{"paper_id":"3b9cc55a-0596-4d49-9859-064a32bc6820","body_text":"npj | women's health Review\nhttps://doi.org/10.1038/s44294-025-00059-x\nAn emerging role for neutrophils in the\npathogenesis of endometriosis\nCheck for updates\nTaylor R. Wilson, Susan Kasper & Katherine A. Burns\nEndometriosis is a chronic gynecological disease negatively impacting the health of women and is\ncharacterized by the presence of ectopic endometrial-like lesions. The immune system is implicated in\nendometriosis pathogenesis by promoting endometrial cell survival and creating a microenvironment\nfor lesion development and growth. Neutrophils are phagocytic cells that degranulate, form neutrophil\nextracellular traps, and recruit immune cells to lesions. Herein we discuss the roles of neutrophils in\nendometriosis pathogenesis.\nEndometriosis is a chronic gynecological disease affecting nearly 10% of\nreproductive-aged women (i.e., people who menstruate) 1,2.S y m p t o m s\ninclude intense pelvic pain with menstruation, chronic pelvic pain,\nincreased incidence of infertility, heavy menstrual bleeding, and associations\nwith autoimmune diseases and ovarian cancer\n3,4. This debilitating disease\nnegatively impacts the woman’s quality of life leading to social and eco-\nnomic burdens to the United State s costing more than $110 billion\nannually5,6. Regrettably, there is no definitive cure for endometriosis7,8.T h e\ncurrent standard for diagnosis is using laparoscopic surgery to visualize the\nperitoneum for ectopic lesions which then must be histologically confirmed\nfor at least two of the three hallmark characteristics 9. The most common\nhistological hallmarks for a positive diagnosis are the presence of endo-\nmetrial glands, organized stroma, and hemosiderin-laden macrophages10.\nAn additional histological hallmark being included for characterizing\nectopic lesions is firbosis\n11. Current treatments primarily target endome-\ntriosis symptoms and are mainly palliative. These treatments include sur-\ngical excision, hormonal therapies, contraceptives, and pelvic physical\ntherapy\n8,12. Surgical excision of lesions is associated with a decrease in\ndisease-associated pain; however, many individuals still require additional\nsurgical treatment within 3 years of their initial surgery7. Additional surgery\noften leads to comorbidities and additional medical complications from scar\ntissue and adhesions7. The peritoneal environment likely recognizes endo-\nmetriosis lesions as a form of injury, and in response, forms bands offibrotic\nscar tissue that adhere organs together and prevents normal movement\nwithin the peritoneum (i.e., a“frozen pelvis”). Post-surgical medical inter-\nventions such as hormonal therapies are frequently utilized to reduce the\nrecurrence of pain following surgery, unfortunately, no conclusive evidence\nis currently available relating to the long-term ef ficacy for decreased\nsymptoms using these preventative methods\n13.\nEndometriosis is classi fied into at least three subtypes: super ficial\nperitoneal, ovarian endometrioma, and deep infiltrating14. The subtypes are\nclassified based on their location and the extent or depth of lesion\ninfiltration15. Deep in filtrating lesions are considered as the most severe\nform of the disease 16,17. Endometriosis research has heavily focused on\nestablished disease, whereas the initiation and early development of endo-\nmetriosis has garnered far less attention. A current theory characterizes the\nperitoneal cavity as a local in flammatory environment whereby inflam-\nmatory cells, including neutrophils and macrophages, exacerbate and pro-\nmote the pathogenesis of endometriosis\n18–21. To date, studies have primarily\nfocused on the role of macrophages i n promoting endometriosis, while\nm u c hl e s si sk n o w no nt h er o l eo fn e u t r o p h i l si nd i s e a s ep a t h o g e n e s i s ,\nparticularly, the role of neutrophils in the early stages of lesion development.\nOur review presents current knowledge of the functions of neutrophils,\nincluding phagocytosis, antigen presentation, cytokine release, immune cell\nrecruitment, degranulation, and NETosis (i.e., the process of releasing\nneutrophil extracellular traps (NETs)) in the pathogenesis of endometriosis\nand includes a discussion on current research gaps in thefield.\nEtiology of endometriosis\nWhile the exact cause of endometriosis is unclear, lesions are known to be\nendometrial-derived tissue22–24 with murine model evidence demonstrating\nthat endometrial tissue (and not mammary gland, bladder, or lung) forms\nthe endometriotic lesions\n25. Although numerous theories surround the\netiology of endometriosis, a leading hypothesis is via retrograde men-\nstruation in which menstrual effluent containing viableendometrial tissue\nflows back through the oviduct and into the peritoneal cavity26,27. In support\nof this hypothesis, laparoscopic surgery performed during the perimenstrual\nperiod, 90% of women had menstrual blood in their peritoneal cavity27.I n\ncontrast, 15% of women with occluded oviducts exhibited evidence of blood\nin their peritoneal cavity\n27. While nearly all women experience retrograde\nmenstruation, only 10% of reproductive aged women are diagnosed with\nendometriosis2,26 suggesting the etiology and pathobiology of endometriosis\nis highly multifaceted. An important caveat is that only humans and non-\nhuman primates develop endometriosis naturally\n28.B o t hs p e c i e sh a v ea n\nopen reproductive system (i.e., the ovary is not connected to the oviduct)\nwhile all other mammalian species have a closed reproductive system (i.e.,\nDivision of Environmental Genetics and Molecular Toxicology, Department of Environmental and Public Health Sciences, University of Cincinnati, C ollege of\nMedicine, Cincinnati, OH, USA. e-mail: Katherine.burns@uc.edu\nnpj Women's Health |             (2025) 3:9 1\n1234567890():,;\n1234567890():,;\n\nthe ovary is surrounded by a bursa from the oviduct) and do not develop\nendometriosis naturally. The open reproductive tract allows for the retro-\ngrade flow to occur\n26; thus, retrograde menstruation is a leading theory of\nhow menstrual effluent is found in the peritoneal cavity and how eutopic\nendometrial tissue can be displaced from the uterus to form ectopic endo-\nmetrial lesions in the peritoneal cavity.\nBesides viable endometrial cells, menstrual ef fluent contains a mix-\nture of red and white blood cells associated with the late secretory phase of\nthe menstrual cycle\n29,30.T h ee ffluent also contains a variety of proteins that\nare required as part of a healthy menstrual cycle 29,30 that regulates the\nfunctions of proliferation, migration, apoptosis, hematopoiesis, and\nreproduction\n29. Menstrual ef fluent is distinct from peripheral blood and\nmore closely resembles the uterine immune microenvironment31. Due to\nthe inherent in flammatory nature of menstruation, a dysfunction of\nimmune signaling during menstruation could disrupt normal processes\nresulting in an altered in flammatory state that would contribute to the\ndevelopment and/or exacerbation of endometriosis. Together, menstrual\neffluent studies are likely to be crucial to understanding the immune\nrelated components of lesion development and the pathogenesis of\nendometriosis.