Inflammation and gynecologic disorders

Authors

Abstract

Inflammation plays a pivotal role in both physiological and pathological processes of the female reproductive system. While tightly regulated inflammatory responses are essential for ovulation, menstruation, implantation, and parturition, dysregulated or chronic inflammation contributes to the onset and progression of several gynecologic disorders. This review synthesizes current evidence on the molecular and cellular mechanisms linking inflammation to major gynecologic conditions, including endometriosis, adenomyosis, polycystic ovary syndrome (PCOS), pelvic inflammatory disease (PID), uterine fibroids, and gynecologic malignancies. Endometriosis and adenomyosis are characterized by sustained inflammatory microenvironments enriched with cytokines, chemokines, activated macrophages, prostaglandins, and oxidative stress, which collectively drive pain, fibrosis, and infertility. In PCOS, low-grade systemic inflammation interacts with metabolic dysfunction, contributing to insulin resistance and hyperandrogenism. Infections leading to PID elicit acute neutrophil-dominated inflammatory responses that may cause long-term reproductive damage. Moreover, chronic inflammation-whether due to infection, hormonal imbalance, or metabolic stress-plays a critical role in the pathogenesis of ovarian, endometrial, and cervical cancers by promoting genomic instability, angiogenesis, and immune evasion. Advances in immunology, transcriptomics, and tumor microenvironment research have enhanced our understanding of disease-specific inflammatory pathways and revealed novel diagnostic biomarkers and therapeutic targets. By integrating current mechanistic and clinical insights, this review underscores inflammation as a unifying pathogenic theme across gynecologic disorders and highlights future opportunities for precision medicine approaches aimed at modulating inflammatory signaling to improve reproductive outcomes and overall women’s health.

