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

The prostaglandin E2 (PGE) 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 PGE receptors (EP2 and EP4) are reduced. This study further investigatedwhether the expression levels of genes involved in the biosynthesis and metabolism of PGEin 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 PGE 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.