A narrative review on the role of IL-1β, IL-8, and the endometrial matrix in heavy menstrual bleeding pathogenesis.

The endometrial ECM plays a crucial role in maintaining the structural integrity and functional stability of the endometrium. It provides a scaffold for cellular interactions, regulates immune responses, and facilitates the cyclic processes of endometrial regeneration, shedding, and repair. However, in HMB, dysregulation of ECM components leads to excessive tissue breakdown, impaired repair mechanisms, and abnormal vascular remodeling, all of which contribute to prolonged and excessive blood loss. Understanding the complex interplay between ECM degradation, inflammatory mediators, and vascular instability is essential for unraveling the pathophysiology of HMB and identifying potential therapeutic targets [ 31 , 32 ] . The ECM of the endometrium is composed of various structural proteins, including collagen, fibronectin, laminin, and proteoglycans, which provide mechanical support and regulate cellular adhesion and signaling. These components undergo controlled degradation during menstruation, allowing for the cyclical shedding and renewal of the endometrial lining. However, in HMB, there is an imbalance between MMPs and their natural inhibitors, tissue inhibitors of TIMPs. MMPs, particularly MMP-2 and MMP-9, are responsible for ECM degradation, facilitating endometrial shedding. In women with HMB, excessive MMP activity leads to premature and excessive ECM breakdown, weakening the endometrial structure and increasing menstrual blood loss [ 33 , 34 ] . Inflammatory cytokines, particularly IL-1β and IL-8, play a pivotal role in modulating ECM dynamics. IL-1β stimulates MMP production, amplifying ECM degradation and perpetuating a cycle of excessive tissue breakdown. IL-8 further exacerbates this process by recruiting neutrophils, which release proteolytic enzymes such as neutrophil elastase and MMP-9. These enzymes not only degrade ECM proteins but also impair endometrial repair, prolonging bleeding episodes. The sustained inflammatory response in HMB disrupts the delicate balance required for efficient ECM turnover, leading to structural instability and persistent menstrual dysfunction[ 3 ]. Beyond its role in structural integrity, the ECM is crucial for vascular stability and angiogenesis. The endometrial microvasculature is embedded within the ECM, and its integrity is dependent on proper ECM composition and remodeling. In HMB, excessive ECM degradation results in the formation of fragile, leaky blood vessels that are prone to rupture, exacerbating menstrual blood loss. Additionally, VEGF, a key regulator of angiogenesis, is upregulated in response to ECM breakdown. While VEGF-mediated angiogenesis is essential for endometrial repair, its dysregulated expression in HMB contributes to the development of abnormal, hyperpermeable blood vessels, further worsening blood loss [ 35 , 36 ] . Another critical aspect of ECM dysfunction in HMB is its impact on endometrial repair mechanisms. Under normal conditions, the ECM serves as a reservoir for growth factors such as transforming growth factor-beta and fibroblast growth factors, which promote tissue regeneration. However, excessive ECM degradation depletes these factors, impairing the ability of the endometrium to undergo efficient repair after menstruation. This results in prolonged bleeding and increased susceptibility to recurrent episodes of HMB. Furthermore, alterations in the composition of ECM glycoproteins, such as fibronectin and laminin, may disrupt cellular adhesion and migration, further delaying endometrial regeneration [ 37 , 38 ] .

