Microscopic anatomical background of unexplained tubal infertility – three new possible causes

Abstract

Infertility is defined as the inability to conceive within 1 year of unprotected intercourse. The infertility evaluation generally includes an assessment of the ovarian cycle and a semen analysis, but the evaluation of tubal patency is an essential part of the fertility workup. However, in the case of the uterine tube, patency may not be the only cause of tubal infertility. Idiopathic or unexplained infertility is a broad subcategory of infertility defined by the absence of obvious or explainable cause. Based on our previous research, we review and discuss three hypotheses associated with new anatomical and histological knowledge of tubal morphology and transport function and its potential impact on reproductive outcomes in women with unexplained tubal infertility. In 2021, Duffy et al. (Fertility and Sterility) published “Top 10 priorities for future infertility research”, based on their survey among healthcare professionals and patients with fertility problems from 40 countries. No mention of tubal infertility was included in their results. On the other hand, the topic “What causes unexplained infertility?” was one of the most important research priorities for female infertility. In 2018, a neglected structure of the human uterine tube, the lymphatic lacunae of the mucosal folds and fimbriae were described by Varga et al. (Annals of Anatomy). We believe that the lymph and lymphatic lacunae are responsible for the thickening of the fimbriae during ovulation. The fimbriae become enlarged and turgescent, coming into contact with the surface of the ovary, what is important in oocyte pick‐up and the maintenance of the tubal fluid. Hypothetically, disturbed lymph flow, caused by e.g., sedentary work, can cause problems with oocyte pick‐up and subsequent fertilization. In 2019, Varga et al. (Annals of Anatomy) described an important regulatory T‐ cell population in the human tubal epithelium. These intra‐epithelial T‐lymphocytes can be involved in the process of immune tolerance, which could lead to the tolerance of non‐self cells (sperm) and partially non‐self cells (a developing embryo) without the activation of local immune responses. An imbalance between the cells of the intra‐epithelial immune system can hypothetically lead to the immune reaction against sperm and/or embryo during transport through the uterine tube. The recently described cell population of tubal telocytes have many possible functions, but one of the most commonly reported is their ability to “sense” the levels of female sex hormones and thus regulate those processes inside the uterine tubes, which are under hormonal control. As reviewed by Klein et al. (2020, Medicina), telocytes are excessively fragile in the presence of noxious factors. In the uterine tubes, possible mechanisms of unexplained infertility include changes in the structural and functional integrity of the cellular microenvironment, including quantitative reduction and/or functional alteration of telocytes.