\nAlthough endometriosis was previously considered only a hormonally\ndriven disease\n32–34, it is now considered both an immune and a hormonally\ndriven disease35. Further, insights into the functions of the immune system\nsupports the likelihood th at the initiation of the disease is regulated by\nimmune interactions21,25. The exact early mechanisms of lesion formation\nare unknown, but the innate immune system is a strong contender as a\ncontributor of the early effector cells inlesion development. Neutrophils are\nthe first immune cells to respond to injury 36, and in a mouse model of\nendometriosis as we cannot study lesi on initiation in women, these cells\nwere identi fied as the initial responding cell after the induction of\nendometriosis21, demonstrating the importance of neutrophils in the early\nstages of lesion formation. Shortly a fter the neutrophil response in the\nmouse model of endometriosis, macrophages respond in the early disease\ndevelopment and are implicated in the processes of tissue remodeling and\nthe angiogenic processes associated with lesion establishment\n37,38.T h ee x a c t\ninteractions among all the different cell types (i.e., immune cells and epi-\nthelial and stromal cells from the endometrium) are in their infancy, but\nn e u t r o p h i l sa n dm a c r o p h a g e se i t h e rw o r ki nc o n j u n c t i o nw i t he a c ho t h e rt o\npromote lesion development or they play independent roles in the patho-\ngenesis of the disease. While macro phages are beyond the scope of this\nreview, strong reviews are published that focused on endometriosis and\nmacrophages (See review by Hogg et al.\n39).\nImmune cell responses are critical to maintaining a balanced and\nhealthy uterine environment as these cells prevent injury and coordinate\nrepair processes during menstruation\n40,41. Neutrophil, macrophage, and\nuterine natural killer cells are recruited to the endometrium during the late\nsecretory phase; the influx of these cells establishes and primes the immune\nmilieu prior to the onset of menses\n40. During menstruation, white blood cells\naccount for ~40% of the cell volume with neutrophil, macrophage, and\nuterine natural killer cells accounting for the majority of the leukocyte\nvolume\n40,42. The presence and importance of these white blood cells in\nmenstrual effluent may indicate why these specific cells are recruited and\nfurther increase during the late secretory phase prior to the onset of\nmenstruation\n41,43. Since the late secretory stage progresses to menses, these\ncells would comprise a majority of the immune cells which would enter the\nperitoneal cavity during retrograde menstruation. This increase of neu-\ntrophils just prior to the onset of menstruation is one key reason why these\ncells are of particular interest in endometriosis.\nNeutrophil origin and functions\nNeutrophils, polymorphonuclear phagocytic leukocytes, are often con-\nsidered the first line of defense in in flammatory processes44.N e u t r o p h i l s\noriginate from hematopoietic stem cells in the bone marrow. An estimated\none-hundred billion white blood ce lls are produced each day and neu-\ntrophils comprise about 70% of leukocytes in the human body\n45.T h ed a t a\nsupporting the lifespan of the neutrophil in circulation is quite variable and\nranges from a half-life of 6–8h 45 to 5.4 days under homeostatic conditions46;\nthus, indicating neutrophil aging is a complex and dynamic process where\nthe neutrophil lifespan greatly depends on responses to physiological stimuli\nor chronic inflammatory events\n47–49. Of note, in ex vivo studies, neutrophils\ntypically do not survive longer than 24 h46, augmenting the complexities and\narduous task of studying neutrophils in healthy and diseased states. Neu-\ntrophils mature in the bone marrow a nd enter blood vessels where they\ncirculate until extravasation towards sites of injury via transendothelial\nmigration\n50. In order to remove neutrophils from circulation or tissues,\neither macrophages clear aged, damag ed, and apoptotic neutrophils via\nphagocytosis and/or neutrophils are returned to the bone marrow for\nclearance\n51. Maintaining a constant homeostatic balance of neutrophils is\ncrucial for health; however, imbalances can exacerbate inflammatory con-\nditions and/or infections. In a healthy state, the number of neutrophils is\nmaintained as a constant homeostatic balance due to strict regulation of the\nnumber of eliminated and newly differentiated neutrophils52.\nThe differentiation and maturation of neutrophils is highly regulated\nby granulocyte colony-stimulating factor (CSF3/GCSF) which serves as a\nregulator for neutrophil proliferation, differentiation, and maturation\n32.\nInterestingly, GCSF receptor expression on neutrophils is not suf ficient\nalone for mobilization from the bone marrow indicating that GCSF indir-\nectly affects neutrophils via trans-ac tivating signals such as the down-\nregulation of stromal cell-derived factor 1 (SDF1/CXCL12) which acts as the\nligand for the C-X-C chemokine receptor 4 (CXCR4)\n53, a chemokine\nreceptor highly expressed on immature and aged neutrophils11.I na d d i t i o n\nto CSF3/GCSF and CXCR4, CXCR2 is another C-X-C chemokine receptor\non the cell surface acting as a maturation signal for neutrophils. As neu-\ntrophils mature, signaling in con cert with CXCR2 permits neutrophil\nmobilization from the bone marrow into the vasculature and circulation\n54,55.\nNeutrophil recruitment and chemotaxis are highly balanced and controlled\nby a CXCR2/CXCR4 axis\n54 with the cell surface expression of these receptors\nfluctuating over the lifetime of the neutrophil. As the neutrophil matures in\nthe bone marrow, a switch occurs between the levels of CXCR2 and CXCR4\non their cell surface. Immature neutrophils express increased CXCR4 levels\non their cell surface in the bone marrow, while increased CXCR2 levels are\nr e q u i r e dt om i g r a t eo u to ft h eb o n em a r r o w\n55. As neutrophils age, they again\nbegin to present higher levels of CXCR4 on their cell surface allowing them\nto migrate back to the bone marrow for clearance from the body54.\nNeutrophils demonstrate these different phenotypic shifts (i.e., aging\nor maturing) which can occur over the course of a single day 49.H y p e r -\nsegmentation of neutrophils, characterized by an increase of nuclear lobules,\nis the result of the aging process 36. Aged neutrophils in circulation upre-\ngulate CXCR4 which allows re-entry into the bone marrow for clearance.\nThis highly coordinated process is important for maintaining a homeostatic\nbalance of neutrophil subtypes in the body\n55,56. For example, CXCR4high cells\nare often senescent and considered towards the end of their lifespan55.W h i l e\nthe bone marrow plays a predominate role in neutrophil clearance, they are\nalso cleared by the liver and spleen 57.A sd e t a i l e da b o v e ,t h eC - X - Cc h e -\nmokine receptors, CXCR2 and CXCR4, are used as a method for differ-\nentiating between the life cycle stagesof neutrophils. In addition to being a\nmarker for age, CXCR4\nhigh neutrophils are also associated with reactive\nfunctions like NET formation is detailed below58.