Jackuliak Peter, Jankovský Martin, Kovářová Magdaléna, Voller Jaroslav, Feitscherová Claudia, Varga Ivan
Fifth Department of Internal Medicine, Faculty of Medicine, Comenius University and University Hospital Bratislava, Bratislava, Slovakia.
Faculty of Healthcare Studies, University of Western Bohemia, Pilsen, Czechia.
Front Cell Dev Biol. 2025 May 23;13:1582039. doi: 10.3389/fcell.2025.1582039. eCollection 2025.
Diabetes mellitus (DM) and associated comorbidities correspond to female infertility by many interrelated mechanisms. Yet most prior research focuses only on ovary dysfunction. Our work evaluates literature mechanisms of DM-induced uterine tube and endometrial dysfunction, corresponding impacts on female fertility, and potential evidence-based intervention targets.
We conducted a scoping review (mapping review) follows the Joanna Briggs Institute (Manual for Evidence Synthesis, 2020 version). After identifying the research questions, we conducted a comprehensive search across four electronic databases by entering the keyword "diabetes", with a combination with other keywords as the uterus, endometrium, uterine/Fallopian tube, infertility and embryo implantation. We excluded manuscripts that address the issue of gestational diabetes. Most of these studies were in animals.
There is compelling evidence for connecting DM with uterine tube infertility endometriosis, thyroid dysfunction, and susceptibility to infectious disease. DM damages the endometrium before pregnancy glucose toxicity, lesions, excessive immune activity, and other mechanisms. DM also hinders endometrium receptivity and embryo-endometrium crosstalk, such as through disrupted endometrium glucose homeostasis. We also hypothesize how DM may affect the function of immune cells in uterine tube and uterus, including changes in the number and types of cells of innate and acquired immunity, disrupting immunological barrier in uterine tube, alterations in formation of neutrophil extracellular traps or polarization of macrophages.
We discuss evidence for clinical practice in terms of glycaemic control, lifestyle modifications, and medical interventions. For example, there is currently substantial evidence from rodent models for using metformin for increase in endometrial thickness, number of stromal cells and blood vessels and restoration of normal endometrial architecture, and bariatric surgery for recruitment of protective immune cell types to the endometrium. We also briefly highlight the future prospects of stem cells, artificial intelligence, and other new approaches for managing DM-associated female infertility. Further studies are necessary for optimizing female reproductive outcomes.
糖尿病（DM）及其相关合并症通过多种相互关联的机制导致女性不孕。然而，大多数先前的研究仅关注卵巢功能障碍。我们的工作评估了糖尿病引起输卵管和子宫内膜功能障碍的文献机制、对女性生育能力的相应影响以及潜在的循证干预靶点。
我们按照乔安娜·布里格斯研究所（《证据综合手册》，2020年版）进行了一项范围综述（图谱综述）。确定研究问题后，我们通过输入关键词“糖尿病”，并与子宫、子宫内膜、子宫/输卵管、不孕和胚胎着床等其他关键词组合，在四个电子数据库中进行了全面检索。我们排除了涉及妊娠期糖尿病问题的手稿。这些研究大多以动物为对象。
有令人信服的证据表明糖尿病与输卵管不孕、子宫内膜异位症、甲状腺功能障碍以及传染病易感性有关。糖尿病在妊娠前会损害子宫内膜，其机制包括葡萄糖毒性、病变、过度免疫活动等。糖尿病还会阻碍子宫内膜容受性以及胚胎与子宫内膜的相互作用，例如通过破坏子宫内膜葡萄糖稳态。我们还推测了糖尿病可能如何影响输卵管和子宫中免疫细胞的功能，包括先天免疫和获得性免疫细胞数量和类型的变化、破坏输卵管的免疫屏障、中性粒细胞胞外陷阱形成的改变或巨噬细胞极化的改变。
我们从血糖控制、生活方式改变和医学干预等方面讨论了临床实践的证据。例如，目前有大量来自啮齿动物模型的证据表明，使用二甲双胍可增加子宫内膜厚度、基质细胞数量和血管数量，并恢复正常的子宫内膜结构，而减肥手术可使保护性免疫细胞类型募集到子宫内膜。我们还简要强调了干细胞、人工智能和其他管理糖尿病相关女性不孕的新方法的未来前景。为了优化女性生殖结局，还需要进一步研究。
