Molecular Basis of Impaired Decidualization in the Eutopic Endometrium of Endometriosis Patients

Abstract

Endometriosis is a chronic gynecological disorder characterized by the presence of endometrial tissue outside the uterine cavity. A common feature of this pathology is the impaired decidualization of endometrial stromal cells, a critical process that prepares the uterus for embryo implantation. This decidualization defect has been mechanistically linked to progesterone resistance in endometriotic lesions. However, the presence and underlying mechanisms of decidualization defects in the eutopic endometrium of women with endometriosis remain controversial. The aim of the present study is to integrate and discuss molecular evidence from both in vivo and in vitro studies examining decidualization alterations in the eutopic endometrium of patients with endometriosis. Multiple studies have demonstrated impaired decidualization in the eutopic endometrium of women with endometriosis. These alterations have been reported on multiple genes, signaling pathways, and epigenetic processes. However, additional functional studies are warranted to elucidate whether these decidualization defects directly contribute to endometriosis-associated infertility. A better understanding of the decidualization process and its dysregulation in endometriosis will not only advance the development of targeted fertility treatments but also facilitate the design of more effective therapeutic strategies for managing this chronic condition.

Keywords: decidualization; endometrial stromal cells; endometriosis; epigenetics; eutopic endometrium; gene expression; signaling pathway.

Figure 1

Molecular Alterations in Sex-Steroid Hormone Receptors and Signaling in Endometriosis. (A) Progesterone receptor (PGR) signaling in the normal and eutopic endometrium of endometriosis patients. In a healthy endometrium, PGR-B and PGR-A isoforms are expressed, and ligand-bound PGR-B regulates the expression of decidualization-associated genes (DAGs). In endometriosis, PGR-B promoter hypermethylation and miR-194-3 mediated degradation reduce its protein levels, impairing decidualization. (B) Membrane progesterone receptor (PAQR) expression patterns across endometrial tissues. Differential expression of membrane progesterone receptors in normal endometrium compared to eutopic and ectopic endometriotic tissues. Expression levels are represented by the number of arrows. (C) Estrogen receptor dysregulation in endometriosis. ESR1 and ESR2 show increased expression in both eutopic and ectopic endometrial tissues in endometriosis patients compared to control endometrium, with ectopic lesions exhibiting the highest ESR2/ESR1 ratio. However, whether the ESR2/ESR1 ratio is altered in eutopic endometrium remains to be determined.

Figure 2

FOXO1 Regulation in the Normal and Eutopic Endometrium of Endometriosis Patients. Signaling pathways involved in the regulation of FOXO1 during in vitro decidualization in ESCs from control endometrium (A) and from eutopic endometrium of endometriosis patients (B). (A) During in vitro decidualization, BMP, SMAD, and NOTCH genes are upregulated. BMP-SMAD and Notch signaling independently promote FOXO1 transcription through SMAD and NICD (Notch Intracellular Domain) activation, respectively. FOXO1 then regulates decidualization markers, including IGFBP1, enabling normal endometrial function. (B) Multiple pathway dysregulation reduces FOXO1 levels during decidualization in the eutopic endometrium of endometriosis patients. Downregulation of SMAD-BMP and Notch signaling decreases FOXO1 expression. Enhanced CAPN7 and pAKT1 activity promotes FOXO1 phosphorylation (Ser319), triggering nuclear exclusion. Overexpression of NEK2 induces FOXO1 phosphorylation (Ser184) that, in turn, promotes ubiquitination and proteasomal degradation, ultimately impairing decidualization.

Figure 3

Epigenetic regulation of gene expression in normal and eutopic endometrium tissues of endometriosis patients. The menstrual cycle is divided into three phases: menstrual, proliferative, and secretory. Normal endometrium (left panel): MLL1, HOXA10, COX4/2, PRMT5, and H3K4me3 levels show progressive upregulation during the menstrual cycle, while COL1A1 and COL1A2 maintain low expression levels. During the secretory phase, HOXA10 expression is enhanced by a transcriptional active chromatin state at its promoter. Eutopic endometrium from endometriosis patients (right panel).