\nThe neutrophil is a versatile cell type with a wide range of functions\nincluding surveillance, aiding in angiogenesis, phagocytosis, antigen\npresentation, releasing a plethora of cytokines, NETosis, and degranu-\nlation (Fig. 1). With a variety of functions, neutrophils are equipped to\nmitigate and exacerbate the in flammatory response at sites of injury.\nAlthough some of these functions have not yet been formally linked to the\npathogenesis of human endometriosis, these cells are likely a contributing\nfactor in inflammatory responses in the peritoneal cavity. By examining\nthe functions of neutrophils, we propose to explain potential applications\nof neutrophils in disease by explaining their functions in similar\ninflammatory conditions while presenting current theories for their\nrole(s) in endometriosis.\nhttps://doi.org/10.1038/s44294-025-00059-x Review\nnpj Women's Health |             (2025) 3:9 2\n\nNeutrophils in endometriosis\nNeutrophils are likely key components in the progression and pathogeny of\nendometriosis20,37,59. Once neutrophils arrive at an injury site, their activa-\ntion responses depend on the source and severity of injury. Neutrophils are\nfound altered in eutopic endometrium as well as ectopic lesion sites. In\nrelation to the role of the CXCR2/CX CR4 axis, CXCR2 transcript levels\nincreased in the eutopic endometriumof endometriosis patients compared\nto control patients\n18. This elevation of CXCR2 in endometriosis patients\nsuggests increased neutrophil recruitment to the uterus which in turn would\ncorrespond with elevated levels in the peritoneal cavity and may provide\ninsight into targeted treatments in the future. Indeed, in the peritoneal cavity\nof endometriosis patients, neutrophil numbers were increased compared to\nhealthy control patients\n60,61. Furthermore, the endometriosis patients had\nincreased levels of human neutrophil peptides 1, 2, and 3 which are also\nk n o w na sd e f e n s i n s\n60,61. The defensins elicit immune regulatory effects;\nhowever, their role in endometriosis is not well understood. Recent data\nsuggest that the upregulation of human β-defensin-2 in ectopic endome-\ntrium may be due to TNF or IL1β, but the activity has not yet been directly\nlinked to neutrophil-speci fica c t i o n s62.A d d i t i o n a l l y ,t h ea b i l i t yo fn e u -\ntrophils to respond to different acti vation signals was dysregulated in\nindividuals with endometriosis suggesting an alteration in the induced\nproinflammatory response\n63. Other neutrophil dysfunctions, such as\ndecreased phagocytosis, were also observed in endometriosis patients to\nfurther support the notion that neutrophils contribute to the pathogenesis\nor the lack of clearance of endometrial tissue in the peritoneal cavity\n64,65.\nThe activity of neutrophils in endometriosis has been largely under-\nstood using murine models as a method of examining lesion initiation and\nprogression in relation to mechanism(s) of the disease development 20,66.\nWhile limitations exist with these models and the induction process is\ndifferent compared to human retrograde menstruation, these pre-clinical\nmodels provide basic mechanistic concepts that mimic aspects of human\ndisease. While no model will ever perfectly recapitulate the pathogenesis of\nendometriosis, animal studies allow for an ethical approach to studying the\ninitiation and progression of the dis ease without causing additional dis-\ncomfort or harm to human subjects. Anexample of the usefulness of mice\nincludes utilizing neutrophil depletion to modify the systemic and perito-\nneal immune microenvironment which contributed to understanding the\nmodulation of angiogenic and pro-inflammatory factors in endometriosis\n20.\nIn addition, neutrophils recruit macrophages which contributed to tissue\nremodeling processes once lesions were established in a mouse model of\nendometriosis\n37. Both neutrophils and macrophages produce proangiogenic\nfactors which are ultimately necessary for the growth and stabilization of\nlesions37. Mouse translational studies are not only utilized for toxicity testing\nof potential therapeutics or drugs 67–71, but can be bene ficial to explicate\npotential mechanisms and roles of neutrophils in human endometriosis\npathogenesis.\nNeutrophil immunosurveillance initiates chemotaxis\nOne of the primary functions of neutrophils is to perform immuno-\nsurveillance where they circulate in the vasculature and transition between\nan adherent and non-adherent state until they encounter an antigen or\nactivation signal where they will then migrate and extravasate to the site of\ninjury\n36,72. Studying immune surveillance in endometriosis is rather complex\ndue to temporal limitations and nonspecific interactions which can initiate\nthe activation of cells. The numbers of neutrophils found in the peritoneal\nfluid of patients with endometriosis is higher compared to other\nleukocytes60, but the underlying initiating factors which activate neutrophils\nto migrate to the peritoneal cavity is largely unknown. Neutrophils do\nparticipate in immunosurveillance, but whether they are hypersensitive or\nreceive an assault of cytokine and chemokine signals causing the initial\nmigration is also unknown. Factors such as CXCL8/IL8, IL6, and C-X-C\nchemokines\n73–75 are potential culprits that may play a role in the initial shift\nfrom surveillance to extravasation a nd activation. Overall, the complex\nprocess is likely a combination of chemotactic factors that results in the\ninherent difficulty of identifying if“one” single instigator exists.\nNeutrophils promote angiogenesis via vascular endothelial\ngrowth factor (VEGF)\nAngiogenesis, the formation of new blood vessels from pre-existing vessels76,\nis essential for the survival of new and developing tissues. The exact\nFig. 1 | Schematic representation of the potential\nactions of neutrophils in endometriosis patho-\ngenesis. Neutrophils (purple) in circulation actively\nmonitor for the presence of antigens or chemokines\nvia surveillance. Upon receiving a chemotactic sig-\nnal, neutrophils extravasate into the peritoneal\ncavity where antigens and cytokines from lesion cells\n(green) activate neutrophils to initiate and/or pro-\nmote corresponding functions: angiogenesis, pha-\ngocytosis, antigen presentation, cytokine release, cell\nrecruitment, NETosis (the process of releasing\nneutrophil extracellular traps), and degranulation.\nIn combination, neutrophils (red line) and lesion\ncells (green line) promote angiogenesis through the\nrelease of proangiogenic factors. Following phago-\ncytosis, neutrophils may participate in antigen pre-\nsentation (dotted line) to T cells (dark blue) similar\nto other antigen presenting cells. Cytokine release\ntriggers cell recruitment of T cells (dark blue),\nmacrophages (light blue), and/or eosinophils (red)\nand may accompany NETosis (dotted line). Degra-\nnulation may occur in conjunction with NETosis\n(dotted line) or independently (solid line). Collec-\ntively, the activated neutrophil functions, both\ndefinitive (solid lines) and proposed (dotted lines),\ncrosstalk with the lesion cells to promote a more\npermissive microenvironment in the peritoneal\ncavity resulting in lesion development and survival.