten Braun","doi":"10.1530/RAF-25-0207","DOIUrl":"10.1530/RAF-25-0207","url":null,"abstract":"<p><strong>Graphical abstract: </strong></p><p><strong>Abstract: </strong>Cesarean delivery (CD) is one of the most common surgical procedures worldwide, with rising rates leading to an increasing impact of complications, such as uterine rupture during a trial of labor in a subsequent pregnancy. To date, only little information on uterine wound healing is available. The current challenge is to establish a suitable model and to define quantifiable outcome parameters of uterine scar tissue with the aim of comparing the effect of different surgical techniques on uterine scarring. This study presents a sheep model to examine the effects of different hysterotomy closure techniques. A total of 48 Merino ewes underwent planned CD. After one year, 40 ewes were mated again following estrus synchronization and received planned repeat CD with peripartum supracervical hysterectomy and sampling of uterine scar tissue without any major complications. Survival rates at repeat CD were 95.0 and 91.4% for ewes and lambs, respectively. Due to placement of non-absorbable sutures around the hysterotomy closure during the first CD, all scarred uterine wall segments could be identified. Of 80 uterine scars, 16 (20%) showed dehiscences with a macroscopic thinning of the uterine wall. A full-thickness uterine rupture was not found. Gomori trichrome staining was used to assess the collagen content histomorphometrically. It revealed a markedly scarred uterine wall. This translational model can be used to evaluate intraoperative approaches to optimize uterine wound healing, such as suturing techniques, pharmacological agents, or biomaterials, with the aim of reducing the risk of uterine rupture in humans and improving maternal outcomes in pregnancies after previous CD.</p><p><strong>Lay summary: </strong>CD is one of the most common operations worldwide. After a cesarean, a scar remains on the uterus. This scar may not heal properly, leading to the risk of serious complications in a subsequent pregnancy, such as uterine rupture. Despite this risk, very little is known about how the uterine wall heals after surgery, because suitable research models are scarce. This study shows that sheep can be used as a model to study uterine scar healing. A planned CD was performed in sheep. Sheep were mated again, and at the next planned cesarean, the uterus was removed and tissue from the scar was collected. The scars could be clearly identified, and some showed thinning similar to what is seen in humans. Microscopic analysis confirmed scar formation. This model will help researchers test new ways to improve uterine healing and make pregnancies after CD safer.</p>","PeriodicalId":101312,"journal":{"name":"Reproduction & fertility","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13261342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148059430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Excess female adrenal androgen secretion is a consequence of in utero androgenic excess in sheep.","authors":"S Ramaswamy, K Siemienowicz, A S McNeilly, W C Duncan, M T Rae","doi":"10.1530/RAF-26-0030","DOIUrl":"10.1530/RAF-26-0030","url":null,"abstract":"<p><strong>Abstract: </strong>Excess androgenic steroid exposure during development in female sheep alters metabolic and reproductive function in postnatal life, with phenotypes reminiscent of health-relevant aspects of Polyendocrine Metabolic Ovarian Syndrome (PMOS) in women. We hypothesised that altered steroid exposure during in utero life would alter female postnatal adrenal function. Prenatal steroid excess was created by fetal steroid injections, on d62 and d82 of gestation, designed to separately create excess androgenic exposure (testosterone propionate, n = 14), oestrogenic exposure (diethylstilbestrol, n = 7) and glucocorticoid excess exposure (dexamethasone, n = 11) with controls (n = 11) treated with vehicle alone. Adrenal function tests and qPCR measurement of adrenal steroidogenic genes were the outcomes measured. In post-pubertal female offspring, specifically prenatal androgenic excess was associated with exaggerated testosterone secretory response to ACTH (P < 0.05), in the absence of alterations in cortisol secretion. Altered androgen secretory response was associated with increased S T AR, HSD3B1 and HSD17B mRNA (P < 0.05). Neither adrenal androgen secretion nor steroidogenic gene expression was altered prior to puberty. During fetal life (day 90 of gestation), only S T AR was altered in prenatal androgenic excess females (P < 0.05), to a similar level as observed in a control cohort of male fetuses. We conclude that the postnatal, post-pubertal ovine adrenal gland is hyperandrogenic because of prenatal androgen excess.</p><p><strong>Lay summary: </strong>Steroid hormones are responsible for our development in fetal life. If there is too much or too little of a steroid hormone before we are born, it can affect our health in the future. If a female fetus is exposed to too much male-type hormone in the middle of pregnancy, after puberty, they develop features seen in women with Polyendocrine Metabolic Ovarian Syndrome (PMOS). The classic feature of PMOS is increased male-type hormones from the ovaries where cells in the ovaries are set up to make more male-type hormone. In women, half of all the male-type hormones come from the adrenal gland. We looked at the effects of giving more male-type hormones in the middle of pregnancy to female sheep fetuses as we know that they get the features of PMOS after puberty. In this study, we showed that the cells in the adrenal gland are also set up to make more male-type hormone after puberty. We checked if this was specifically due to the effects of male hormone exposure before birth and found that increased female hormone or stress hormone does not have the same effect. This means that it is likely not just the ovary whose function is altered in PMOS but also the adrenal gland.</p>","PeriodicalId":101312,"journal":{"name":"Reproduction & fertility","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13250651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148038906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}