Uterine Leukocyte Function and Dysfunction: A Hypothesis on the Impact of Endometriosis

Abstract

Endometriosis is a chronic inflammatory disease characterized by the growth of endometrial glands and stroma outside of the uterus. The disease affects approximately 10–15% of women of reproductive age and presents with clinical symptoms of pelvic pain and infertility. Changes in the leukocyte populations within the ectopic tissue and eutopic endometrium have been reported, and data suggest these alterations contribute to the pathology and symptoms of the disease. In this review, we discussed differences when comparing uterine NK cells and regulatory T cells within the eutopic endometrium between patients with endometriosis and healthy patients, and how these differences relate to implantation failure and/or decreased clearance of menstrual tissue in patients with the disease. The data demonstrate a critical need to examine endometrium and menstrual tissue in patients with endometriosis excluded from studies examining unknown causes of infertility and heavy menstrual bleeding. The information gathered from excluded patients will further enhance our understanding of how the immune system contributes to the pathophysiology of endometriosis and help to identify biomarkers for patients at higher risk for developing endometriosis‐associated infertility.

Pathogenesis of deep endometriosis

“…Pelvic endometriosis is associated with a low-grade inflammation of the peritoneal cavity with higher concentrations of activated macrophages and thus with higher concentrations of the many different cytokines (68-72) and angiogenic factors (73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91). The many immunologic disturbances were recently reviewed (92)(93)(94)(95)(96)(97)(98)(99). Specific attention was given to natural killer cells (95,100) and recently to the role of platelets in their function (101,102).…”

Pleiotropic roles of melatonin in endometriosis, recurrent spontaneous abortion, and polycystic ovary syndrome

“…11 Under both physiological and pathological conditions, melatonin and reproductive system are closely related. Oxidative stress, inflammation, and immune dysregulation are associated with the pathogenesis of the female reproductive system which causes endometriosis (EMS), 12 recurrent spontaneous abortion (RSA) 13 , and polycystic ovary syndrome (PCOS). 14 In this review, we systematically summarize and evaluate the pleiotropic roles of melatonin in EMS, RSA, and PCOS from the perspectives of neuroendocrine immunity to explore its pathological implications and treatment potential.…”

The extracellular signal‐regulated kinase 1/2 triggers angiogenesis in human ectopic endometrial implants by inducing angioblast differentiation and proliferation

“…Levels of angiogenic and growth factors in the peritoneal fluid of patients with endometriosis have been shown to correlate with the morphological severity of the disease . In addition to genetic and hormonal changes, paracrine and autocrine growth‐promoting factors as well as pro‐angiogenic and pro‐inflammatory cytokines contribute to the development of endometriosis by impairing immune regulation of endometrial tissue …”

“…Endometriosis is a chronic inflammatory and estrogen‐dependent disease characterized by the presence of endometrial tissue outside of the endometrium, with the ovarian surface, pelvic cavity, and occasionally extra pelvic organs . Endometriosis affects more than 10%‐15% of reproductive age women . Unlike normal endometrium, aberrant regulation of ectopic endometrial implants by ovarian steroids results in endometriotic tissue growth accompanied by severe dysmenorrhea, chronic pelvic pain, and infertility .…”

“…Several etiologies for this disorder have been postulated, including coelomic metaplasia of cells lining the visceral and abdominal peritoneum and/or stem cells that persist in the embryonic remnants of the Mullerian system . However, the most accepted etiological theory is retrograde menstruation, which enables recruitment of viable endometrial tissues into ectopic sites such as the peritoneal cavity with subsequent cellular attachment to peritoneal surfaces, implantation, and neovascularization prompting endometriotic tissue growth . Previous studies demonstrated elevated peritoneal levels of pro‐inflammatory chemokines monocyte chemo‐attractant protein (MCP)‐1, Interleukin (IL)‐8, fractalkine, and increased inflammatory cell recruitment, and/or elevated levels of IL‐6 and prostaglandins associated with pelvic pain in women with endometriosis …”