\nhttps://doi.org/10.1038/s44294-025-00059-x Review\nnpj Women's Health |             (2025) 3:9 3\n\nmechanism for the angiogenesis of dev eloping endometriotic lesions is\nunclear, but evidence exists to supportthat neutrophils act as active effector\ncells in this process. In endometrial samples collected from normal cycling\nparticipants, neutrophils were the predominant immune cell that stained for\nVEGF, suggesting these cells actively regulate vascular proliferation in the\nendometrium77. Neutrophils release chemokines and cytokines like VEGF to\npromote angiogenesis by activating endothelial cells. The release of enzymes\nfrom neutrophils (e.g., elastase and cathepsin G) activate matrix metallo-\nproteinases (MMPs) in the stroma which leads to the breakdown and the\nprocess of tissue remodeling of the extracellular matrix\n40. Recent findings\nshowed neutrophil functions were modified by IL6 and CSF3/GCSF via the\nSTAT3 pathway resulting in an alter ation of gene expression levels of\nangiogenic-related genes (i.e., MMP9, PROK2, and TNFSF10) to enhance\nangiogenesis78 which, in turn, could promote the survival of endometriotic\nlesions. MMPs and VEGF work in conjunction with one another by first\ndegrading and/or remodeling the extracellular matrix allowing for\nneovascularization79.V E G Fw a sf o u n dt ob ee l e v a t e di nt h ep e r i t o n e a lfluid\nand serum of patients with endometriosis80 supporting the hypothesis that\nactive angiogenesis occurs in the per itoneal cavity mic roenvironment.\nNeutrophils are one of the predominant immune cells associated with VEGF\nand are most abundantly found in the late secretory phase and pre-\nmenstrual phase of the menstrual cycle. A major function of the neutrophil\nin these phases is regulation of the endometrial vasculature\n77 which suggests\nthat neutrophils are critical in the homeostasis of menstruation.\nVEGF is crucial in periods of oxygen deprivation events like hypoxia81.\nHigher transcript levels of endocrine-gland-derived VEGF (EG-VEGF) was\nfound in lesions compared to eutopic endometrium82 demonstrating that\nthe lesions are actively attempting to survive by promoting angiogenesis.\nTypically, CXCL8/IL8 is considered a proinflammatory cytokine, but it can\nalso be pro-angiogenic in function. Both VEGF and CXCL8/IL8 are elevated\nin ovarian endometriomas\n83 which indicates a connection to angiogenesis.\nIntriguingly, when neutrophils fr om healthy patients were exposed to\nperitonealfluid isolated from endometriosis patients, thefluid induced the\nsecretion of VEGF from the neutrophils84. However, when CXCL8/IL8 or\nTNF were blocked using antibody treatment ex vivo, the endometriosis\npatient-derived neutrophils still rel eased VEGF indicating that patient-\nderived neutrophils are a source of peritoneal VEGF independent of\nCXCL8/IL8 and TNF\n84 suggesting that neutrophils from endometriosis\npatients may respond to or promote angiogenesis utilizing pathways or\nmechanisms that are not readily used by the neutrophils in healthy patients.\nTogether, these findings suggest the plasticit y of angiogenesis within\nendometriosis lesions is able to shift to CXCL8/IL8 independent pathways\naccommodating the needs of the peritoneal cavity. Additional endome-\ntriosis studies also demonstrated increased VEGF levels in the peritoneal\nfluid of endometriosis subjects compared to healthy controls\n85,86.I n t e r e s t -\ningly, in an oral contraceptive study,VEGF was elevated in the peritoneal\ncavity of patients with endometriosis; however, the use of birth control\nwhich is a common treatment modality for endometriosis did not affect the\nlevels of VEGF\n87. Thus, angiogenesis of lesions does not appear to be directly\ninfluenced by hormonal treatments. Theeffects of hormonal therapies and\ntreatments for endometriosis cause additional complications to elucidate\nthe underlying mechanism(s) of angiogenesis and neutrophil function.\nEndometriosis lesions may be classified by coloration (e.g., red or black). In a\nstudy comparing red and black endom etriosis lesions, red lesions were\nobserved with elevated VEGF levels compared to black lesions, likely indi-\ncating that the red lesions are at an earlier stage of development than black\nlesions\n88.T h e s efindings also highlight that variability in VEGF levels will be\nobserved based on lesion stage and activity (i.e., early implantation versus\nfully established). In general, the elevated VEGF levels identified in endo-\nmetriosis patients and lesions suggests that angiogenesis is a key component\nof lesion survival and that neutrophils are likely effector cells for angio-\ngenesis during lesion development.\nA normal function of the uterus is tissue growth during endometrial\nrepair post-menstruation—t h i sp r o c e s si ss t r o n g l yh y p o x i ca n ds e r v e st h e\nlocal microenvironment as a stimulus for VEGF expression and subsequent\nneoangiogensis of the endometrium\n89. In patients with ovarian endome-\ntriomas, gene expression ofhypoxia-inducible factorα (HIF-1/2A), VEGF,\nand protease-activated receptors 1 and 4 (PAR1 and PAR4) were con-\nsiderably elevated over healthy control patients\n90. However, in patients with\ndeep infiltrating endometriosis, these difference were not observed90 sug-\ngesting that more established disease already has a well-established blood\nsupply\n88 and would not require these factors or the factors may be cyclical in\nnature dependent on the stage of the menstrual cycle. As mentioned above,\nhypoxic events promote angiogenesis, but these events also serve as an\ninducer of epithelial-mesenchymal transition (EMT). Thus, the hypoxic\nnature of menstruation likely acts as an inducer of the EMT found in lesion\ntissue\n91,92, but also supports hypoxia as an inducer of angiogenesis and cell\nmigration. Hypoxia occurs in the end ometrium during menstruation by\ninducing HIF1A, a process that is important for healthy repair and function\nduring a healthy menses\n93. Individuals with heavy menstrual bleeding have\ndecreased endometrial HIF1A during menstruation and have prolonged\nmenstrual bleeding93 which may suggest that the inability to repair the\nendometrium properly during menstruation leads to a disruption of normal\nfunction. HIF1A is stabilized by the release of mitochondrial reactive oxygen\nspecies (ROS) by neutrop hils during NETosis\n94, thus linking neutrophil\ndysfunction to potential alterations in the hypoxic conditions during\nmenstruation. In regard to the retro grade hypothesis, since HIF1A is\nnaturally a part of menstruation, ab errant hypoxic function may induce\nmechanistic changes during menstrual flow modifying retrograde men-\nstrual ef fluent resulting in an altered microenvironment inside of the\nperitoneal cavity permissive to lesion establishment\n93.I no t h e ro r g a n sl i k e\nthe lungs, hypoxia can increase deg ranulation and protease release in\nneutrophils95. Whether these similar functions occur in endometriosis has\nnot yet been identified but may be an area of scienti fici n t e r e s t .W h i l et h e\nexact mechanism of how neutrophils influence angiogenesis is unclear, the\nsupporting evidence suggests neutro phils mediate angiogenesis directly\nthrough secretion of VEGF and their interactions with hypoxic factors.\nNeutrophil phagocytosis is reduced in endometriosis\nPhagocytosis by neutrophils and other effector cells is the primary method\nof clearance used for antigens and cellular debris to maintain homeostatic\nbalance in the body. Sites of in flammation often enhance phagocytosis;\nhowever, a defect in this process can alter how neutrophils respond to\ninflammation (i.e., inducing additionalNETs or increased cytokine release).