Keywords

Introduction

Inflammation is a fundamental biological response that plays a critical role in host defense, tissue repair, and the maintenance of homeostasis. Although acute and well-regulated inflammatory activity is essential for protecting the organism against pathogens and injury, chronic or dysregulated inflammation can contribute to a wide spectrum of pathological processes. The female reproductive system is particularly sensitive to inflammatory stimuli due to its cyclical hormonal regulation, unique immunological milieu, and continuous exposure to endogenous and exogenous antigens. Consequently, inflammation is increasingly recognized as a central pathophysiological mechanism linking diverse gynecologic disorders, including endometriosis, polycystic ovary syndrome (PCOS), pelvic inflammatory disease (PID), uterine fibroids, adenomyosis, and gynecologic malignancies.^1,2,3,4,5
Over the past decade, major advances in immunology, molecular biology, and –omics technologies have enabled a deeper understanding of the complex interplay between hormonal fluctuations, the innate and adaptive immune systems, and tissue-specific responses in the female reproductive tract. These insights suggest that many gynecologic diseases, once considered primarily hormonal or structural in origin, may have a substantial inflammatory component. For example, endometriosis, traditionally defined by ectopic endometrial tissue growth, is now recognized as a chronic inflammatory disease driven by aberrant macrophage activation, pro-inflammatory cytokine secretion, oxidative stress, and altered immune clearance mechanisms.⁶ Similarly, PCOS, among the most common endocrine disorders in reproductive-aged women, is increasingly conceptualized as a low-grade inflammatory state marked by elevated inflammatory cytokines, insulin resistance–linked immune activation, and adipose tissue–derived inflammatory mediators.⁵
Inflammation also plays a pivotal role in gynecologic conditions associated with infection. Pelvic inflammatory disease represents a paradigm of acute inflammatory pathology, in which ascending microbial pathogens trigger intense neutrophilic activation, tissue destruction, and long-term sequelae such as chronic pelvic pain, infertility, and tubal factor subfertility.⁷ The cervicovaginal mucosa, with its intricate immunological defenses and microbiome composition, is another critical component influencing inflammatory outcomes in gynecologic health. Disruptions in the vaginal microbiota, particularly reductions in Lactobacillus dominance and increases in anaerobic species, can precipitate inflammatory responses that contribute to bacterial vaginosis, persistence of sexually transmitted infections, and increased susceptibility to upper genital tract infections.⁸
Beyond benign disorders, inflammation is increasingly implicated in the initiation, progression, and prognosis of gynecologic cancers, including ovarian, cervical, and endometrial carcinomas.⁹ Chronic inflammatory microenvironments may promote carcinogenesis through mechanisms such as reactive oxygen species (ROS)–mediated DNA damage, activation of pro-tumorigenic transcription factors (e.g., nuclear factor kappa B [NF-κB]), angiogenesis induction, and evasion of antitumor immunity.¹⁰ Persistent infection with high-risk human papillomavirus (HPV), the primary etiologic factor in cervical cancer, represents a prime example of how chronic viral-induced inflammation and immunologic dysregulation can drive neoplastic transformation.¹¹
A growing body of evidence indicates that systemic inflammatory markers-including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and oxidative stress parameters-may serve as accessible biomarkers for diagnosis, disease severity assessment, prognostication, and treatment monitoring across gynecologic conditions.^12,13 Simultaneously, local inflammatory mediators such as interleukins, tumor necrosis factor-alpha (TNF-α), prostaglandins, and chemokines are being explored as potential therapeutic targets. Anti-inflammatory agents, immunomodulators, and targeted therapies represent emerging avenues in the management of gynecologic diseases, especially in endometriosis and gynecologic malignancies.¹⁴
Understanding inflammation as a unifying mechanism across gynecologic disorders has significant clinical implications. It shifts diagnostic strategies toward integrating systemic and local inflammatory markers, refines disease phenotyping, encourages individualized therapeutic approaches, and supports preventive strategies aimed at modulating inflammation, such as lifestyle interventions, microbiome regulation, and novel immunotherapies.
Despite substantial progress, many questions remain unanswered. The specific molecular triggers that initiate chronic inflammation, the role of genetic and epigenetic predisposition, the bidirectional interactions between sex hormones and immune pathways, and the contribution of environmental and lifestyle factors require further elucidation.¹⁵ Additionally, heterogeneity within gynecologic disorders suggests that inflammation may not represent a uniform mechanism but rather a spectrum of immune dysregulation unique to each disease phenotype.
This review article aims to comprehensively examine the role of inflammation in major gynecologic disorders, synthesize current evidence on inflammatory mechanisms and biomarkers, and highlight future research directions that may advance understanding, diagnostics, and therapeutic strategies.
