Peritoneal Fluid Cytokines Reveal New Insights of Endometriosis Subphenotypes

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.

CD200 and CD200R Expression on Peripheral Blood Lymphocytes and Serum CD200 Concentration as a New Marker of Endometriosis

“…More recent studies consider the chronic inflammatory response as an important part of the pathomechanism of this disease. Initially, it may appear as an increased influx of cells, followed by an acute inflammatory process that involves the local vasculature, a specific cytokine profile, and the recruitment of immunocytes [ 8 , 9 , 10 , 11 ].…”

Pain in Endometriosis

“…A recent study showed that cytokine analysis of peritoneal fluids could differentiate women diagnosed and stratified laparoscopically with ovarian endometrioma, peritoneal endometriosis, or deep infiltrating endometriosis. This suggests that certain cytokine signatures could be driving different biological signaling events and immune responses in these patients ( Zhou et al, 2020 ).…”

Peritoneal lavage cytology in the diagnosis of pelvic endometriosis

“…It occurs in 10% of women of reproductive age, 1,2 causing chronic pelvic pain and infertility. Half of the women with infertility have endometriosis 3 …”

“…The lesions can manifest as follows: superficial peritoneal implants (SPIs) in the pelvic peritoneum or pelvic organs, ovarian cysts or endometriomas, and deep infiltrating endometriosis (DIE) referring to lesions that invade the organs, such as the bladder and bowel. Interestingly, superficial lesions can have different colors on laparoscopy (white, red, or black) depending on the time that the endometriosis occurred 3 . SPIs are regulated by peritoneal fluid‐related factors, while endometriomas and DIE may be influenced by ovarian‐ and blood‐related factors 4…”