\nMacrophages are often distinguished as the main phagocytic cell type which\ningest apoptotic and non-apoptotic neutrophils\n96. However, macrophages\nmay not be the only cells involved in neutrophil clearance—findings in mice\nshow neutrophil cannibalism, the act of neutrophils phagocytosing other\nneutrophils, has been observed in lung in flammatory conditions when\nmacrophages do not suf ficiently quell or regulate the neutrophil in flam-\nmatory response\n97. While this mechanism is not yet characterized in\nhumans, it could be an area of future study for inflammatory conditions like\nendometriosis. Additionally, while neutrophil autophagy (e.g., self-\ncannibalism or self-ingestion) is known to occur in human neutrophils98,\nthis function is also not yet linked to endometriosis. These phagocytic\nprocesses pose for an intriguing area of endometriosis research to determine\nif these functions occur and whether they alter clearance of immune cells to\nalter the proin flammatory responses in the peritoneal cavity during\npathogenesis. A compelling study e xamined the phagocytic activity of\nneutrophils from peripheral blood and found that patients with endome-\ntriosis had reduced phagocytic function\n64,99, but their neutrophil phagocytic\nfunction increased 1-week post operatively and was comparable to the\nphagocytic function of non-endometriosis controls\n64. Additionally, the\nsame research group, found that pre-operative, peripheral blood neutrophils\nfrom endometriosis patients demonstrated improved phagocytic function\nwhen exposed to plasma from individuals without endometriosis. On the\nother hand, when healthy control neutrophils were exposed to plasma from\npatients with endometriosis, phagocytic function decreased\n65 suggesting\nthat the cytokine and/or chemokine com p o s i t i o ni np l a s m ad i r e c t l yn e g a -\ntively alters neutrophil phagocytic function in endometriosis. Together\nhttps://doi.org/10.1038/s44294-025-00059-x Review\nnpj Women's Health |             (2025) 3:9 4\n\nthesefindings suggest that ectopic lesions in endometriosis patients initiate a\nlocal altered immune response (i.e.,immune suppressive) which may lead to\nreduced function in circulating neutrophils resulting in a systemic inflam-\nmatory dysfunction64.\nThe altered phagocytic function of neutrophils could result in the\ninability to clear ectopic endometrial tissue, thus, increasing the likelihood of\nlesion development and a chronic pro-inflammatory environment in the\nperitoneal cavity. In contrast to neutrophils where heme is an activator of\nphagocytosis via oxidative burst\n100, in macrophages elevated concentrations\nof heme in peritoneal fluid of endometriosis patients impairs their phago-\ncytic activity101 which suggests that during events like retrograde men-\nstruation, neutrophil function may or may not be a compensatory\nmechanism for impaired macrophage phagocytic activity. Whether heme\nactivates neutrophils in the peritoneal cavity in endometriosis or neutrophils\nare desensitized to heme resulting in reduced clearance of viable endo-\nmetrial tissue is unknown, but these functions are compelling research\navenues worth delving into deeper to understand the mechanisms in the\ninitiation phase of endometriosis. O verall, these changes in phagocytic\nactivity could indicate that neutrophils, macrophages, and other immune\ncells are desensitized to the heme fo und in menstrual blood leading to a\nphagocytic dysfunction in endometriosis. Although many differences exist\nbetween peripheral blood and menstrual effluent, an underlying difference\nin activity may be present in the overallphagocytic activities in neutrophils\nfrom individuals with endometriosis. Further studies are necessary to\ndetermine the characteristic differences in phagocytosis to understand\nwhether cytokines, heme, or some other unknown factor(s) is the direct\ncause of this dysfunction found specifically in patients with endometriosis.\nNeutrophils serve as antigen presenting cells\nMore recent findings suggest that neutrophils possess the ability to act as\nantigen-presenting cells, specifically in response to CD4+ memory T cells.\nAlthough monocytes and dendritic cells show a higher affinity and efficiency\nfor antigen presentation, human and primate neutrophils have demon-\nstrated the ability to adapt and participate in the antigen presenting\nprocesses\n102,103. When human neutrophils phagocytose red blood cells, they\npossess the ability to express MHC II along with the primary costimulatory\nmolecules (e.g., CD40 and CD80) required for antigen presentation to\nTc e l l s\n103. In humans, subsets of T memory cells have been identi fied as\nparticipating in surveillance functions in the female reproductive tract and\nthese cells are regulated throughout the stages of the menstrual cycle through\na CCR5 signaling pathway\n104.A d d i t i o n a l l y ,i nh i g h l yi nflammatory events\nl i k es e p s i s ,a g e dn e u t r o p h i l sa r ea b l et oi n d u c eC D 4+ T cells to exacerbate the\ninflammatory environment105. While the presence of these subpopulations\nof memory T cells in lesions nor their interactions between neutrophils and\nCD4\n+ T cells have not been elucidated in endometriosis, the communication\nof how the neutrophils communicate with T cells via antigen presentation in\nendometriosis would be a compelling area of research. The ability of antigen\npresentation by neutrophils in endometriosis pathogenesis is an undeve-\nloped area of research that would help refine the role of neutrophil migration\nand/or lymphocyte responses directly in lesion development.\nNeutrophil associated cytokines are modulated in endometriosis\nNeutrophils, as well as other immune ce lls, release cytokines to regulate\ninflammatory responses to recruit additional cells, initiate angiogenesis, or\ntrap foreign materials that promote injury72,106,107.C X C L 8 / I L 8 ,ac h e m o k i n e\nproduced by neutrophils, plays a role in the chemotaxis, release of lysosomal\nenzymes, and upregulation of adhesion molecules and initiation of oxidative\nburst in neutrophils\n108–110. CXCL8/IL8 was found to be abnormally regulated\nand elevated in the peritoneal ca vity of women with endometriosis111–113.\nInterestingly, in a study of infertility, endometriosis patients had increased\nIL6 and CXCL8/IL8 in their peritonealfluid and also had increased CXCL8/\nIL8 in their serum114. The increase of CXCL8/IL8 in the serum suggests a\nsystemic inflammatory reaction from neutrophils that is not confined to the\nectopic lesions or the peritoneal cavity environment. When neutrophil\ncultures were treated with peritonealfluid from endometriosis patients, the\nlevels of CXCL8/IL8 and CXCL10 were elevated\n115 indicating neutrophils\nnot only produce but are a source of these cytokines in the peritonealfluid.