Update on the pathogenesis of endometriosis-related infertility based on contemporary evidence

Abstract

Endometriosis, the most prevalent cause of infertility, is associated with anatomical distortion leading to adhesions and fibrosis, as well as endocrine abnormalities and immune disorders. This review discusses the mechanisms underlying endometriosis-related infertility. Firstly, alterations in the hypothalamic-pituitary-ovarian axis lead to the secretion of gonadotropins and steroid hormones, with adverse effects on ovulation and implantation, leading to fertility decline. Secondly, dysregulation of the hypothalamic-pituitary-adrenal axis induces elevated serum cortisol and prolactin levels in patients with endometriosis, accounting for its regulation of stress, depression, and anxiety. Abnormal interactions between endometrial cells and the immune system change the local microenvironment, resulting in epithelial-mesenchymal transition and inflammation. Activated epithelial cells, stromal cells, and immunocytes produce various chemokines, cytokines, or autoantibodies, creating an unfavorable environment for embryo implantation. These findings suggest that alterations in the immune spectrum play a crucial role in endometriosis-related infertility. Thirdly, oxidative stress has adverse effects on the ovarian reserve and subsequent embryonic development, predicting another promising strategy for endometriosis-related infertility. An unbalanced redox state, including impaired mitochondrial function, dysregulated lipid metabolism, and iron-induced oxidative stress, generates a pro-oxidative microenvironment, which negatively impacts oocyte quality and sperm and embryo viability. Thus, an updated understanding of the mechanisms involved in this disease will help to develop effective strategies to manage endometriosis-related infertility.

Keywords: endocrine; endometriosis; immune dysfunction; infertility; oxidative stress.

Figure 1

Respective roles of endocrine-related receptors in normal endometrial and endometriotic lesions. Firstly, SNP in the FSHR gene and LHR gene are associated with ovulation disorders. Deletion of FSHR, LHR, or both impedes granulosa cell survival and follicle development. Secondly, circulating E2 acts mainly on ERα; ERβ expression is upregulated, and ERα expression is weakened in endometriosis lesions. There is local accumulation of E2, mainly because of the ability of endometriotic lesions to synthesize E2, resulting from higher expression of 17β-hydroxysteroid dehydrogenase 1, a key enzyme for E2 production. Thirdly, PRA and PRB regulate the progesterone response. An imbalanced PRA: PRB ratio alters the progesterone pathway, inducing progesterone resistance, which finally inhibits apoptosis and promotes proliferation and inflammation. ER, estrogen receptor; FSH, follicle-stimulating hormone; FSH receptor, FSHR; LH, luteinizing hormone; LH receptor, LHR; PR, progesterone receptor; SNP, single nucleotide polymorphism.

Figure 2

Interactions between endometrial cells and the immune system involved in endometriosis-related infertility. Firstly, causal relationships between endometrial cells and immune cells are well-established. EMT biological processes and stromal cell dysfunction account for fibrosis and exposed antigens, which cause ongoing inflammation and impaired immune surveillance. Immune cell populations, including T cells, macrophages, and NK cells, are involved in the development and maintenance of endometriotic lesions. The inflammatory environment of endometriosis induces immune complexes and an unbalanced pro-oxidant status, which affects ovarian reserve and oocyte quality, thereby reducing the chance of fertilization and implantation. EMT, epithelial-mesenchymal transition; IL, interleukin; MCP, monocyte chemoattractant protein; TNF, tumor necrosis factor.