HMB is a debilitating gynecological condition characterized by excessive and prolonged menstrual blood loss. While hormonal imbalances and structural abnormalities are commonly implicated, increasing evidence suggests that immune dysregulation plays a significant role in its pathogenesis. IL-8, a potent chemokine, is a key regulator of neutrophil recruitment and activation within the endometrium. Although IL-8 is essential for normal endometrial shedding and repair, its excessive expression in HMB contributes to chronic inflammation, uncontrolled ECM degradation, and abnormal vascular remodeling, all of which exacerbate excessive bleeding[ 25 ]. IL-8 is primarily produced by endometrial epithelial cells, stromal cells, and immune cells in response to inflammatory stimuli such as IL-1β and tumor necrosis factor-alpha (TNF-α). Acting through its receptors, CXCR1 and CXCR2, IL-8 orchestrates the migration and activation of neutrophils into the endometrial tissue. In women with HMB, elevated IL-8 levels have been correlated with increased neutrophil infiltration, leading to prolonged inflammatory responses and excessive tissue breakdown. The sustained presence of neutrophils amplifies local inflammation by releasing additional pro-inflammatory cytokines, proteolytic enzymes, and ROS, which further disrupt endometrial homeostasis[ 26 ]. Neutrophils play a crucial role in ECM degradation, a process essential for normal endometrial shedding. Upon activation by IL-8, neutrophils release MMPs, particularly MMP-9, which degrade structural components of the ECM, including collagen and fibronectin. While controlled ECM degradation is necessary for normal menstruation, excessive neutrophil-derived MMP activity in HMB leads to premature and extensive ECM breakdown, weakening the endometrial structure and contributing to increased menstrual blood loss. Furthermore, neutrophil elastase, another proteolytic enzyme, exacerbates ECM degradation and interferes with proper tissue repair, prolonging menstrual bleeding[ 27 ]. Beyond its effects on ECM remodeling, IL-8 also influences angiogenesis, the process of new blood vessel formation. In the normal endometrium, IL-8-mediated angiogenesis ensures adequate tissue perfusion and repair after menstruation. However, in HMB, IL-8-driven angiogenesis results in the formation of fragile, dysfunctional blood vessels that are prone to rupture. This leads to increased vascular permeability and impaired hemostasis, further contributing to excessive menstrual bleeding. Additionally, neutrophils recruited by IL-8 enhance endothelial cell activation and vascular destabilization, worsening blood loss during menstruation[ 28 ]. IL-8’s role in HMB extends beyond neutrophil recruitment and vascular remodeling; it also sustains a chronic inflammatory environment in the endometrium. Acting in synergy with IL-1β and other cytokines, IL-8 perpetuates immune cell infiltration, disrupts the balance between MMPs and their inhibitors, and impairs normal endometrial repair mechanisms. This chronic inflammatory state prevents the resolution of menstruation, leading to recurrent episodes of excessive bleeding[ 29 ]. Given its pivotal role in neutrophil recruitment, ECM degradation, and vascular dysfunction, IL-8 represents a potential therapeutic target for managing HMB. Inhibiting IL-8 signaling through CXCR1/2 antagonists, anti-inflammatory agents, or monoclonal antibodies may help regulate neutrophil infiltration, reduce excessive ECM breakdown, and restore vascular stability. Additionally, MMP inhibitors that counteract IL-8-driven proteolysis could provide a novel approach to reducing menstrual blood loss in affected women[ 30 ].