\nIn a surgical excision study, 2 weeks following surgery, the levels of CXCL8/\nIL8 in plasma decrease signi ficantly\n116 suggesting that communication\nbetween lesions and immune cells regulate the inflammatory state not only\nof the microenvironment, but systemically as well. A unique and recent\nhypothesis regarding the menstrual cycle is that the levels of CXCL8/IL8 do\nnot vary and are not affected by the cyclical variation of the menstrual cycle;\nhowever, this finding was debunked by the ability of estrogen which\nenhances cell responsiveness to IL1 in endometriosis lesions and in turn, IL1\ninduces CXCL8/IL8\n117 which aids in explaining the elevated CXCL8/IL8\nlevels found in endometriosis patients. Furthermore, progesterone also\nstimulates CXCL8/IL8 which indicates that the sex steroid hormones pro-\nmote inflammatory responses indirectly by elevating CXCL8/IL8 mRNA\nand protein\n73. Even though IL1 is not a direct recruiter of neutrophils118,t h i s\ncytokine leads to the increase of othe r chemokine ligands which attract\nneutrophils to the site of injury 119. However, neutrophils do not express\nestrogen receptor alpha or progesterone receptor 77, indicating that neu-\ntrophil responses are indirectly hormonally driven.\nIL6 is a unique chemokine which acts as both a pro-inflammatory and\nanti-inflammatory regulator120,121, and has been observed to be elevated in\nthe peritoneal cavity of women with endometriosis87. In mice, IL6 is elevated\nin the first few days of disease initiation, but drops after lesion\nestablishment21 suggesting this cytokine is influential in the early stages of\nlesion development. Upon in flammatory progression, IL6 can promote\nneutrophilia, an increase of neutrophils in peripheral blood, and can control\ntrafficking of leukocytes74 which could lead to an overabundance of neu-\ntrophils and a dysregulated inflammatory microenvironment. The increase\nof IL6 in patients with endometriosis leads to the hypothesis that this\ncytokine is important to lesion development and survival.\nIn comparison to the role of IL6 in lesion development, in the early\nstages of injury, damage-associated molecular patterns (DAMPs) are\nreleased. DAMPs directly recruit neutrophils to sites of injury\n122; however,\nwith endometriosis no external wound or infection is present. The endo-\nmetriosis microenvironment may be considered a sterile in flammatory\nevent suggesting that neutrophils may also be recruited to sites of lesion\nestablishment by DAMPs. In ovarian endometriomas, neutrophil responses\npossessed an immunosuppressive function and an extended lifespan59 due\nto the induction of programmed death-ligand 1 (PD-L1), a controller of T\ncell responses and immune tolerance59, which suppressed the proliferation\nand function of T cells in endometriosis patients. Importantly, regulatory\nT cells are de ficient in endometriosis\n123 and can produce the potent neu-\ntrophil chemoattractant CXCL8/IL8124. Whether the regulatory T cells\ndirectly contribute to the dysregulation of normal immune functions and\nthe ability to properly regulate the immune inflammatory response in the\ncase of neutrophil recruitment is unclear. Together, the reduction of T cells\nmay possibly stem from neutrophil dysfunction in endometriosis patients.\nAdditional clinical research is needed to determine the neutrophil effects on\nT cell regulation in endometriosis and the direct role that DAMPs play in\nactivation of neutrophils specifically in patients with endometriosis.\nNeutrophil extracellular trap formation is elevated in\nendometriosis\nEarly NET formation was initially considered a form of apoptosis or necrosis\nand was named accordingly as it was often accompanied by cell death125,126.\nNETosis, or the process of NET formation, occurs via two pathways: a lytic\nor cell death pathway and a non-lytic pathway. The lytic pathway involves\nchromatin decondensation accompanied with the loss of cell polarization\nwhere chromatin is expelled via plasma membrane rupture. The non-lytic\nformation of NETs involves the excretion of chromatin and is accompanied\nby degranulation. In the non-lytic form of NETosis, the cell is viable and\nprovides conventional neutrophil effector functions\n127 such as the formation\nof anucleated cytoplasts that ingest and clear foreign substances 128.O n e\nvariation from apoptosis is that NETosis does not require activation of\ncaspases\n128,129. Although the initiation process of NETosis is not entirely\nhttps://doi.org/10.1038/s44294-025-00059-x Review\nnpj Women's Health |             (2025) 3:9 5\n\nunderstood in diseases such as endometriosis, one hypothesis is that\nNETosis is centered around mitochondrial induction. Neutrophil mito-\nchondria produce ROS via NADPH oxidase in glycolysis. The ROS pro-\nduced via the mitochondria are speculatedt ob er e s p o n s i b l ef o rt h ei n i t i a t i o n\nof NETosis\n130,131. Current research areas related to neutrophils are focused\non the function of NETs in the progression of endometriosis. NETs are\nincreased in circulation in endometriosis patients as observed in venous\nblood collected at time of laparoscopic surgery\n19,132 with the highest levels\nquantified in patients with deep infiltrating endometriosis132. In peritoneal\nfluid, the presence and quantification of NETs was elevated in endometriosis\npatients compared to patients without the disease 19. Interestingly, in the\nsame study, neutrophils from control patients treated with peritonealfluid\nfrom patients with endometriosi s did not stimulate NET production 19\nindicating that NETs released in endometriosis may be due to an\nendometriosis-specific dysfunction in neutrophils and not due to the\nresponse to the cytokines or products found in the peritoneal fluid.\nIncreased NET levels in endometriosis patients indicates the likelihood of a\nmore chronic in flammatory status\n19,20 which may contribute to a more\nsystemic effect as evidenced by theincrease of NETs in the circulation19,132.\nMyeloperoxidase (MPO), a byproduct of NETs, was elevated in ovarian\nendometriomas in comparison to eutopic endometrium\n20, illustrating that\nthe release of NET byproducts in the lesion microenvironment promotes a\nmore inflammatory state compared to the eutopic endometrium. MPO is\nalso suspected as a contributing infertility factor in endometriosis because\nthe follicular fluid of patients with endometriosis undergoing IVF treat-\nments contained MPO levels that were significantly higher than in control\nfollicularfluid\n133, and is thus proposed as a potential target in the treatment\nof infertility in endometriosis. Utilizing a surface plasmon resonance ima-\nging biosensor, cathepsin G levels , another byproduct of NETs, were\nobserved to be doubled in the endometrium from patients with endome-\ntriosis as compared to the control group\n134 which again demonstrates the\ninflammatory microenvironment of endometrium in endometriosis\npatients is amplified or exacerbated in comparison to control samples. In\nmenstruation, neutrophils positive for elastase, an indicator of NETosis,\npeak during menstruation\n135. The increase in elastase expressing neutrophils\nmay explain the increase of NETs in peritoneal fluid of endometriosis\npatients due to the introduction of these neutrophils via retrograde men-\nstruation. NETs found in the peritonealfluid indicate this process is linked\nin either the cell-based initiation or exacerbation of the disease19.C l e a r a n c e\nof NETs can be taxing for the body, but in many cases, macrophages are able\nto clear them. The inherent difficulty in NET clearance may promote lesion\nsurvival and attachment due to a delay in tissue removal\n136. Although the\nmajority of the information surrounding NETs in endometriosis is quan-\ntitative in respect to byproducts of the process, mechanistic studies to further\nexamine the effect of NETs on endometriosis and the exacerbation of disease\nis greatly needed.