Physiological Inflammation in the Female Reproductive SystemPhysiological inflammation represents a tightly regulated, cyclical, and essential component of reproductive function in women. Unlike chronic pathological inflammation, which is persistent and tissue-damaging, physiological inflammation is transient, self-limited, and precisely orchestrated to support key reproductive events such as ovulation, menstruation, implantation, cervical remodeling, and parturition.¹⁶ The female reproductive system is therefore an immunologically unique environment-one that must simultaneously facilitate fertilization and pregnancy while maintaining adequate host defense against pathogens. Understanding the mechanisms of physiological inflammation provides critical insight into both normal reproductive biology and the pathogenesis of gynecologic disorders that emerge when these systems are dysregulated.^17,18
Hormonal Modulation of Immune ResponsesThe cyclical hormonal fluctuations of the menstrual cycle profoundly influence inflammatory pathways. Estrogen exerts dose-dependent effects on immunity, promoting leukocyte recruitment, enhancing B-cell–mediated humoral responses, and modulating cytokine expression.^19,20 Progesterone, in contrast, induces an anti-inflammatory state by suppressing macrophage activation, attenuating T-cell proliferation, and reducing pro-inflammatory cytokines such as interleukin (IL)-1β and TNF-α.²¹ These hormonal shifts generate predictable cycles of immune activation and suppression, permitting controlled inflammatory events during ovulation and menstruation and immune tolerance during the luteal phase and early pregnancy.²²
Ovulation as a Physiological Inflammatory ReactionOvulation is recognized as an acute and highly coordinated inflammatory event.²³ The preovulatory luteinizing hormone (LH) surge initiates a cascade involving increased prostaglandin production, cytokine release, transient oxidative stress, leukocyte infiltration, and rapid remodeling of the follicular wall. Neutrophils and macrophages secrete matrix metalloproteinases (matrix metalloproteinase (MMP)-2 and MMP-9), which degrade the extracellular matrix to enable follicular rupture.²⁴ Vascular changes-including transient edema and increased permeability-further mimic classical inflammation. Importantly, this process resolves promptly through specialized pro-resolving mediators (SPMs) such as lipoxins and resolvins, restoring tissue integrity after oocyte release.²⁵
Role of the Vaginal Microbiome in Modulating Physiological InflammationThe cervicovaginal microbiome is now recognized as a key regulator of reproductive tract immunity.²⁶ Lactobacillus-dominant communities maintain a low-inflammatory, acidic environment through lactic acid and antimicrobial peptide production.²⁷ These metabolites modulate local cytokine expression and protect against pathogenic colonization. Microbiome composition fluctuates during the menstrual cycle, reflecting endocrine–immune–microbial interactions.²⁸ Disruptions in this homeostatic relationship can shift physiologic inflammation toward chronic inflammation, contributing to bacterial vaginosis, infertility, and increased susceptibility to sexually transmitted infections.
Physiological inflammation is a cornerstone of normal female reproductive function. It governs crucial processes, including ovulation, menstruation, implantation, and labor, and is shaped by intricate interactions among hormones, immune cells, cytokines, and the microbiome. This cycle of activation and resolution distinguishes healthy inflammation from pathological states that arise when these mechanisms are disrupted. As research continues to elucidate the immunological landscape of the reproductive system, novel diagnostic markers and targeted therapies are emerging, reinforcing the importance of distinguishing physiological from pathological inflammation in clinical practice.
Molecular and Cellular Mechanisms of Inflammation in Gynecologic DiseasesInflammation is a fundamental biological process that preserves tissue integrity by eliminating pathogens, clearing damaged cells, and initiating repair.²⁹ However, when dysregulated, inflammation becomes a key driver of several gynecologic pathologies, including endometriosis, adenomyosis, pelvic inflammatory disease, PCOS, and gynecologic malignancies (Figure 1, Supplementary Table 1).¹⁶
The female reproductive system is uniquely prone to inflammatory fluctuations due to cyclical hormonal changes, exposure to ascending pathogens, and the immunologically specialized microenvironment required for menstruation, ovulation, fertilization, and implantation. These distinctive physiological dynamics create a setting in which disruptions of innate and adaptive immune pathways can lead to chronic, low-grade, or excessive inflammation, ultimately contributing to disease onset and progression.
At the molecular level, inflammatory cascades in gynecologic disorders are orchestrated by pattern-recognition receptors (PRRs), notably Toll-like receptors (TLRs) and NOD-like receptors (NLRs), which detect microbial and endogenous danger signals.³⁰ Their activation triggers downstream signaling through NF-κB, mitogen-activated protein kinase (MAPK), and the NLRP3 inflammasome, resulting in the production of pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, TNF-α, and chemokines that recruit neutrophils, macrophages, dendritic cells, and T-lymphocytes.³¹ Dysregulation of these pathways underlies chronic inflammatory states observed in gynecologic diseases. For example, heightened NF-κB activation and increased macrophage infiltration in the endometrium are hallmark features of endometriosis, contributing to ectopic tissue survival, angiogenesis, and neuroinflammation-associated pelvic pain. Similarly, aberrant activation of the NLRP3 inflammasome has been implicated in ovarian dysfunction and hyperandrogenism in PCOS.^32,33
