Unexplained infertility and impaired decidualization: A case for studying endometrial mechanics and microstructure

Unexplained infertility affects approximately 20 % of couples seeking reproductive assistance, often leading to the use of treatments such as in vitro fertilization (IVF) despite their limited efficacy in these cases. Emerging evidence implicates endometrial dysfunction - specifically impaired decidualization - as an underlying cause. The endometrium is the inner lining of the uterus that undergoes cyclical regeneration, breakdown, and repair during the menstrual cycle, and plays a critical role in embryo implantation and early pregnancy. Decidualization is a hormonally driven transformation of the endometrium involving dramatic cellular and extracellular matrix (ECM) changes essential for successful implantation and pregnancy. While the cellular and hormonal aspects of decidualization have been studied extensively, the required alterations to ECM composition, organization, and mechanical function remain largely unknown. This review summarizes the current knowledge about the anatomy, structure, composition, and mechanical function of the uterus, with a particular focus on the endometrium throughout the menstrual cycle and during pregnancy. A special focus is placed on the role of the ECM in impaired decidualization, a key contributor to endometrial dysfunction. We suggest that an interdisciplinary approach, integrating insights from reproductive physiology, ECM biology, imaging science, and engineering mechanics, will enable a more complete understanding of reproductive function and dysfunction, leading to improved diagnostics and more targeted therapies for infertility. STATEMENT OF SIGNIFICANCE: Unexplained infertility affects millions of couples, often leading to costly and ineffective treatments like IVF. Emerging research implicates endometrial dysfunction-specifically, impaired decidualization-as a key contributor. While hormonal and cellular aspects of this process are well-studied, the role of the extracellular matrix (ECM) in supporting implantation remains largely unknown. This review presents a comprehensive synthesis of endometrial anatomy, microstructure, and mechanics, highlighting novel interdisciplinary opportunities that combine reproductive biology with engineering and imaging science. By emphasizing mechanical biomarkers and ECM remodeling, this work lays a foundation for new diagnostic tools and therapies that could transform how we identify and treat infertility, offering hope to those with unexplained reproductive challenges.