Heavy menstrual bleeding (HMB) is one of the most common gynecological disorders, affecting up to 30% of reproductive-age women. It is defined as excessive menstrual blood loss exceeding 80 mL per cycle and is often associated with anemia, fatigue, and a significant decline in quality of life. The underlying causes of HMB are diverse, including hormonal imbalances, coagulation disorders, uterine structural abnormalities, and chronic inflammation. Emerging evidence suggests that inflammatory cytokines, particularly interleukin-1 beta (IL-1β) and interleukin-8 (IL-8), play a crucial role in the dysregulation of endometrial function, leading to excessive menstrual bleeding [ 1 – 5 ] . Cytokines are key mediators of immune responses and tissue remodeling in the endometrium. The menstrual cycle is a dynamic process involving cycles of endometrial proliferation, differentiation, and shedding, all of which are tightly regulated by cytokines and growth factors. IL-1β and IL-8, in particular, have been implicated in endometrial inflammation, extracellular matrix (ECM) remodeling, and vascular changes. Dysregulation of these cytokines disrupts the delicate balance required for normal menstruation, leading to increased vascular permeability, excessive leukocyte infiltration, and abnormal ECM breakdown – all of which contribute to HMB [ 6 – 9 ] . HIGHLIGHTS IL-1β triggers inflammation, promoting matrix degradation and endometrial instability. IL-8 attracts neutrophils, amplifying local inflammatory responses in the endometrium. Endometrial matrix breakdown is accelerated by cytokine-induced MMP activation. Synergistic action of IL-1β and IL-8 disrupts vascular integrity, increasing bleeding. Cytokine-matrix interplay underlies chronic endometrial dysfunction in heavy menstrual bleeding. IL-1β triggers inflammation, promoting matrix degradation and endometrial instability. IL-8 attracts neutrophils, amplifying local inflammatory responses in the endometrium. Endometrial matrix breakdown is accelerated by cytokine-induced MMP activation. Synergistic action of IL-1β and IL-8 disrupts vascular integrity, increasing bleeding. Cytokine-matrix interplay underlies chronic endometrial dysfunction in heavy menstrual bleeding. IL-1β is a potent pro-inflammatory cytokine that amplifies immune responses by stimulating the release of additional inflammatory mediators. It activates matrix metalloproteinases (MMPs), which degrade ECM components such as collagen and fibronectin, thereby destabilizing endometrial tissue. Additionally, IL-1β increases vascular permeability and promotes angiogenesis, leading to fragile and leaky blood vessels that contribute to excessive menstrual bleeding. Studies have shown that IL-1β levels are elevated in the endometrial tissue of women with HMB, suggesting a strong association between IL-1β-driven inflammation and abnormal menstrual bleeding[ 10 ]. IL-8, a chemokine primarily involved in neutrophil recruitment and activation, also plays a pivotal role in endometrial function. Under normal conditions, IL-8 facilitates leukocyte infiltration to aid in tissue breakdown and immune defense. However, excessive IL-8 production leads to increased neutrophil activation, release of proteolytic enzymes, and oxidative stress, all of which contribute to exaggerated ECM degradation and endometrial instability. Additionally, IL-8 promotes endothelial cell proliferation and abnormal angiogenesis, leading to structurally weak blood vessels that rupture easily, further exacerbating menstrual blood loss [ 11 , 12 ] . The ECM serves as a structural scaffold for endometrial tissue and regulates cellular interactions critical for tissue stability and regeneration. The IL-1β/IL-8 axis significantly influences ECM homeostasis by altering the balance between MMPs and their tissue inhibitors of metalloproteinases (TIMPs). An overactive MMP response, triggered by IL-1β, results in excessive ECM degradation, while IL-8-mediated neutrophil infiltration further amplifies the inflammatory cascade. This disruption in ECM integrity weakens the endometrial lining and contributes to prolonged and heavy bleeding[ 13 ]. HMB is a prevalent gynecological concern affecting women across all reproductive age groups, with significant implications for quality of life and health system burden. According to the Global Incidence Study 2023 , HMB affects an estimated 18–25% of menstruating women worldwide, with higher prevalence reported in low-resource settings where access to diagnostic and therapeutic services remains limited. The WHO estimates that HMB accounts for nearly one-third of all gynecologic outpatient visits and contributes substantially to iron-deficiency anemia in women of reproductive age. Despite its clinical significance, the biological underpinnings of HMB remain incompletely understood, particularly the role of inflammatory cytokines in its diverse etiologic subtypes. HMB is a heterogeneous condition encompassing structural (e.g., fibroids), ovulatory, coagulopathic, iatrogenic, and idiopathic causes. However, current research has not adequately delineated cytokine expression patterns, including IL-1β and IL-8, across these subtypes. For instance, it remains unclear whether women with ovulatory HMB exhibit distinct inflammatory signatures compared to those with coagulopathic or iatrogenic forms. This knowledge gap limits the development of targeted diagnostics and therapies and highlights a critical direction for future research: defining inflammatory phenotypes specific to each HMB subtype to enable more personalized and effective interventions [ 14 – 18 ] . The aim of this review is to explore the pathophysiological mechanisms underlying HMB, with a focus on the role of inflammatory cytokines such as IL-1β and IL-8 in endometrial dysfunction, matrix degradation, and vascular instability. The review methodology employed involved a comprehensive and systematic examination of both primary research and clinical studies related to HMB, specifically focusing on the inflammatory cytokines IL-1β and IL-8, their roles in endometrial dysfunction, and the therapeutic interventions targeting these pathways. The review process consisted of several key stages: literature search, selection of relevant studies, data synthesis, and analysis of treatment approaches.

IL-1β is a potent proinflammatory cytokine upregulated during menstruation and has been shown to induce MMPs, disrupt endometrial integrity, and promote vascular leakage. Anakinra, a recombinant IL-1R antagonist approved for rheumatoid arthritis and other autoinflammatory conditions, has demonstrated favorable modulation of MMP expression and vascular permeability in various preclinical models. While no clinical trials have yet evaluated Anakinra specifically for HMB, rodent models of endometriosis and uterine inflammation show that IL-1β blockade reduces leukocyte infiltration, angiogenesis, and tissue destruction – hallmarks relevant to HMB pathophysiology (1,2). Moreover, ex vivo studies on human endometrial stromal cells treated with IL-1β inhibitors have reported downregulation of MMP-9 and VEGF, suggesting potential for therapeutic stabilization of the endometrial matrix (3). Given these findings, repurposing IL-1β inhibitors warrants investigation in women with inflammation-driven HMB, particularly those unresponsive to hormonal therapy[ 44 ].

Current medical management of HMB largely focuses on hormonal modulation, antifibrinolytics (e.g., tranexamic acid), and in selected cases, agents such as desmopressin for those with bleeding disorders. However, a growing body of evidence implicates dysregulated inflammation – particularly involving IL-1β, interleukin-8 (IL-8/CXCL8), and ECM degradation – in the pathogenesis of HMB. This has prompted exploration of novel therapeutics that target these molecular pathways [ 49 ] .

