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

Kirstin Parkin, Asgerally T Fazleabas
American journal of reproductive immunology (New York, N.Y. : 1989) · 2016 · vol. 75(3) , pp. 411–417 · doi:10.1111/aji.12487 · PMID:26782366 · PMC6309859 · W2252778104
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⚙ AI-generated summary by claude@2026-06, 2026-06-09 ⓘ

This review examines uterine leukocyte and T cell differences in endometriosis patients, linking them to implantation failure and poor tissue clearance.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-11 · read from full text ⓘ

This paper is a hypothesis-focused review arguing that dysregulated uterine leukocyte populations in eutopic endometrium may contribute to endometriosis-associated implantation failure and impaired clearance of menstrual tissue. It discusses mechanistic roles of uterine natural killer (uNK) cells and T cells, including variable findings across studies: some report altered uNK cytotoxic receptor phenotypes and receptor–ligand KIR associations, while uNK percentages can be unchanged, and Treg markers (e.g., FoxP3) appear altered in both a baboon endometriosis model and some human ectopic-versus-eutopic comparisons, with explicit acknowledgement that human data are inconsistent and that endometriosis often excludes key menstruation-related studies. A major caveat is that much of the evidence is heterogeneous across laboratories, models, and endpoints (fertility vs recurrent pregnancy loss vs heavy menstrual bleeding), limiting firm conclusions about which immune changes are causal. This paper is centrally about endometriosis — it proposes that endometriosis-driven dysfunction of uterine leukocytes (especially uNK cells and regulatory T cells) affects implantation and menstrual tissue survival during retrograde menstruation.

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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.
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Concluding

Endometriosis is a complex, systemic disease. The two models presented in Fig. 1 demonstrate how the ‘pro-growth/pro-survival,’ indicated as ‘regulatory’ leukocyte populations, may arise in the ectopic lesions. As shown in the endogenous model, it is possible that some patients may inherit factors that promote development of more ‘regulatory’ leukocytes within their eutopic endometrium. Following retrograde menstruation, these ‘regulatory’ leukocytes promote the survival of the lesions once the eutopic endometrial tissue enters the peritoneal cavity. On the other hand, as shown in the exogenous model, it is possible that other patients may have ‘non-regulatory’ leukocytes in the ectopic endometrium. However, following retrograde menstruation, these leukocytes may respond to factors in the peritoneal microenvironment and differentiate into a ‘regulatory’ phenotype. Both pathophysiologies are possible and are difficult to dissect in human patients, as the average delay in diagnosis of endometriosis is 8–10 years from the onset of the disease. 59 In either case, the cells within the ectopic lesions survive, differentiate, and invade the serosa, resulting in the activation of an inflammatory response. The models in Fig. 1 also portray how the ectopic lesions, developed through either the ‘endogenous’ or ‘exogenous’ mechanism, may eventually affect the leukocyte populations in the eutopic endometrium. This could easily occur when cells and/or secreted factors derived from the ectopic sites circulate through the mesenteric lymphatic drainage and systemic blood that eventually recirculates through uterine blood vessels. To further enhance our understanding of the relationship between the ectopic and eutopic endometrium, results comparing the ratios of leukocytes within the ectopic endometrium, peritoneal cavity, peripheral blood, eutopic endometrium, and menstrual tissue are needed. Determining the ratios of leukocytes between these tissues within individual patients may provide an internal control for comparisons. Likewise, it is possible that comparing ratios between patients may reduce the variability in the data reported among different studies. In addition, samples from patients with endometriosis are often excluded from studies involving patients with unexplained recurrent pregnancy loss, infertility, or heavy menstrual bleeding. However, the data reviewed above demonstrate a critical need to examine the tissue in these excluded patients to understand the infertility associated with endometriosis. The information gathered from excluded group of 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. Finally, the changes in the eutopic endometrium that relate to implantation defects and/or ineffective clearance of menstrual tissue may serve as targets for future treatments.

