Progesterone Alleviates Endometriosis via Inhibition of Uterine Cell Proliferation, Inflammation and Angiogenesis in an Immunocompetent Mouse Model.

Yanfen Li,Juanmahel Davila,Yuechao Zhao,Athilakshmi Kannan,Indrani C Bagchi,Quanxi Li,Malavika K Adur,Milan K Bagchi,Romana A Nowak,Jae-Wook Jeong

doi:10.1371/journal.pone.0165347

Yanfen Li, Juanmahel Davila + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0165347

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Journal: PloS one	Publication Date: Oct 24, 2016
Citations: 55	License type: CC BY 4.0

Affiliation: University of Illinois Urbana-Champaign

Abstract

Endometriosis, defined as growth of the endometrial cells outside the uterus, is an inflammatory disorder that is associated with chronic pelvic pain and infertility in women of childbearing age. Although the estrogen-dependence of endometriosis is well known, the role of progesterone in development of this disease remains poorly understood. In this study, we developed a disease model in which endometriosis was induced in the peritoneal cavities of immunocompetent female mice, and maintained with exogenous estrogen. The endometriosis-like lesions that were identified at a variety of ectopic locations exhibited abundant blood supply and extensive adhesions. Histological examination revealed that these lesions had a well-organized endometrial architecture and fibrotic response, resembling those recovered from clinical patients. In addition, an extensive proliferation, inflammatory response, and loss of estrogen receptor alpha (ERα) and progesterone receptor (PR) expression were also observed in these lesions. Interestingly, administration of progesterone before, but not after, lesion induction suppressed lesion expansion and maintained ERα and PR expressions. These progesterone-pretreated lesions exhibited attenuation in KI67, CD31, and pro-inflammatory cytokine expression as well as macrophage infiltration, indicating that progesterone ameliorates endometriosis progression by inhibiting cell proliferation, inflammation and neovascularization. Our studies further showed that suppression of global DNA methylation by application of DNA methyltransferase inhibitor to female mice bearing ectopic lesions restrained lesion expansion and restored ERα and PR expression in eutopic endometrium and ectopic lesions. These results indicate that epigenetic regulation of target gene expression via DNA methylation contributes, at least in part, to progesterone resistance in endometriosis.

Highlights

Endometriosis is a gynecological disorder defined as the growth of endometrial glands and stroma in extrauterine locations, primarily on the surfaces of the pelvic peritoneum, ovaries, and rectovaginal septum [1, 2]
The P4-resistance is primarily due to the low level of progesterone receptor (PR) expression in the eutopic endometrium and the ectopic lesions of patients [30,31,32,33,34]
In our mouse model of endometriosis we observed that expression of ERα, PR, and PR-stromal targets progressively declined in the diseased tissues, leading to unresponsiveness to the subsequent P4 treatment

Summary

Introduction

Endometriosis is a gynecological disorder defined as the growth of endometrial glands and stroma in extrauterine locations, primarily on the surfaces of the pelvic peritoneum, ovaries, and rectovaginal septum [1, 2]. The presence of an E2 biosynthesis machinery, including elevated levels of 17β-hydroxysteroid dehydrogenase-1 and aromatase, which produces excess E2 in ectopic lesions has been reported [6,7,8]. This local E2 activates estrogen receptors (ER) to stimulate mitotic activity and inflammatory responses. Ample evidence indicates that ERβ is excessively expressed in the ectopic lesions when compared with normal endometrium [14]

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