In addition to conventional therapies, innovative treatments are being developed to address the underlying pathophysiological mechanisms of HMB. These include targeting the molecular and inflammatory pathways that drive excessive bleeding. For example, therapies that focus on the inhibition of MMPs, which play a crucial role in endometrial matrix degradation, have shown promise in regulating abnormal tissue breakdown and reducing excessive menstrual loss. Similarly, targeting cytokines like IL-1β and IL-8, which mediate inflammatory responses and neutrophil recruitment, offers the potential to reduce endometrial inflammation and matrix degradation associated with HMB[ 38 ]. Gene therapies, including those aimed at modulating angiogenesis and regulating vascular stability, are also being explored. For instance, the inhibition of VEGF, which is upregulated in response to endometrial tissue breakdown, could prevent the formation of abnormal blood vessels and reduce the fragility of the endometrial vasculature, thereby minimizing excessive bleeding. The development of selective estrogen receptor modulators and other targeted therapies that focus on the regulation of estrogen activity may also offer new treatment options, particularly for women with conditions like endometriosis or adenomyosis, where estrogen plays a significant role in disease progression[ 47 ].

For women with persistent or severe HMB that does not respond to medical therapies, surgical options may be necessary. One of the most common surgical interventions is endometrial ablation, which involves the destruction of the endometrial lining to reduce or stop bleeding. This procedure is effective for women who do not wish to preserve fertility, as it can result in permanent cessation of menstruation. Another surgical approach is myomectomy, which is recommended for women with uterine fibroids that are contributing to HMB. Myomectomy involves the removal of fibroids while preserving the uterus and may be an option for women desiring future fertility. Hysterectomy, the complete removal of the uterus, is considered a last resort for women with refractory HMB, particularly when other treatments have failed, or if there are significant structural abnormalities[ 36 ]. Emerging surgical techniques, such as hysteroscopic surgery, allow for the removal or destruction of abnormal tissue in a minimally invasive manner. These procedures, including the resection of fibroids, polyps, or adenomyosis, provide alternatives to more invasive surgeries like hysterectomy and can lead to a reduction in menstrual bleeding while preserving reproductive function. Hysteroscopic myomectomy and polypectomy have been associated with reduced bleeding, improved fertility outcomes, and shorter recovery times compared to traditional open surgery[ 46 ].

In addition to medical and surgical treatments, lifestyle modifications can play an important role in managing HMB. Maintaining a healthy weight, engaging in regular exercise, and managing stress are all factors that can influence hormonal balance and reduce menstrual bleeding. Nutritional interventions, such as increasing the intake of iron-rich foods or iron supplementation, can help mitigate the anemia associated with HMB. For some women, acupuncture and other complementary therapies may provide symptom relief, although more research is needed to establish their efficacy in the treatment of HMB[ 44 ].

The selection criteria for inclusion focused on studies that investigated the role of IL-1β and IL-8 in the pathogenesis of HMB, as well as those that assessed the effectiveness of various medical, surgical, and novel therapies targeting these pathways. Articles that explored the underlying molecular mechanisms of endometrial dysfunction, matrix degradation, and vascular instability were prioritized. Studies examining the outcomes of cytokine-targeted therapies, anti-inflammatory treatments, and alternative approaches were also included. Exclusion criteria included studies that lacked robust methodological rigor, non-English language articles, and those with insufficient data on cytokine-related mechanisms in HMB.

A thorough literature search was conducted using multiple databases, including PubMed, Google Scholar, Scopus, and Embase. The search terms used included “heavy menstrual bleeding,” “IL-1β,” “IL-8,” “endometrial inflammation,” “matrix degradation,” “cytokines in HMB,” and “therapeutic strategies for HMB.” Both basic science studies focusing on the molecular mechanisms and clinical trials evaluating therapeutic interventions were considered. Relevant articles were selected based on their relevance to the cytokine pathways involved in HMB and their potential clinical applications.

This review highlights the pivotal roles of IL-1β, IL-8, and ECM disruption in the complex pathogenesis of HMB, emphasizing how inflammatory cascades and matrix degradation synergistically compromise endometrial vascular integrity. While current therapeutic options largely focus on hormonal modulation and symptomatic management, emerging evidence underscores the potential of targeting inflammatory pathways to improve outcomes. A practical recommendation arising from this synthesis is the implementation of early screening for inflammatory markers, such as menstrual fluid IL-1β and IL-8 assays, particularly in women with unexplained HMB or those exhibiting poor response to conventional hormonal therapies. This approach may be especially valuable for patients at heightened risk of coagulopathies or immune dysregulation, enabling personalized treatment strategies. Future prospective studies are essential to validate the clinical utility of such biomarkers and to explore targeted anti-inflammatory interventions in HMB management.