Cellular contributors to inflammation in gynecologic tissues are diverse. Macrophages, which constitute a substantial proportion of immune cells in the endometrium and peritoneal cavity, undergo phenotypic switching between pro-inflammatory and tissue-repairing states; disequilibrium between these phenotypes is characteristic of endometriosis and adenomyosis.³⁴ Neutrophils and mast cells participate in early inflammatory responses, releasing proteases, histamine, matrix metalloproteinases, and reactive oxygen species that remodel the extracellular matrix but can also contribute to fibrosis and neurovascular changes when persistently activated. Moreover, chronic inflammation shapes the tumor microenvironment in gynecologic cancers by facilitating immune evasion, promoting angiogenesis, and enhancing genomic instability.³⁵
Hormonal regulation interacts intricately with immune signaling pathways. Estrogens generally exert anti-inflammatory effects by inhibiting NF-κB activation, whereas progesterone modulates cytokine production and promotes immune tolerance. Disturbances in hormonal-immune crosstalk contribute to disease pathogenesis, such as progesterone resistance in endometriosis, which perpetuates an inflammatory phenotype despite circulating hormone levels.³⁶ Together, these molecular and cellular mechanisms illustrate the central role of inflammation in gynecologic diseases. A comprehensive understanding of these pathways provides not only insights into disease etiology but also a foundation for developing targeted anti-inflammatory and immunomodulatory therapies, which represent promising avenues to improve outcomes in women’s reproductive health.
Role of Inflammation in Major Gynecologic DisordersEndometriosisEndometriosis is one of the clearest examples of a disease fundamentally driven by inflammation. Ectopic endometrial tissue releases pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α), chemokines, and growth factors, sustaining a chronic inflammatory microenvironment within the pelvis. Activated macrophages in the peritoneal fluid produce prostaglandins and reactive oxygen species (ROS), amplifying pain and inducing neuroangiogenesis. This inflammatory cascade not only contributes to cyclic pelvic pain and dyspareunia but also disrupts folliculogenesis, oocyte quality, and implantation, thereby impairing fertility. Furthermore, persistent inflammation leads to fibrosis and adhesion formation-the hallmarks of advanced disease. Current evidence strongly supports that targeting inflammatory mediators may serve as an effective adjunct to hormonal suppression, particularly in refractory cases.^3,37
Polycystic Ovary Syndrome (PCOS)PCOS, traditionally conceptualized as an endocrine-metabolic disorder, is now increasingly viewed through the lens of low-grade chronic inflammation. Women with PCOS exhibit elevated circulating levels of C-reactive protein (CRP), TNF-α, IL-18, and monocyte chemoattractant proteins. Adipose tissue dysfunction and insulin resistance further amplify systemic inflammation, creating a self-perpetuating cycle. Hyperandrogenism has been shown to stimulate inflammatory signaling pathways, while inflammation exacerbates granulosa cell apoptosis and follicular arrest. The ovarian stroma also demonstrates inflammatory infiltration, contributing to the characteristic thickened capsule and impaired ovulation. Clinically, these inflammatory processes manifest as metabolic comorbidities, increased cardiovascular risk, and subfertility. Thus, anti-inflammatory interventions-including lifestyle modification, insulin sensitizers, and emerging cytokine-targeting therapies-have gained prominence alongside classic ovulation-induction strategies.³⁸
Uterine Fibroids (Leiomyomas)Inflammation plays a crucial role in the development and growth of uterine fibroids. Leiomyoma tissue demonstrates increased expression of inflammatory mediators, including IL-6, TGF-β, and COX-2–derived prostaglandins. Chronic inflammation stimulates extracellular matrix production and fibrosis, the primary drivers of tumor growth and bulk-related symptoms. The interplay between sex steroid hormones and inflammation is particularly striking: estrogen and progesterone enhance inflammatory signaling, while inflammatory pathways increase hormonal sensitivity, creating a bidirectional loop. Additionally, local hypoxia within fibroid tissues activates HIF-1α–dependent inflammatory pathways, promoting angiogenesis. Understanding fibroids as hormonally responsive inflammatory lesions helps explain variability in symptom severity and treatment response and supports the rationale for anti-inflammatory therapeutic approaches such as selective progesterone receptor modulators and COX-2 inhibitors.³⁹
Pelvic Inflammatory Disease (PID)PID is an overt inflammatory disorder resulting from ascending genital tract infections, most commonly due to Chlamydia trachomatis or Neisseria gonorrhoeae. The initial infectious insult triggers a robust innate immune response involving neutrophils, macrophages, and pro-inflammatory cytokines. However, what determines long-term sequelae is not merely the infection itself but the magnitude and duration of the inflammatory response. Excessive or prolonged inflammation causes tubal scarring, loss of ciliary function, and fibrosis, ultimately predisposing patients to infertility, chronic pelvic pain, and ectopic pregnancy. Emerging evidence highlights that certain Chlamydia-induced inflammatory pathways persist even after infection is eradicated, suggesting that post-infectious immune dysregulation contributes to chronic symptoms. Early recognition and prompt antimicrobial therapy remain essential, yet modulating the inflammatory response may be key to preventing long-term reproductive damage.^4,40
