Peritoneal Fluid Cytokines Reveal New Insights of Endometriosis Subphenotypes.

Jieliang Zhou,Chee Wai Ku,Veronique Viardot-Foucault,Jessie Wai Leng Phoon,Heng Hao Tan,Yie Hou Lee,Bernard Su Min Chern,Jerry Kok Yen Chan,Peter Barton-Smith,Tse Yeun Tan

doi:10.3390/ijms21103515

Abstract

Endometriosis is a common inflammatory gynecological disorder which causes pelvic scarring, pain, and infertility, characterized by the implantation of endometrial-like lesions outside the uterus. The peritoneum, ovaries, and deep soft tissues are the commonly involved sites, and endometriotic lesions can be classified into three subphenotypes: superficial peritoneal endometriosis (PE), ovarian endometrioma (OE), and deep infiltrating endometriosis (DIE). In 132 women diagnosed laparoscopically with and without endometriosis (n = 73, 59 respectively), and stratified into PE, OE, and DIE, peritoneal fluids (PF) were characterized for 48 cytokines by using multiplex immunoassays. Partial-least-squares-regression analysis revealed distinct subphenotype cytokine signatures—a six-cytokine signature distinguishing PE from OE, a seven-cytokine signature distinguishing OE from DIE, and a six-cytokine-signature distinguishing PE from DIE—each associated with different patterns of biological processes, signaling events, and immunology. These signatures describe endometriosis better than disease stages (p < 0.0001). Pathway analysis revealed the association of ERK1 and 2, AKT, MAPK, and STAT4 linked to angiogenesis, cell proliferation, migration, and inflammation in the subphenotypes. These data shed new insights on the pathophysiology of endometriosis subphenotypes, with the potential to exploit the cytokine signatures to stratify endometriosis patients for targeted therapies and biomarker discovery.

Highlights

Endometriosis inflicts 6–10% of women of reproductive age, with affected women suffering from debilitating pelvic pain, dysmenorrhea, dyspareunia, and painful defecation
Endometriotic lesions can be classified into three subphenotypes: superficial peritoneal endometriosis (PE), ovarian cysts, and deep infiltrating endometriosis (DIE) [2]
Immunohistochemical analyses showed a higher prevalence of cyclooxygenase-2 protein expression in ovarian endometrioma (OE) (78.5%) compared to 11.1% and 13.3% in PE and DIE [38], whereas nerve growth factor is expressed higher in DIE compared to PE and OE [39]

Summary

Introduction

Endometriosis inflicts 6–10% of women of reproductive age, with affected women suffering from debilitating pelvic pain, dysmenorrhea, dyspareunia, and painful defecation. Endometriotic lesions can be classified into three subphenotypes: superficial peritoneal endometriosis (PE), ovarian cysts (ovarian endometrioma; OE), and deep infiltrating endometriosis (DIE) [2]. Superficial peritoneal lesions refer to implants found on the pelvic organs or pelvic peritoneum. They are typically white, red, or blue–black power burns and may be phenotypically progressive over time [3,4,5]. DIE involves nodular lesions which invade the surrounding organs beneath the peritoneum [9]. They are commonly found on the uterosacral ligaments, bladder, vagina, and intestine and are more aggressive in nature [10]. The endometriosis subphenotypes are being recognized as clinicopathologically different from one another and are thought to be separate entities [3,10,11]

Methods

Discussion

Conclusion