Chronic Endometritis: A Silent Contributor to Infertility and Reproductive Failure—A Comprehensive Review

Abstract

Chronic endometritis (CE) is a persistent, often asymptomatic inflammatory condition of the endometrium, increasingly recognized as a potential contributor to infertility and recurrent implantation failure. Despite its clinical significance, CE remains underdiagnosed due to a lack of standardized diagnostic criteria and its subtle clinical presentation. Objective: This review aims to synthesize the current evidence on the pathophysiology, diagnosis, and treatment of CE, highlighting its impact on reproductive outcomes and the effectiveness of therapeutic interventions. A comprehensive literature review was conducted, analyzing 85 peer-reviewed studies published in the last decade, of which 65 were deemed relevant and retained for further analysis. These studies were selected based on their relevance to the pathophysiology, diagnostic methodologies, and treatment outcomes for CE, focusing on their implications for fertility and assisted reproductive technologies (ARTs). The findings suggest that CE is associated with impaired endometrial receptivity, increased inflammatory markers, and reduced implantation and pregnancy rates with ARTs. Histopathological assessment using CD138 immunostaining remains the gold standard for diagnosis, while hysteroscopy and molecular microbiological techniques provide complementary diagnostic value. Antibiotic treatment has been shown to significantly improve implantation rates and pregnancy outcomes, particularly in women with recurrent implantation failure. Emerging therapies, including probiotics and regenerative medicine approaches, are being explored as potential adjuncts to the conventional treatment. Early and accurate diagnosis of CE is essential for optimizing reproductive outcomes. Standardized diagnostic protocols and individualized treatment strategies are crucial for improving implantation success and pregnancy rates in affected women. Future research should focus on refining the diagnostic methods and exploring novel therapeutic options to enhance endometrial health and fertility outcomes.

1. Introduction

Chronic endometritis (CE) is a chronic inflammatory condition of the endometrial lining, characterized by plasma cells in the stroma. Unlike acute endometritis, which presents with overt symptoms of infection, CE is often asymptomatic or manifests with subtle clinical signs, such as abnormal uterine bleeding, pelvic discomfort, or infertility. Due to its silent nature, CE remains underdiagnosed, leading to potential reproductive complications, particularly in women undergoing assisted reproductive technologies (ARTs) [1].

Chronic endometritis is defined histologically by the infiltration of plasma cells into the endometrial tissue, often confirmed using CD138 immunohistochemical staining. It is frequently associated with microbial infections, particularly by Ureaplasma urealyticum, Mycoplasma hominis, and Escherichia coli. In contrast, Chlamydia trachomatis, a well-known pathogen in acute endometritis, is less commonly detected in chronic endometritis, with the reported rates ranging from 2% to 7% [2].

The prevalence of CE varies significantly across different populations and diagnostic methods. Studies indicate that CE affects approximately 10–30% of women with infertility, with even higher rates (up to 60%) in those experiencing recurrent implantation failure (RIF) or recurrent pregnancy loss (RPL) [3]. However, due to variations in the diagnostic criteria and the asymptomatic or oligosymptomatic nature of the disease, the actual prevalence of chronic endometritis may be underestimated [2]. Overdiagnosis may also occur, especially when hysteroscopic observations are interpreted without supporting histological or immunohistochemical evidence [4,5].

CE is increasingly recognized as a silent contributor to infertility, as it alters the endometrial receptivity necessary for successful embryo implantation. The inflammatory milieu induced by CE disrupts endometrial function, leading to suboptimal conditions for embryo attachment and development [4].

Women with CE undergoing in vitro fertilization (IVF) have been shown to have lower implantation and pregnancy rates compared to the rates in those without CE. Furthermore, studies suggest that untreated CE is associated with increased risks of early miscarriage and adverse pregnancy outcomes [5]. Given that CE is often missed in the standard infertility assessments due to its subtle or absent clinical presentation, it has been hypothesized that some cases of unexplained infertility may be linked to undetected chronic endometrial inflammation. However, further studies are needed to clarify this association.