AdenomyosisAdenomyosis, once considered a purely structural disorder, is now increasingly understood as an inflammatory condition with immune-endocrine dysregulation. Ectopic endometrial glands within the myometrium release cytokines that attract macrophages, mast cells, and T-lymphocytes, promoting local inflammation. This inflammatory environment enhances prostaglandin production, contributing to severe dysmenorrhea and heavy menstrual bleeding. Simultaneously, inflammation destroys surrounding smooth muscle cells and triggers reactive hyperplasia, explaining the characteristic thickened, boggy uterus. Neuroinflammation and increased nerve fiber density within adenomyotic lesions account for heightened pain sensitivity. The recognition of inflammation as a central mechanism has led to renewed interest in anti-inflammatory agents, including NSAIDs, aromatase inhibitors, and immune-modulating therapies.^41,42
Gynecologic CancersInflammation plays both a tumor-initiating and tumor-promoting role in gynecologic malignancies such as ovarian, endometrial, and cervical cancer. Chronic inflammatory conditions-endometriosis, pelvic infections, obesity, and persistent HPV infection-contribute to malignant transformation by inducing DNA damage, oxidative stress, and genomic instability. Tumor-associated macrophages (TAMs), regulatory T-cells, and inflammatory cytokines create an immunosuppressive microenvironment that promotes angiogenesis, tumor invasion, and metastasis. In ovarian cancer, the peritoneal cavity becomes a highly inflammatory niche, facilitating dissemination. Endometrial cancer is strongly linked to metabolic inflammation driven by obesity and insulin resistance. Cervical cancer is sustained by chronic HPV-induced inflammation and immune evasion. These insights have paved the way for immunotherapeutic strategies targeting inflammatory pathways, including checkpoint inhibitors and anti-cytokine treatments.^43,44
Future DirectionsFuture research on the interplay between inflammation and gynecologic disorders should prioritize multi-dimensional approaches that integrate molecular, clinical, and technological advancements. First, large-scale, longitudinal cohort studies are urgently needed to clarify causal relationships between chronic inflammation and disease onset, progression, and recurrence across gynecologic conditions such as endometriosis, polycystic ovary syndrome, pelvic inflammatory disease, and gynecologic malignancies. Such datasets would enable the identification of inflammatory trajectories and patient-specific risk profiles, ultimately informing preventive strategies.
Second, the development of novel biomarkers-including cytokine signatures, extracellular vesicles, non-coding RNAs, metabolomic profiles, and microbiome-derived indicators-represents a critical research avenue. Future work should assess the diagnostic, prognostic, and therapeutic relevance of these markers, with an emphasis on high specificity and reproducibility across diverse populations. The integration of systems biology tools and machine learning may facilitate the creation of personalized inflammatory maps capable of guiding individualized treatment algorithms.
Third, there is a growing need to expand mechanistic studies that decipher how immune–endocrine–metabolic interactions contribute to gynecologic pathophysiology. Particular attention should be given to the role of innate immune sensors, inflammasome activation, oxidative stress pathways, and tissue-resident immune cell populations within the female reproductive tract. Advancements in single-cell transcriptomics, spatial omics, and organ-on-chip models will allow researchers to dissect these complex networks with unprecedented resolution.
In parallel, evaluating the therapeutic potential of targeted anti-inflammatory interventions-including immunomodulatory agents, biologics, cytokine inhibitors, antioxidants, and microbiome-directed therapies-is an important future direction. Trials should also investigate combination approaches that pair anti-inflammatory agents with hormonal treatments, analgesics, or fertility-preserving strategies to optimize clinical outcomes while minimizing adverse effects.
Finally, addressing research gaps related to reproductive health disparities remains essential. Future studies must consider how socioeconomic factors, environmental exposures, diet, lifestyle, and access to care influence inflammatory burden and disease severity among different populations. Incorporating these variables will ensure that emerging diagnostic tools and therapeutic strategies are equitable, culturally sensitive, and broadly applicable.
Collectively, these future directions highlight the need for integrative, precision-oriented research efforts that redefine how inflammation is understood, monitored, and targeted across gynecologic disorders.
Ethical ApprovalThis article is a review of previously published studies and does not involve human participants or animals. Therefore, ethical approval and informed consent were not required.
Reporting GuidelinesReporting guidelines were not applicable because this article is a narrative review.

