title: Progesterone Alleviates Endometriosis via Inhibition of Uterine Cell Proliferation, Inflammation and Angiogenesis in an Immunocompetent Mouse Model.
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.
authors: Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
authors: Yanfen
authors: Y
authors: Li
authors: Department of Animal Science, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
authors: Malavika K
authors: MK
authors: Adur
authors: Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
authors: Athilakshmi
authors: A
authors: Kannan
authors: Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
authors: Juanmahel
authors: J
authors: Davila
authors: Department of Molecular & Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
authors: Yuechao
authors: Y
authors: Zhao
authors: Department of Animal Science, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
authors: Romana A
authors: RA
authors: Nowak
authors: Department of Molecular & Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
authors: Milan K
authors: MK
authors: Bagchi
authors: Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
authors: Indrani C
authors: IC
authors: Bagchi
authors: Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
authors: Quanxi
authors: Q
authors: Li
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D019175:DNA Methylation; D018450:Disease Progression; D004715:Endometriosis / Q000188:drug therapy* / Q000473:pathology; D044127:Epigenesis, Genetic; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D007121:Immunocompetence; D051379:Mice; D010052:Ovariectomy; D011374:Progesterone / Q000494:pharmacology / Q000627:therapeutic use*; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction; D014599:Uterus / Q000473:pathology*
chemical_list: D047628:Estrogen Receptor alpha; D011980:Receptors, Progesterone; D011374:Progesterone; D004958:Estradiol