Chronic endometritis may be associated with decreased endometrial receptivity by reducing the expression of genes involved in implantation, such as HOXA10 and HOXA11, thus contributing to implantation failure and early pregnancy loss [6]. Moreover, CE has been linked to an increased risk of preterm birth and fetal growth restriction, emphasizing its broader implications beyond conception [7].

A retrospective study suggested that antibiotic treatment of chronic endometritis may be associated with improved pregnancy outcomes, particularly in women with recurrent miscarriages or previous ART failure [8]. However, given the methodological limitations of retrospective analyses, including the lack of randomization and risk of regression to the mean, these findings should be interpreted cautiously and confirmed in future prospective studies. Research also suggests that endometrial microbiome modulation through probiotics and regenerative therapies may offer additional benefits in restoring a healthy uterine environment [9].

This review will comprehensively analyze chronic endometritis, including its pathophysiology, diagnostic approaches, and treatment strategies. By examining the latest evidence, we seek to highlight the clinical relevance of CE in infertility and pregnancy loss, emphasizing the need for increased awareness and improved diagnostic protocols. Additionally, we will explore emerging therapeutic options that may enhance the reproductive outcomes for affected women.

2. The Pathophysiology of Chronic Endometritis

2.1. Microbial Causes

Chronic endometritis (CE) is a low-grade, chronic inflammatory condition of the endometrial lining that is frequently asymptomatic but may contribute to infertility. While its natural history remains incompletely understood, ongoing research into its etiology and pathophysiology is essential to improve diagnostic accuracy and guide appropriate therapeutic strategies.

CE is predominantly associated with the bacterial pathogens given in

Table 1. Bacterial pathogens associated with chronic endometritis.

Bacterial Pathogen	Description	Refernces
Ureaplasma and Mycoplasma species	It is commonly implicated in genital tract infections and linked to CE.	[9,10,11,12,13]
Chlamydia trachomatis	This well-known sexually transmitted pathogen has been identified as a causative agent in cases of endometritis.	[14,15,16,17]
Enterobacteriaceae (e.g., Escherichia coli)	These include various Gram-negative bacteria, such as Escherichia coli, isolated from the endometrial tissues of women with CE.	[18,19,20,21,22]
Polymicrobial infections	CE often results from infections involving multiple bacterial species, reflecting the complex microbial environment of the female reproductive tract.	[23,24,25,26,27]

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2.2. Pathophysiology

Ongoing or recurrent microbial exposure may sustain a chronic inflammatory response, which can alter the endometrial environment required for optimal embryo implantation. This chronic inflammatory state can result in altered tissue remodeling and impaired endometrial receptivity [28]. Alterations in cytokine profiles (IL-6, TNF-α) and immune dysregulation: CE is associated with dysregulated cytokine production, notably increased levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). These alterations can impair the immune tolerance for successful embryo implantation [29,30,31,32,33].

2.3. Its Impact on Endometrial Receptivity and Implantation Failure

The inflammatory milieu in CE adversely affects endometrial receptivity by altering the expression of key implantation markers and disrupting the balance of the immune cells within the endometrium. Consequently, these changes can lead to implantation failure and contribute to infertility [34].

Chronic endometritis (CE) disrupts the endometrial milieu, leading to impaired receptivity and subsequent implantation failure through several key mechanisms:

2.4. Alteration of Endometrial Gene Expression

Chronic endometritis (CE) has been associated with significant changes in the expression of genes that regulate endometrial receptivity. Key molecular markers involved in implantation, such as HOXA10, HOXA11, LIF, and IGFBP-1, are downregulated in patients with CE, leading to impaired receptivity and implantation failure [6,17],

Table 2. Key implantation markers and their expression in chronic endometritis.