Differences

Minimal information currently exists regarding the role of Tregs in menstruation and the viability of shed endometrial tissue. As proposed by Berbic et al., 58 macrophages, mast cells, dendritic cells, neutrophils, and eosinophils all play a role in menstruation and their functions are affected by regulatory T cells. If the functions of uterine regulatory T cells are altered by endometriosis, this may promote increased survival of shed endometrial fragments, contributing to the progression of the disease. Additional studies examining uterine Treg activity and leukocytes in the menstrual tissue from patients with endometriosis are needed to test this hypothesis.

Introduction

Endometriosis is a chronic inflammatory disease characterized by the growth of endometrial glands and stroma outside of the uterus. 1 The disease affects approximately 10–15% of women of reproductive age, 2 and the pathogenesis is due to multiple factors that vary among patients. 3 The primary clinical symptoms of endometriosis are infertility, 4 – 7 poor oocyte development, 8 dysmorphology of the Fallopian tubes, and intense abdominal pain from ectopic lesion growth. 9 , 10 Sampson’s theory of retrograde menstruation is currently the most widely accepted theory for the initiation of endometriosis. 11 However, additional mechanisms have also been proposed to explain endometriotic lesions in locations other than the peritoneal cavity such as coelomic metaplasia and metastasis of endometrial cells through the lymphatic system. 12 , 13 Sampson’s theory of retrograde menstruation is supported by animal models, 14 including the baboon model that we have used extensively in our laboratory. 15 Ectopic lesions, with similar histology to those reported in human cases, develop in the animals following inoculation of menstrual tissue into the peritoneal cavity. Leukocytes within the ectopic tissues in patients with endometriosis contribute to the survival and growth of the lesions. Studies examining ectopic endometrium have reported presence of regulatory T cells 16 , 17 and M2 macrophages, 18 low phagocytic activity of macrophages, 19 high ratios of Th2:Th1 cells, 20 and absence of NK cells 21 in the lesions. This combination of leukocytes contributes to a ‘pro-growth’ and ‘pro-survival’ environment, rather than destruction, for ectopic endometrial tissue. In addition, the leukocyte populations within the ectopic tissues of patients with endometriosis may induce changes in the leukocyte populations of the eutopic endometrium. The leukocytes within the eutopic endometrium contribute to the stromal microenvironment of the uterus through multiple mechanisms, as reviewed below. Thus, endometriosis-induced changes in the eutopic endometrial leukocyte populations may directly affect the ability of the uterus to function. The main function of the uterus is to provide an environment for implantation and growth of the developing embryo and the fetus. Each month, under the control of ovarian hormones, the stratum functionalis of the endometrium proliferates and the endometrium then differentiates in response to luteal phase progesterone in preparation for implantation. If implantation does not occur, the endometrium must be shed and the shed fragments must be eliminated to allow for the cycle to continue. Both of these stages in the monthly life cycle of the uterus, rebuilding the endometrium and shedding and eliminating the stratum functionalis in the absence of implantation, involve orchestration of endometrial leukocytes. When the endometrial leukocyte populations are dysregulated in number and/or function, the ability of the uterus to correctly regenerate the endometrium and/or eliminate shed endometrial cells is likely to be dysregulated as well. This review will focus on differences regarding the leukocytes populations within the eutopic endometrium of patients with endometriosis compared to patients without endometriosis. We will also discuss how these differences relate to implantation failure and/or decreased clearance of menstrual tissue in patients with the disease.

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Condition tags

endometriosischronic_pelvic_paininfertility

MeSH descriptors

Endometriosis Endometrium Infertility, Female Killer Cells, Natural T-Lymphocytes Endometriosis Endometriosis Endometrium Endometrium Female Humans Infertility, Female Infertility, Female Killer Cells, Natural Killer Cells, Natural Pelvic Pain Pelvic Pain Pelvic Pain Pregnancy T-Lymphocytes

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