Mechanisms of Decidual Dysfunction and Infertility in Endometriosis: Roles of Prostaglandins and SASP

Abstract

Background: Endometriosis is a challenging disease to treat and one of the leading causes of infertility. Impaired endometrial receptivity, and particularly inadequate decidualization of endometrial stromal cells (ESCs), is a crucial component. Multiple inflammatory factors disrupt decidualization.

Methods: A comprehensive search of PubMed and Google Scholar (peer-reviewed journals only from 2000 to 2025) was performed in April 2025. The keyword "decidualization" was combined with "endometriosis", "infertility", and "inflammation". We summarize recent findings regarding the mechanisms of endometrial receptivity, focusing on the decidualization of ESCs, and discuss the impact of endometriosis, particularly in relation to PG metabolism and the senescence-associated secretory phenotype (SASP).

Main findings: Endometriotic lesions demonstrate progesterone (P4) resistance and heightened inflammation due to elevated local estrogen levels and feedback loops involving PGE₂ and steroidogenic enzymes. Oxidative stress secondary to inflammation and menstrual blood in ectopic locations promotes lesion growth. Excessive numbers of senescent cells with SASP contribute to fibrosis in the lesions. Impaired decidualization also occurs in eutopic ESCs, which show epigenetic dysregulation and inflammation, and these have effects through P4 and PGE₂ signaling.

Conclusion: Both endometriotic lesions and eutopic endometrium in endometriosis patients exhibit changes that contribute to infertility, with abnormal inflammation and epigenetic modifications leading to impaired decidualization.

Keywords: decidualization; endometriosis; infertility; prostaglandin; senescence‐associated secretory phenotype.

FIGURE 1

Acquisition of uterine receptivity and possible effects of endometriosis‐related pathology during implantation. Implantation and decidualization in the endometrium can only be successful during the appropriate window of implantation (WOI). The decidualization of endometrial stromal cells, which is the process of becoming receptive to the blastocyst, is essential for progesterone (P4)/cAMP signaling. This process involves increases in cyclooxygenase‐2 (COX2), prostaglandins (PGs), and leukemia inhibitory factor (LIF), and a decrease in progesterone receptor membrane component 1 (PGRMC1) expression. In addition, some of the decidualized cells transform into senescent decidual cells and display the SASP, which is associated with the secretion of various cytokines that regulate immune cells, such as uterine natural killer cells. These steps may be influenced by abnormalities related to endometriosis, potentially leading to infertility.

FIGURE 2

Schematic of the role of PGE₂ and other crucial factors in the decidualization of the endometrium. Prostaglandin E2 (PGE₂), which is produced by endometrial glandular epithelial cells and promotes implantation and decidualization, facilitates decidualization via EP2/4 receptors on stromal cells (ESC) and cAMP signaling. The inhibition of PGRMC1 function promotes PGE₂ production through the expression of cyclooxygenase‐2 (COX2) in both epithelial and stromal cells, thereby enhancing decidualization. In addition, senescent ESCs, which increase in number during decidualization, show high expression of IL‐15, activin A, Insulin‐like growth factor‐binding protein (IGFBP)7, and IGF2 receptor (IGF2R).

FIGURE 3

Schematic of the possible effects of endometriosis lesions on the function of eutopic endometrial stromal cells in patients with endometriosis and infertility. Inflammation, fibrosis, and senescence‐related pathology in endometriosis lesions may negatively affect the eutopic endometrium through humoral factors. These mechanisms are likely to be intricately intertwined and exacerbate the consequences of genetic susceptibilities via epigenetic alterations and impaired decidualization signaling. COX‐2, cyclooxygenase‐2; CXCL12, C‐X‐C motif chemokine ligand 12; CXCR4, C‐X‐C chemokine receptor type 4; CTGF, connective tissue growth factor; EMT, epithelial–mesenchymal transition; ERβ, estrogen receptor β; PR, progesterone receptor.