Implantation Marker	Function	Expression in Normal Endometrium	Expression in CE	Impact on Implantation
HOXA10	Regulates endometrial receptivity and stromal cell differentiation	High in the mid-secretory phase	Reduced expression of HOXA10	Impaired endometrial receptivity and failure to prepare the endometrium for embryo attachment
HOXA11	Essential for glandular function and decidualization	High during the implantation window	Reduced expression of HOXA11	Defective implantation and inability to support embryo attachment
LIF (Leukemia Inhibitory Factor)	Mediates embryo–endometrial communication	Upregulated in the receptive endometrium	Reduced expression of LIF	Reduced embryo adhesion and impaired communication between the embryo and the endometrium
IGFBP-1 (Insulin-like Growth Factor Binding Protein-1)	Supports trophoblast invasion	High during implantation	Decreased secretion of IGFBP-1	Poor endometrial–embryo interaction and impaired trophoblast invasion
Integrin αvβ3	Promotes blastocyst adhesion	Expressed during the implantation window	Reduced expression of integrin αvβ3	Failure of attachment of blastocysts to the endometrial lining

. Endometrial receptivity arrays (ERAs) have been used to evaluate the expression profiles of these genes, revealing that women with CE have a significantly higher proportion of non-receptive endometria compared to that in those without CE (84.2% vs. 42.4%) [34].

In addition, CE alters the window of implantation (WOI), when the endometrium is most receptive to embryo implantation. A disrupted WOI can lead to implantation failure in both natural and assisted reproductive cycles [34]. Studies suggest that persistent endometrial inflammation shifts the WOI by modifying the expression of progesterone receptors and integrins, crucial for endometrial–embryo interactions [6,25].

The table presents key implantation markers (HOXA10, HOXA11, LIF, IGFBP-1, and integrin αvβ3), highlighting their essential roles in endometrial receptivity, their regular expression during implantation, the downregulation observed in chronic endometritis (CE), and the resulting negative impact on embryo implantation and fertility.

2.5. Immune Cell Infiltration and Cytokine Imbalance

Chronic endometritis (CE) is characterized by the abnormal infiltration of immune cells into the endometrial stroma, particularly plasma cells, macrophages, and activated T cells. These immune changes lead to the overproduction of pro-inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which create a hostile environment for implantation [28,35,36,37].

One of CE’s most significant immunological imbalances is Th17/Treg cell ratio disruption. Th17 cells are involved in inflammation and autoimmunity, while regulatory T cells (Tregs) help maintain immune tolerance. In CE, an increased Th17 response and a deficiency in Tregs contribute to persistent endometrial inflammation and reduced implantation success [38,39,40,41,42,43,44,45],

Table 3. Immune cell alterations and cytokine imbalance in CE.

Immune Component	Role in a Healthy Endometrium	Changes in CE	Impact on Implantation
Plasma Cells	Usually absent or in very low numbers	Increased infiltration	Chronic inflammation
Macrophages	Regulate tissue repair and immune balance	Elevated pro-inflammatory M1 subtype	Impaired endometrial regeneration
Th17 Cells	Pro-inflammatory, involved in autoimmunity	Increased levels	Excessive inflammation, reduced tolerance
Treg Cells	Maintain immune tolerance and prevent rejection	Decreased levels	Loss of immune balance, increased embryo rejection
NK Cells	Support trophoblast invasion and placental development	Altered number and phenotype; potential dysregulation of function [29]	Impaired trophoblast invasion, possible contribution to implantation failure
IL-6	Promotes implantation at physiological levels	Elevated	Disrupts endometrial receptivity
TNF-α	Regulates immune homeostasis	Increased levels	Induces apoptosis in endometrial cells, impairing implantation

.

Moreover, elevated levels of natural killer (NK) cells in CE can impair endometrial receptivity by reducing trophoblast invasion, leading to implantation failure [35,46].