Limitations

This review has several limitations. First, much of the existing evidence is based on observational and cross-sectional studies, limiting causal interpretation between inflammation and gynecologic disorders. Second, considerable heterogeneity in study design, patient populations, diagnostic criteria, and biomarker assessment methods reduces comparability and may account for inconsistent findings. Third, many studies evaluate isolated inflammatory markers without fully accounting for confounding factors such as age, metabolic status, environmental exposures, and microbiome composition. Finally, although multi-omics and precision-medicine approaches are promising, their clinical applicability remains limited by insufficient standardization, small sample sizes, and lack of large-scale longitudinal validation.

Conclusion

Inflammation represents a central biological axis underpinning both physiological processes and pathological conditions within the female reproductive system. While tightly regulated inflammatory cascades are essential for ovulation, implantation, menstruation, and parturition, dysregulated or chronic inflammation contributes to the initiation, progression, and clinical heterogeneity of numerous gynecologic disorders, including endometriosis, polycystic ovary syndrome, pelvic inflammatory disease, adenomyosis, and gynecologic malignancies. Accumulating evidence highlights the complexity of immune–endocrine–metabolic interactions, illustrating that aberrant activation of inflammatory mediators, oxidative stress pathways, and tissue-remodeling mechanisms can profoundly impact reproductive function and overall women’s health.
Despite significant advancements, major gaps remain in delineating causal pathways, identifying reliable biomarkers, and translating mechanistic insights into effective therapeutic strategies. The heterogeneity of inflammatory signatures across disorders and among individuals underscores the necessity for integrative approaches that utilize multi-omics platforms, advanced imaging techniques, and precision-medicine frameworks. In addition, the role of environmental exposures, microbiome composition, lifestyle factors, and reproductive aging warrants deeper investigation to fully contextualize inflammation-driven gynecologic pathology.
Ultimately, a more comprehensive understanding of the molecular and cellular mechanisms governing inflammation will be instrumental in improving early diagnosis, refining risk stratification, and developing targeted, patient-centered interventions. Continued interdisciplinary research efforts hold promise for transforming the management of gynecologic disorders, reducing disease burden, and enhancing reproductive and long-term health outcomes for women globally.

Declarations

Abbreviations

CRP: C-reactive protein
HPV: human papillomavirus
IL: interleukin
LH: luteinizing hormone
MAPK: mitogen-activated protein kinase
MMP: matrix metalloproteinase
NF-κB: nuclear factor kappa B
NLRP3: NLR family pyrin domain containing 3
NLR: neutrophil-to-lymphocyte ratio
PCOS: polycystic ovary syndrome
PID: pelvic inflammatory disease
PLR: platelet-to-lymphocyte ratio
PRR: pattern-recognition receptor
ROS: reactive oxygen species
SII: systemic immune-inflammation index
SPM: specialized pro-resolving mediator
TAM: tumor-associated macrophage
TLR: Toll-like receptor
TNF-α: tumor necrosis factor alpha

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March 23, 2026