\nNeutrophil degranulation may exacerbate inflammatory\nresponses\nNeutrophils have an altered response orare desensitized to activation signals\nin endometriosis which may affect t he release of additional granules\nrequired to achieve an essential phys iological response in endometriosis\npatients63. Currently, it is unclear whether neutrophil activation is the result\nof pro-inflammatory cytokines released from the lesion sites or whether\nneutrophils are recruiting each other in a positive feedback loop 63.N e u -\ntrophilic granules contain a multitude of proteins which are released in\nresponse to various stimuli\n44. Lactoferrin, an anti-inflammatory protein, and\nmyeloperoxidase, a proinflammatory enzyme, are indicators of neutrophil\nactivation—both of these proteins are found in neutrophil granules 137.\nLactoferrin was elevated in the peritonealfluid of endometriosis stages II, III,\nand IV138 indicating a potential neutrophil degranulation release. Interest-\ningly, anti-lactoferrin antibodies were found in serum of endometriosis\npatients prior to surgical excision of lesions, but levels decreased post-\noperatively\n139 which may point to a dysfunction in the degranulation of\nneutrophils leading to an autoimmune type response.\nMPO and other NET byproducts can be released either during\ndegranulation with or without the release of NETs (these molecules are\ndescribed in the NET section). Epithelial neutrophil-activating peptide\n(ENA-78/CXCL5), a chemoattractant and activator or neutrophil function\ninvolved in degranulation, was elevated in the peritoneal fluid of patients\nwith endometriosis and is expressed in both ectopic glandular and stromal\ncells\n140. In addition, the levels of this chemokine correlated to disease stage\nand high pain severity 140,141. Elevated levels of ENA-78/CXCL5 in the\nperitoneal fluid demonstrates that degranulation does play a role in the\npathogenesis of endometriosis and leads to increased peritoneal in flam-\nmation. As mentioned above, defensins,released during degranulation, are\nelevated in peritoneal fluid in patients with endometriosis 61. Thus, these\nfindings in conjunction with each other indicate that changes in degranu-\nl a t i o nf r o mn e u t r o p h i l si se v i d e n ti np atients with endometriosis; however,\ngaps remain in our understanding of how these functions may in fluence\nearly lesion development, iron met abolism, and/or advanced disease\npathogenesis.\nChallenges of translating mouse models to human\ndisease\nThe use of murine and animal models has immensely benefited endome-\ntriosis research with mechanistic studies67–71, especially in the early stages of\nlesions development which cannot be easily or ethically conducted in\nhumans. Although there are differen ces in endometriosis pathobiology\nbetween human patients and mouse models, murine models have\ndemonstrated the usefulness of studying the initiation and pathogenesis of\ndisease. An important caveat with using mouse models is to acknowledge\nthat no model can recapitulate all aspects of endometriosis pathogenesis due\nto the differences in the immune system of mice, mouse models are useful\ntools for examining prospective mechanisms which may translate into\nhuman diagnostics or treatments. An area of variance between humans and\nmice is that mouse neutrophils are often identi fied by the cell surface\nmarker, Ly6G, whereas human neutrophils do not possess Ly6G on their\nsurface and require more complex strategies for identification\n142.I nh u m a n\nperipheral blood, neutrophils account for about 70% of the white blood cell\ncomposition\n45 and while mice contain less peripheral blood neutrophils, the\nneutrophil is still the highes t granulocyte in abundance 143,144.M i c ea n d\nhumans can also differ in granule composition within the neutrophil itself:\ndifferences include murine neutrophils do not make defensins145 and the\namount of MPO levels under normal conditions are higher in humans 146\nwhich can pose a challenge when studying NETs and degranulation.\nDefensins (e.g., human neutrophil p e p t i d e s1 ,2 ,a n d3 )a r ee l e v a t e di n\nhumans with endometriosis\n61 which poses an issue when trying to elucidate\nt h er o l ea n d / o rm e c h a n i s mo ft h e s em olecules if utilizing a mouse model\nthat is not humanized. Additionally, mice lack the gene coding for CXCL8/\nIL8, but do have homologs to human CXCR2, CXCL2, and CXCL1\n44,45\nwhich can still be utilized to study chemotaxis of neutrophils. The lack of\nCXCL8/IL8 cannot be studied in endo metriosis rodent models, but this\nchemokine has been an area of interest in human studies due to its elevation\nin the peritoneal fluid of endometriosis patients112. With the use of huma-\nnized or transgenic mice, this hurdle could be surmounted to observe the\neffect of CXCL8/IL8 on neutrophils in the pathogenesis of endometriosis.\nH o w e v e r ,m o u s em o d e l sh a v em a n a g e dt oexplore neutrophil depletion and\nknockout studies to further understand their role in lesion development and\ntargets have included Ly6G\n20,147 and CXCR2 148.A l t h o u g h ,t h em o u s e\nimmune system has some variances from the human immune system, these\nmodels provide an ethical approach to understanding mechanisms of lesion\ndevelopment and, when paired with human data, may lead to improved\ndiagnostics and treatments for women. Despite differences between these\ntwo species, mouse models are essential for understanding the mechanistic\nfunctions of neutrophils in endometriosis and how they exacerbate disease.\nNeutrophil targeted therapies and diagnostics\nCurrently, endometriosis treatments are more palliative in nature 8 and\ntreatments which provide longer relief from symptoms are desperately\nhttps://doi.org/10.1038/s44294-025-00059-x Review\nnpj Women's Health |             (2025) 3:9 6\n\nneeded. Understanding neutrophils and other innate immune cells are a key\ncomponent to finding better endometriosis treatments. A promising\napproach may be to block or deplete neutrophil numbers to reduce disease\nseverity. Neutrophil depletion causesa delay in the repair and breakdown of\nthe endometrium\n149. Since lesions are composed of endometrial-like tissue,\nthis process may be used as a target for either prevention or elimination of\nendometriotic lesions. In mice, neutrophil depletion did decrease the\nnumber of lesions, but did not significantly affect the lesion weight\n147.T h e\nreduction of lesion number indicatesthat there may have been attachment\nissues early in the lesion initiation process. If the early attachment and\nangiogenesis phases are targeted, then prevention or reduction of lesion\ndevelopment may be possible. While it is not possible to deplete neutrophils\nin human patients, alternative possi bilities could be to try and block or\nreduce neutrophil recruitment durin g menstruation. In another study,\nretinoic acid reduced VEGF mRNA and protein\n150,151. Retinoic acid