This table summarizes the immune alterations observed in chronic endometritis (CE), highlighting the increased infiltration of inflammatory cells (plasma cells, macrophages, and Th17 cells), the reduction in regulatory T cells (Tregs), and the overactivation of natural killer (NK) cells, along with elevated pro-inflammatory cytokines (IL-6 and TNF-α), all of which contribute to impaired endometrial receptivity and implantation failure.

2.6. Microbiota Dysbiosis

The endometrial microbiota play a crucial role in maintaining reproductive health. Dysbiosis, or imbalance, in the microbial community has been linked to reduced implantation success. Studies have shown that an abnormal composition of the endometrial microbiota is associated with lower pregnancy rates, highlighting the importance of a balanced microbial environment to optimal endometrial receptivity [36,47].

Lactobacillus dominated microbiota (≥90% of the total bacterial composition) are associated with higher implantation and pregnancy success rates in a healthy endometrium. However, in chronic endometritis (CE), microbial dysbiosis characterized by a lower proportion of Lactobacillus and an overgrowth of pathogenic bacteria such as Gardnerella, Atopobium, and Enterococcus has been linked to poor reproductive outcomes [34]. Studies show that women with a non-Lactobacillus-dominant endometrium have significantly lower pregnancy rates than those with a balanced microbiota (30.6% vs. 60.7%) [45]. The presence of pro-inflammatory bacteria leads to persistent immune activation and cytokine imbalance, further impairing endometrial receptivity [27].

Table 4. Endometrial microbiota alterations in chronic endometritis and their impact on receptivity.

Microbiota Profile	Dominant Bacteria	Implantation Success Rate (%)	Impact on Endometrial Receptivity
Healthy Microbiota	Lactobacillus spp. (≥90%)	60.7%	Supports implantation and pregnancy [22]
Mild Dysbiosis	Lactobacillus < 90%, presence of Gardnerella	45.3%	Moderate inflammation, reduced receptivity [34,36]
Severe Dysbiosis	Gardnerella, Atopobium, and Enterococcus are dominant	30.6%	Persistent inflammation, high risk of implantation failure [34,36]

illustrates how different microbiota compositions influence endometrial receptivity. It shows that a Lactobacillus-dominated microbiota supports implantation. In contrast, microbial dysbiosis, particularly the dominance of Gardnerella, Atopobium, and Enterococcus, is associated with lower implantation success rates due to increased inflammation and impaired endometrial function.

2.7. Histopathological Changes

Chronic endometritis (CE) induces significant histopathological alterations in the endometrium, leading to impaired receptivity and increased implantation failure. Persistent inflammation triggers stromal fibrosis, glandular atrophy, and vascular changes, compromising the endometrium’s structural and functional integrity [48,49,50,51,52,53].

Histological studies of CE patients show a higher density of stromal plasma cells, indicating chronic inflammation, reduced glandular density, and abnormal vascularization [52]. Additionally, the fibrosis associated with CE leads to excessive extracellular matrix (ECM) deposition, reducing endometrial elasticity and impairing embryo implantation [36,38],

Table 5. Histopathological changes in chronic endometritis and their impact.

Histopathological Feature	Description	Impact on Endometrial Receptivity
Stromal Fibrosis	Excessive deposition of extracellular matrix (ECM) components reduces endometrial flexibility	Impaired implantation due to reduced tissue remodeling
Glandular Atrophy	Decreased glandular density and function	Reduced secretion of implantation-supportive factors
Increased Plasma Cell Infiltration	Chronic inflammation with accumulation of plasma cells in the stroma	Persistent immune activation, impairing implantation
Abnormal Vascularization	Irregular blood vessel formation and poor angiogenesis	Disrupted nutrient supply to the embryo
Endometrial Thickening or Thinning	Structural imbalance in endometrial layers	Alters the implantation window and embryo adhesion

.

This table shows the significant histopathological changes in chronic endometritis (CE), highlighting how stromal fibrosis, glandular atrophy, plasma cell infiltration, abnormal vascularization, and endometrial thickness alterations contribute to impaired endometrial receptivity and implantation failure by disrupting tissue remodeling, angiogenesis, and immune homeostasis.

