Progressively Diminished Prostaglandin E2 Signaling in Concordance with Increasing Fibrosis in Ectopic Endometrium

The prostaglandin E2 (PGE2) signaling has traditionally been viewed to play a pivotal role in endometriosis, linking inflammation and hyperestrogenism. We have previously reported that asectopic endometrium becomes more fibrotic, the expression of both COX-2 and PGE2 receptors (EP2 and EP4) are reduced. This study further investigatedwhether the expression levels of genes involved in the biosynthesis and metabolism of PGE2in ectopic endometrium diminish in concordance with increasing lesional fibrosis. We performed immunohistochemistry analyses of COX-2, mPGES-1, mPGES-2, cPGES, 15-PGDH, EP2 and EP4 and Masson trichrome staining for ovarian endometrioma (OE), adenomyosis (AD), and deep endometriosis (DE) tissue samples and control endometrial tissue samples (CT). Gene and protein expression analyses were performed by real-time RT-PCR and Western blotting, respectively. We found that as the extent of lesional fibrosis increased, immunoexpression of COX-2, mPGES-1/2, cPGES, EP2 and EP4 in OE lesions was increased but no change in these genes/proteins in DE lesions as compared with CT. Immunoexpression of COX-2 was found to be reduced while that of 15-PGDH was found to be elevated in DE lesions. In AD lesions, only EP2 and COX-2 were overexpressed. Thus, our data indicate that when the extent of lesional fibrosis is high, the PGE2 signaling pathway is depressed, manifesting as reduced COX-2 expression and elevated expression of 15-PGDH. They underscore the fact that not all ectopic endometria are the same and equal, and highlight the importance of the extracellular matrix in shaping the lesional behavior and response to drug treatment. Similar content being viewed by others Data Availability The data presented in this study are available upon written request from the corresponding author explaining the use and purposes. Code Availability Not applicable.

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This research was supported in part by grant 82071623 (SWG) from the National Natural Science Foundation of China, and grant SHDC2020CR2062B (SWG) from Shanghai Shenkang Center for Hospital Development. We thank the two anonymous reviewers and the Associate Editor for their constructive comments and suggestions that improved the presentation of our manuscript. Author information Authors and Affiliations Corresponding author Ethics declarations Ethics Approval and Informed Consent All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and its later amendments. Informed consent was obtained from all patients for being included in the study. The study was approved by the institutional ethics review board of Shanghai OB/GYN Hospital (No. 2021-35), Fudan University. Each patient enrolled in this study signed an informed consent for all the procedures and to allow data collection and analysis for research purposes. Consent to Participate All subjects enrolled in this study signed an informed consent for all the procedures and to allow data collection and analysis for research purposes. Consent for Publication All authors approved this manuscript and consented for publication. Conflict of interest S.W.G. is a member of the Scientific Advisory Board of Heranova, BioSciences and of FimmCyte A.G., and has provided consultancy advice to these companies, as well as to Sound Bioventures and BioGeneration, but these activities had no bearing on this work. All authors state that they have no competing interest. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Electronic Supplementary Material Below is the link to the electronic supplementary material. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Yi, Y., Nie, J., Liu, X. et al. Progressively Diminished Prostaglandin E2 Signaling in Concordance with Increasing Fibrosis in Ectopic Endometrium. Reprod. Sci. 32, 1271–1286 (2025). https://doi.org/10.1007/s43032-024-01658-w Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s43032-024-01658-w