Higher fibrotic content of endometriotic lesions is associated with diminished prostaglandin E2 signaling

Abstract

Purpose While the prevailing view holds that the prostaglandin E2 (PGE 2 ) signaling plays a vital role in endometriosis, PGE 2 also is known to be anti‐fibrotic. We investigated the immunostaining of COX‐2, EP2, and EP4, along with fibrotic content in ovarian endometrioma (OE) and deep endometriosis (DE) lesions, and in OE lesions from adolescent and adult patients. In addition, we evaluated the effect of substrate stiffness on the expression of COX‐2, EP2, and EP4 in endometrial stromal cells. Methods Immunohistochemistry analysis of COX‐2, EP2, and EP4, along with the quantification of lesional fibrosis, was conducted for OE and DE lesion samples and also OE lesion samples from adolescent and adult patients. The effect of substrate rigidity on fibroblast‐to‐myofibroblast transdifferentiation (FMT) and the expression of COX‐2, EP2, and EP4, with or without TGF‐β1 stimulation, were investigated. Results The immunostaining of COX‐2, EP2, and EP4 was substantially reduced in endometriotic lesions as lesions became more fibrotic. Both TGF‐β1 stimulation and stiff substrates induced FMT and reduced the expression of COX‐2, EP2, and EP4. Conclusions Since fibrosis is a common feature of endometriosis, our results thus cast doubts on the use of therapeutics that suppresses the PGE 2 signaling pathway, either by inhibiting COX‐2 or EP2/EP4.

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

“…Indeed, endometrial stromal cells cultured on a stiff matrix display reduced expression of COX‐2, EP2, and EP4 with or without TGF‐β1 stimulation. 28 Furthermore, the combined use of a recently established mouse model of adenomyosis 25 and a mouse model of simulated menstruation 49 lends further support for this proposal (Mao et al, in preparation).…”

“… 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

“…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.…”

“… 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.…”

“… 96 As OE lesions in adolescent and adult patients display different fibrotic content, 52 older women with OE may have more reduced ovarian reserve. In addition, compared with adolescent patients, OE lesions in adult patients display reduced prostaglandin E2 (PGE2) signaling as manifested as expression of COX‐2, EP2, and EP4, concomitant with increased extent of lesional fibrosis, 97 suggesting that adolescent patients with OE may be more responsible to NSAID treatment.…”