2.8. The Impact on Assisted Reproductive Technologies (ARTs)

Women with untreated CE undergoing ART procedures, such as in vitro fertilization (IVF), have been reported to have lower implantation and pregnancy rates. Treatment of CE with appropriate antibiotics has been associated with improved reproductive outcomes, underscoring the significance of diagnosing and managing CE in infertile patients [39]. Although evidence suggests the potential benefits of antibiotic treatment for chronic endometritis (CE), most of these data come from retrospective studies. Further randomized trials are needed to confirm these findings and establish standardized treatment protocols.

Chronic endometritis (CE) can compromise implantation success due to its multifactorial impact on the endometrium. Timely diagnosis and appropriate treatment are essential to improving reproductive outcomes.

2.9. Clinical Presentation and Challenges in the Diagnosis of Chronic Endometritis

Chronic endometritis (CE) is a subtle and often overlooked condition due to its frequently asymptomatic nature. However, its symptoms can significantly impact reproductive health and well-being in cases where they manifest [40,41,42,43],

Table 6. Effects of chronic endometritis on implantation and fertility.

Affected Factor	Pathophysiological Changes	Impact on Fertility
Implantation Markers	Downregulation of HOXA10, HOXA11, LIF, IGFBP-1	Reduced endometrial receptivity
Immune Response	Increased Th17 cells, plasma cells, macrophages; decreased Tregs	Chronic inflammation, failed implantation
Microbiota	Decreased Lactobacillus, increased Gardnerella	Higher risk of implantation failure
Endometrial Structure	Stromal fibrosis, glandular atrophy	Impaired embryo support
ART Success Rates	Lower implantation, pregnancy, and live birth rates	Increased recurrent implantation failure (RIF)

.

Even though chronic endometritis (CE) is often asymptomatic, some patients may still experience nonspecific symptoms such as abnormal uterine bleeding, pelvic or lower abdominal discomfort, urinary frequency, or dyspareunia. Its subtle clinical presentation frequently delays diagnosis, yet the underlying inflammation can significantly compromise endometrial receptivity and has even been associated with adverse reproductive outcomes, including recurrent implantation failure [40].

3. Diagnosis of Chronic Endometritis

The diagnostic process for CE involves multiple modalities, each with its advantages and limitations,

Table 7. Diagnostic methods.

Diagnostic Method	Description
Histopathology (gold standard)	Endometrial biopsy followed by CD138 immunohistochemical staining to identify plasma cells, a hallmark of CE [37].
Hysteroscopy	Direct visualization of the endometrial lining reveals abnormalities such as hyperemia, micropolyps, and stromal edema [7]. Hysteroscopy-guided biopsy enhances the diagnostic accuracy compared to that of blind endometrial sampling [54].
Microbiological testing	Traditional endometrial biopsy cultures detect common causative bacteria, including Escherichia coli, Enterococcus faecalis, and Streptococcus spp. [43]. Polymerase chain reaction (PCR) testing offers a higher sensitivity in detecting bacterial DNA within the endometrial tissue [39].
Endometrial fluid analysis	Emerging approaches are exploring endometrial fluid proteomics and metabolomics to identify inflammatory markers linked to CE [42]. Non-invasive collection techniques are being studied to improve accessibility and diagnostic efficiency.

:

The diagnosis of CE remains challenging due to its often subtle or asymptomatic presentation. A structured diagnostic approach typically begins with clinical suspicion in patients with unexplained infertility or recurrent pregnancy loss. The gold standard is a histopathological evaluation using CD138 immunohistochemistry, with >5 plasma cells per high-power field (HPF) suggesting CE [47]. Hysteroscopy is a valuable complementary tool, identifying visual hallmarks such as endometrial micropolyps, stromal edema, and focal hyperemia. Molecular methods, including PCR or next-generation sequencing (NGS), can detect microbial dysbiosis, particularly the loss of Lactobacillus dominance and the presence of pathogens like Gardnerella or Atopobium [49]. Combining these modalities improves the diagnostic accuracy. In addition, research on endometrial fluid biomarkers is ongoing and may shortly lead to more accessible and non-invasive diagnostic options [41].