While this review highlights important insights into the potential roles of IL-1β, IL-8, and the endometrial matrix in the pathogenesis of HMB, several limitations must be acknowledged. First, there is a notable paucity of direct clinical trial data evaluating IL-1β and IL-8-targeted therapies specifically in women with HMB. Much of the therapeutic discussion in this review is therefore extrapolated from preclinical models or studies of related inflammatory and gynecologic conditions, which may not fully reflect the unique pathophysiology of HMB. Second, the existing body of literature may be subject to publication bias, with a tendency to report positive findings more frequently than negative or inconclusive data. This bias may skew the perceived strength of associations between inflammatory markers and HMB severity. Third, HMB is a highly heterogeneous condition, encompassing structural, hormonal, coagulopathic, and idiopathic causes. The degree to which inflammatory pathways, such as IL-1β and IL-8 signaling, contribute across these subtypes remains incompletely understood. This heterogeneity limits the generalizability of pathophysiological mechanisms and therapeutic extrapolations across all women with HMB. Finally, variations in study design, diagnostic criteria, and sample characteristics across the reviewed studies further complicate direct comparisons and synthesis. Future studies with standardized methodologies and subgroup-specific analyses are needed to clarify the role of inflammation across the spectrum of HMB etiologies.

Emerging evidence suggests that the inflammatory microenvironment of the endometrium in HMB is not solely driven by individual cytokines, but rather by synergistic interactions between key mediators such as IL-1β and TNF-α. These cytokines act in concert to amplify the local immune response, particularly during the perimenstrual phase. IL-1β and TNF-α synergistically enhance neutrophil recruitment via upregulation of chemokines such as IL-8 (CXCL8), leading to increased ROS generation, protease release, and amplified production of downstream cytokines like IL-6 and GM-CSF. This creates a positive feedback loop of inflammation that can exacerbate tissue breakdown and vascular permeability. Such cooperative signaling has been shown to upregulate MMPs, further driving ECM degradation and compromising endometrial vascular integrity [ 39 , 40 ] . In the context of ECM remodeling, recent studies have drawn attention to specific alterations in collagen composition in women with HMB. Notably, a disproportionate reduction in collagen types I and III expression has been observed in the perivascular regions of the endometrium. Collagen I, known for its tensile strength, and collagen III, which contributes to vascular compliance and repair, are essential for maintaining microvascular stability. The depletion or disorganization of these structural proteins leads to increased vessel fragility, impaired tissue remodeling, and excessive menstrual blood loss. Furthermore, degraded collagen fragments may themselves act as damage-associated molecular patterns, perpetuating inflammatory signaling and MMP activation [ 41 , 42 ] .

HMB is a common condition that significantly impacts the quality of life for many women, leading to physical, emotional, and social distress. The management of HMB is multifaceted, often requiring a combination of medical, surgical, and lifestyle interventions to address the underlying causes and alleviate symptoms. Although several treatment options are available, selecting the most appropriate approach depends on the severity of bleeding, underlying etiologies, and the individual’s reproductive goals. The therapeutic landscape for HMB is evolving, with new treatments focused on targeting the pathophysiological mechanisms that contribute to excessive bleeding, such as inflammation, endometrial dysfunction, and vascular abnormalities[ 43 ].

Given the significant impact that HMB can have on a woman’s physical and mental well-being, psychological and emotional support should be integrated into treatment plans. Cognitive-behavioral therapy and counseling can help women manage the emotional burden associated with chronic menstrual bleeding, particularly for those who experience anxiety, depression, or diminished quality of life due to the condition. Providing women with access to support groups or counseling services can also help normalize their experience and reduce the stigma surrounding menstrual health[ 48 ].

IL-8 (CXCL8), a key neutrophil chemoattractant and angiogenic mediator, has been associated with excessive leukocyte recruitment and vascular fragility in the endometrium of women with HMB. Experimental therapies targeting CXCL8 or its receptor CXCR2 have shown efficacy in reducing neutrophil-driven inflammation and pathological angiogenesis in gynecologic and autoimmune disease models. For instance, CXCR2 antagonists (e.g., reparixin) have demonstrated anti-inflammatory and anti-angiogenic effects in endometriosis models and in early-phase clinical trials for other inflammatory conditions (4,5). Although direct data in HMB are lacking, these mechanistic parallels support the hypothesis that targeting the CXCL8/CXCR2 axis could mitigate inflammatory endometrial degradation and abnormal bleeding[ 46 ].