Changing prostaglandin E2 (PGE₂) signaling during lesional progression and exacerbation of endometriosis by inhibition of PGE₂ receptor EP2 and EP4

Abstract

Purpose We investigated the change, if any, in prostaglandin E2 (PGE 2 ) signaling in endometriotic lesions of different developmental stages in mouse. In addition, we evaluated the effect of treatment of mice with induced deep endometriosis (DE) with inhibitors of PGE 2 receptor subtypes EP2 and EP4 and metformin. Methods Three mouse experimentations were conducted. In Experiment 1, female Balb/C mice were induced with endometriosis or DE and were serially sacrificed after induction. Experiments 2 and 3 evaluated the effect of treatment with EP2 and EP4 inhibitors and metformin, respectively, in mice with induced DE. Immunohistochemistry analysis of COX‐2, EP2, and EP4, along with the extent of lesional fibrosis, was evaluated. Results The immunostaining of COX‐2, EP2, and EP4 turned from activation to a stall as lesions progressed. Treatment with EP2/EP4 inhibitors in DE mice exacerbated endometriosis‐associated hyperalgesia and promoted fibrogenesis in lesions even though it suppressed the PGE 2 signaling dose‐dependently. In contrast, treatment with metformin resulted in increased PGE 2 signaling, concomitant with improved hyperalgesia, and retarded lesional fibrogenesis. Conclusions The PGE 2 signaling diminishes as endometriotic lesions progress. Treatment with EP2/EP4 inhibitors in DE mice exacerbates endometriosis, but metformin appears to be promising seemingly through the induction of the PGE 2 signaling.

How does the extent of fibrosis in adenomyosis lesions contribute to heavy menstrual bleeding?

“…Second, fibrosis inevitably begets tissue stiffening, which turns fibroblasts from a quiescent state to progressive increases in proliferation and synthesis of ECM products, concomitant with decreases in matrix proteolytic gene expression, reduced expression of COX‐2 and synthesis of PGE 2 , 27 as occurred in endometriosis. 28 , 29 In fact, PGE 2 is reported to be anti‐fibrotic. 21 , 23 , 56 , 57 , 58 This should take place irrespective of menstrual cycle phase, as found in our regression analyses.…”

“…With the progression of fibrogenesis, and in the present context of uterine adenomyosis, 10,11,25,26 the lesional stiffness has been observed to increase, 15 which thus would be accompanied by downregulation of COX‐2 expression and consequent decrease in PGE 2 production 27 . Indeed, we recently reported that, in the context of endometriosis, the expression of COX‐2 and E‐series receptor type 2 (EP2) and EP4 is reduced as endometriotic lesions became more fibrotic 28,29 . In addition, endometriotic stromal cells cultured in stiffer matrices demonstrate decreasing expression of COX‐2, EP2, and EP4, 28 suggesting reduced PGE 2 signaling as the extracellular matrix (ECM) becomes stiffer.…”

“… 27 Indeed, we recently reported that, in the context of endometriosis, the expression of COX‐2 and E‐series receptor type 2 (EP2) and EP4 is reduced as endometriotic lesions became more fibrotic. 28 , 29 In addition, endometriotic stromal cells cultured in stiffer matrices demonstrate decreasing expression of COX‐2, EP2, and EP4, 28 suggesting reduced PGE 2 signaling as the extracellular matrix (ECM) becomes stiffer. As ectopic endometrium, both adenomyosis and endometriotic lesions share the same and defining hallmark of cyclic bleeding, 30 they also share similar, but not exactly identical molecular processes that underpin lesional progression owing to different microenvironment.…”

Age‐dependent phenotypes of ovarian endometriomas

“… 97 They may also respond to therapies that target the EP2 and/or EP4 receptors. 139 In contrast, OE lesions in adults may not respond well to either NSAID treatment 97 or therapies that target the EP2 and/or EP4 receptors, 139 especially when the lesions are highly fibrotic.…”

“…For example, on average the OE lesions in adolescents would be more likely to be cystic and less fibrotic than those in adults, which would mean that these patients would be more likely to respond to non‐steroid anti‐inflammatory drugs (NSAIDs) therapy since the PGE2 signaling is less likely to be attenuated 97 . They may also respond to therapies that target the EP2 and/or EP4 receptors 139 . In contrast, OE lesions in adults may not respond well to either NSAID treatment 97 or therapies that target the EP2 and/or EP4 receptors, 139 especially when the lesions are highly fibrotic.…”