4. Its Impact on Reproductive Outcomes

The Impact of Chronic Endometritis on Infertility and Assisted Reproductive Technologies (ARTs)

CE has been increasingly recognized as a factor influencing infertility and reproductive failures, particularly in cases of recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL) [53,55,56,57,58].

Accurate identification relies on an integrated approach combining histopathology, hysteroscopic evaluations, and molecular diagnostics, particularly in patients facing infertility or recurrent pregnancy loss. Advances in the research on endometrial fluid biomarkers hold promise for developing more accessible, non-invasive diagnostic strategies. Significantly, the timely recognition and appropriate treatment of CE may improve reproductive outcomes, especially in the context of assisted reproductive technologies (ARTs) [13,44].

5. Treatment Strategies

Managing endometrial infections and dysfunctions requires a multifaceted approach, incorporating antibiotic therapy, adjuvant treatments, and emerging regenerative techniques, as shown in

Table 8. Managing endometrial infections and dysfunction.

Treatment Approach	Mechanism of Action	Clinical Benefits	Challenges
Antibiotic Therapy	Targets CE-associated pathogens	Reduces infection, improves receptivity	Risk of antibiotic resistance, recurrence
Probiotics	Restore Lactobacillus dominance	Modulate immune response, improve microbiota	Strain-specific effects, variable efficacy
Anti-Inflammatory Agents	Suppress chronic inflammation	Reduce cytokine imbalance	Long-term safety concerns
Platelet-Rich Plasma (PRP)	Stimulates tissue regeneration	Enhances endometrial function, restores receptivity	Limited large-scale studies
Stem Cell Therapy	Promotes endometrial repair	Potential for refractory CE cases	High cost, ethical considerations

. The success of these strategies is primarily evaluated based on their impact on implantation rates and pregnancy outcomes [45].

5.1. Antibiotic Therapy

Antibiotics remain the cornerstone of treatment for endometrial infections, particularly in cases of chronic endometritis, which has been associated with implantation failure and recurrent pregnancy loss [2,3,11].

5.2. Empirical vs. Targeted Treatment

While targeted antibiotic therapy based on microbial cultures or molecular diagnostics remains the preferred approach, empirical treatment may be considered in selected cases where such results are inconclusive, unavailable, or delayed, particularly in patients with recurrent reproductive failure and clinical or hysteroscopic signs suggestive of CE. The standard empirical regimens include broad-spectrum antibiotics such as doxycycline, metronidazole, and ciprofloxacin [47,48]. However, targeted therapy based on microbial cultures and antibiotic sensitivity testing is preferred whenever possible, as it ensures the eradication of specific pathogens, reduces the risk of antibiotic resistance, and minimizes unnecessary alterations in the microbiota [43].

5.3. Adjuvant Therapies

Given the increasing recognition of the role of the endometrial microbiota in reproductive health, adjuvant therapies are being explored to optimize treatment outcomes [1].

5.4. Probiotics—Restoring Normal Endometrial Microbiota

Disruptions in the endometrial microbiome, particularly a deficiency in Lactobacillus species, have been linked to poor implantation and pregnancy outcomes [37,48]. Probiotics, particularly Lactobacillus-containing formulations, aim to restore a healthy microbial balance, enhancing the receptivity of the endometrium. Studies suggest probiotic supplementation can improve the implantation rates in women undergoing assisted reproductive techniques [52,53,55,56].

5.5. Steroids and Anti-Inflammatory Agents

Steroids and other anti-inflammatory drugs are sometimes used to mitigate endometrial inflammation, particularly in cases where chronic endometritis persists despite antibiotic treatment. The rationale behind this approach is that excessive inflammatory responses can impair endometrial receptivity [59]. Corticosteroids such as prednisone have been investigated for their potential to improve implantation rates, but their use remains controversial due to concerns regarding their systemic side effects [60,61,62].