is\nsynthesized in endometrial cells when exposed to progesterone which lends\nto a proposal of retinoid being beneficial as a treatment for endometriosis,\nbut retinoic acid will cause complications during pregnancy and would be\nnot advisable\n151. Additionally, reducing angiogenic factors may lead to the\ninability of lesions to attach, but the teratogenic effects of retinoids may\nreduce the likelihood of this treatm ent in the future. One proposed pre-\ndictive diagnostic to evaluate the prevalence of recurrence of endometriotic\nlesions is the neutrophil to lymphocyte ratio\n152 or to assess this ratio as a\ngeneral risk factor for endometriosis153. This metric has not been imple-\nmented in a clinical setting, but with further consideration and testing may\nlead to a diagnostic. In a primate model, an CXCL8/IL8 antibody, AMY109,\nwas a treatment to reduce CXCL8/IL8 and was successful in reducing\ninflammation and fibrosis154. This antibody may present potential for an\nCXCL8/IL8 targeted treatment. A further area of consideration is to\ndetermine whether immunosurveillance is defective and what steps are\nneeded to correct this defect in endometriosis patients. Some suggest that\ntargeting neutrophil degranulation would act to treat endometriosis by\nreducing in flammation\n155. Examining menstrual fluid for variations in\nimmune components will likely lead to non-invasive diagnosis and/or\ntreatment possibilities. A dire need exists for better and non-invasive\ntreatments and whether neutrophils may be the key has yet to be\ndetermined.\nConclusion\nEndometriosis is a debilitating disease which negatively impacts the lives of\naffected patients, both mentally and physically. The early initiation of the\ndisease is influenced by immune cell interactions. Although less is known\nabout some of the early interactions,mouse models have been illuminating\nfor determining early disease initiation mechanisms. During each menstrual\nperiod, retrograde menstruation provides a potential opportunity to expose\nthe peritoneal cavity to immune cells and viable endometrial tissues which\nmay promote an exacerbation and p rogression of the disease. The\nmechanisms of how lesions are formed is unclear, but recent research shows\nthat immune cell responses are heavily implicated in disease pathogenesis\nand may be the key to understanding this disease. Neutrophils are thefirst\nresponders and likely play a key role in early responses to lesion formation\nand clearance of retrograde menstruation. The release of VEGF is one way\nthat neutrophils can promote angiogenesis and lesion development.\nAlthough other cells like macrophages aid in the remodeling and neo-\nvascularization, the effects of neutrophils are still a factor in the early stages.\nCytokines like IL6 and CXCL8/IL8 are found at abnormal levels in endo-\nmetriosis. Both of these cytokines affect neutrophil recruitment and alter the\nperitoneal cavity microenvironment. Currently, determining which cyto-\nkine has the greatest influence on neutrophils is difficult due to crosstalk and\ntemporal limitations of studying neu trophil surveillance. In addition,\nN E T o s i sm a yb eal a r g ef a c t o ri nt h ep athogenesis of endometriosis. With\nmore NETs found in endometriosis patients, evidence supports that the\nfunctions may differentiate healthy women from women with endome-\ntriosis. Whether NETs are the primary driving force or whether the mul-\ntifactorial actions of neutrophils work in conjunction to promote disease, it\nis apparent that neutrophils are an understudied aspect of early disease\ninitiation and progression, thus highlighting the critical need to determine\nall of the roles of this important cell type. Determining the speci fics of\nneutrophil and immune functions in e ndometriosis may provide insight\ninto potential non-surgical diagnoses or treatment targets. Neutrophils,\nalong with other immune cells, may be the key to finding the potential\nbiomarkers needed for earlier diagnoses and understanding this complex\ndisease.\nData availability\nNo datasets were generated or analyzed during the current study.\nReceived: 26 September 2024; Accepted: 30 January 2025;\nReferences\n1. Buck Louis, G. M. et al. Incidence of endometriosis by study\npopulation and diagnostic method: the ENDO study.Fertil. Steril. 96,\n360–365 (2011).\n2. Eskenazi, B. & Warner, M. L. Epidemiology of endometriosis. Obstet.\nGynecol. Clin. North Am. 24, 235–258 (1997).\n3. Giudice, L. C. & Kao, L. C. Endometriosis. Lancet 364, 1789–1799\n(2004).\n4. Zondervan, K. T., Becker, C. M. & Missmer, S. A. Endometriosis. N.\nEngl. J. Med. 382, 1244–1256 (2020).\n5. Simoens, S. et al. The burden of endometriosis: costs and quality of\nlife of women with endometriosis and treated in referral centres.\nHum. Reprod. 27, 1292–1299 (2012).\n6. Soliman, A. 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Transl.\nMed. 15, eabq5858 (2023).\n155. Bao, C., Wang, H. & Fang, H. Genomic evidence supports the\nrecognition of endometriosis as an in flammatory systemic disease\nand reveals disease-specific therapeutic potentials of targeting\nneutrophil degranulation. Front. Immunol. 13, 758440 (2022).\nAcknowledgements\nSources of support to K.A.B. include NIH R01 HD097597 and the University\nof Cincinnati College of Medicine Startup. The funders played no role in the\ninterpretations found in or writing of this manuscript.\nAuthor contributions\nThe Burns Laboratory studies neutrophils in endometriosis (K.A.B.). T.R.W.\nwrote the first draft of the review article. K.A.B., S.K., and T.R.W. revised,\nadded, critiqued, and reformatted the manuscript. Thefigure was drawn by\nT.R.W. and S.K. All authors read and approved the final manuscript.\nCompeting interests\nThe authors declare no competing interests.\nAdditional information\nCorrespondenceand requests for materials should be addressed to\nKatherine A. Burns.\nReprints and permissions informationis available at\nhttp://www.nature.com/reprints\nPublisher’s noteSpringer Nature remains neutral with regard to jurisdictional\nclaims in published maps and institutional affiliations.\nOpen Access This article is licensed under a Creative Commons\nAttribution-NonCommercial-NoDerivatives 4.0 International License,\nwhich permits any non-commercial use, sharing, distribution and\nreproduction in any medium or format, as long as you give appropriate\ncredit to the original author(s) and the source, provide a link to the Creative\nCommons licence, and indicate if you modi fied the licensed material. You\ndo not have permission under this licence to share adapted material\nderived from this article or parts of it. The images or other third party\nmaterial in this article are included in the article ’s Creative Commons\nlicence, unless indicated otherwise in a credit line to the material. If material\nis not included in the article’s Creative Commons licence and your intended\nuse is not permitted by statutory regulation or exceeds the permitted use,\nyou will need to obtain permission directly from the copyright holder. To\nview a copy of this licence, visit http://creativecommons.org/licenses/by-\nnc-nd/4.0/\n.\n© The Author(s) 2025\nhttps://doi.org/10.1038/s44294-025-00059-x Review\nnpj Women's Health |             (2025) 3:9 11","source_license":"CC0","license_restricted":false}