5.6. Platelet-Rich Plasma (PRP) Therapy—Its Emerging Role in Endometrial Repair

PRP therapy is an innovative treatment gaining attention for its regenerative potential in endometrial repair. PRP is rich in growth factors that promote tissue healing, angiogenesis, and cellular proliferation. Recent studies indicate that intrauterine PRP administration may benefit patients with thin endometria or refractory endometrial pathologies, improving the implantation success in vitro fertilization (IVF) cycles [63,64,65].

5.7. Vitamins and Nutraceutical Supplements

Vitamin imbalances have been increasingly associated with disorders of endometrial receptivity and embryo implantation. Deficiencies in vitamins D and E and the B complex vitamins may affect the expression of genes involved in immunological tolerance, angiogenesis, and endometrial maturation, contributing to a suboptimal uterine environment. In particular, vitamin D is essential for regulating regulatory T lymphocytes and producing anti-inflammatory cytokines, while vitamin E protects the endometrial cells against oxidative stress. In this context, nutraceutical supplements—such as omega-3 fatty acids, resveratrol, curcumin, or probiotics—have gained interest as therapeutic adjuvants due to their anti-inflammatory and immunomodulatory effects. Recent studies suggest that these interventions may restore a balanced endometrial microenvironment, especially in cases of chronic silent inflammation, such as chronic endometritis, thus increasing the chances of implantation and reproductive success in assisted reproductive techniques [66,67].

5.8. The Success Rates of Treatment

The impact on reproductive outcomes is often used to assess the effectiveness of these therapeutic interventions.

The successful eradication of chronic endometrial infections through targeted antibiotic therapy has been associated with significantly improved implantation rates and reduced pregnancy loss [40,41,48].

Integrating probiotics to reestablish a favorable endometrial microbiota further enhances endometrial receptivity, leading to better clinical pregnancy rates [37].

PRP therapy, in particular, has shown promising results in cases of persistent implantation failure, with studies reporting an improvement in endometrial thickness and subsequent pregnancy outcomes in women undergoing assisted reproductive treatments [63,64,65].

So, combining antibiotic therapy, adjuvant treatments, and emerging regenerative approaches such as PRP therapy offers a comprehensive strategy for improving endometrial health and optimizing reproductive success. Future research should continue to refine these treatment modalities and explore personalized approaches tailored to individual microbiological and immunological profiles [61].

6. Practical Insights for the Diagnosis and Treatment of CE

A synthesis of the diagnostic and therapeutic steps, as supported by the current evidence, is presented in

Table 9. Practical steps in the diagnosis and treatment of chronic endometritis (CE).

Step	Description	The Supporting Literature
Patient Selection	Women with unexplained infertility, recurrent implantation failure (RIF), or recurrent pregnancy loss (RPL).	[3,5,57]
Diagnostic Workup	Endometrial biopsy with CD138 immunostaining; hysteroscopy for a visual assessment; molecular microbiological tests (PCR/NGS).	[7,37,54,68]
Microbiological Evaluation	Culture or PCR from biopsy samples to identify pathogens (e.g., Gardnerella, Ureaplasma).	[43,49,68]
Antibiotic Treatment	Empirical (e.g., 100 mg of doxycycline BID for 14 days) or targeted based on antibiograms.	[2,11,47]
Adjuvant Therapies	The use of probiotics, corticosteroids, PRP, or regenerative approaches to support endometrial repair.	[52,60,63]
Follow-Up	Repeat hysteroscopy or biopsy to confirm the resolution of CE before ARTs.	[49,54,65]

.

7. Future Research Directions

Chronic endometritis (CE) remains underdiagnosed due to a lack of universally accepted diagnostic criteria. The current approaches vary significantly across studies, ranging from histopathological assessments using CD138 immunostaining to hysteroscopic evaluations and molecular microbiological techniques. In addition to CD138, the immunohistochemical marker MUM-1 has been proposed for confirming plasma cell identity and increasing the diagnostic reliability in challenging cases [68].

7.1. Advances in Molecular Diagnostics

Emerging technologies in molecular diagnostics, such as next-generation sequencing (NGS) and metagenomic analyses, hold promise for identifying CE-associated pathogens with greater sensitivity and specificity. NGS enables comprehensive profiling of the endometrial microbiome, allowing for the detection of polymicrobial infections that may contribute to CE. Metagenomic approaches provide deeper insights into the microbial diversity, antimicrobial resistance patterns, and host–microbe interactions within the endometrial environment. Integrating these advanced diagnostic tools into routine clinical practice could improve early detection and guide targeted therapeutic interventions [35,39,68,69,70].

Key molecular technologies such as next-generation sequencing (NGS), quantitative PCR (qPCR), and 16S rRNA sequencing are emerging as valuable tools in the detection of CE-associated pathogens, offering improved sensitivity and microbiome-level insights [71].

7.2. The Potential for Personalized Medicine Approaches in CE Treatment

The heterogeneity of CE suggests that a one-size-fits-all treatment strategy may not be optimal. Personalized medicine approaches based on molecular diagnostics and microbiome profiling could enable tailored therapies for affected individuals. For instance, the antibiotic regimens could be customized based on the identification of specific pathogens, while probiotics and microbiome-modulating therapies could be explored as adjunctive treatments [70]. Integrating host immune response biomarkers with molecular diagnostics could also refine the treatment strategies, optimizing the reproductive outcomes for patients with CE [43,72,73]. Future research should investigate individualized therapeutic protocols to enhance the treatment efficacy and minimize recurrence rates.

Recent studies have demonstrated that deep learning models, such as convolutional neural networks (CNNs), can effectively analyze hysteroscopic images to identify subtle endometrial abnormalities, including micropolyps, which are indicative of CE. Kitaya et al. and Mihara et al. have applied deep learning and computer-aided diagnostic models to hysteroscopic imaging, enabling the automated identification of chronic endometritis with a diagnostic accuracy comparable to that of expert-level gynecological assessments [73,74,75]. Such AI-driven approaches represent a promising future direction, with the potential to minimize inter-observer variability, standardize the interpretation of images, and improve early diagnostic accuracy in infertile women.

The present key areas for future research in chronic endometritis (CE) emphasize the need for standardized diagnostic criteria, advancements in molecular diagnostics, and the potential of personalized medicine approaches to improve treatment outcomes through pathogen-specific therapies, microbiome modulation, and immune profiling.

8. Conclusions

Chronic endometritis (CE) is increasingly recognized as a silent yet significant factor contributing to infertility and recurrent implantation failure. Its asymptomatic nature and lack of standardized diagnostic criteria often lead to its underdiagnosis, delaying appropriate intervention. The inflammatory changes associated with CE disrupt endometrial receptivity, impairing implantation success and pregnancy outcomes, particularly in women undergoing assisted reproductive technologies (ARTs). Histopathological examination using CD138 immunostaining remains the gold standard for diagnosis while emerging molecular and microbiome-based techniques offer promising advancements in detection. Antibiotic therapy has demonstrated efficacy in restoring endometrial health and improving reproductive outcomes. Additionally, novel approaches such as probiotics and regenerative medicine hold potential as adjunctive therapies.

Future research should prioritize the development of standardized diagnostic protocols, integrating next-generation sequencing and metagenomic analyses for improved pathogen detection and personalized treatment strategies tailored to individual microbial profiles. Addressing these challenges will enhance early diagnosis, optimize the therapeutic outcomes, and ultimately improve the fertility prospects for affected individuals. A multidisciplinary approach incorporating advances in molecular diagnostics and targeted therapies is essential for mitigating CE’s reproductive impact and maximizing pregnancy success rates.