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11 July 2026

Narrative Review on Chronic Endometritis and Its Diagnosis in the Reproductive Process: Focus on Possible Future Diagnostic Perspectives

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1
Gynecology and Obstetrics Unit, Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy
2
Department of Obstetrics and Gynecology, “Valle d’Itria” Hospital, 74015 Martina Franca, Italy
3
Department of Health Science, School of Medicine, University of Eastern Piedmont Amedeo Avogadro, 28100 Novara, Italy
4
Department of Surgical Sciences Gynecology and Obstetrics, “AOU Città della Salute e Della Scienza di Torino”, University of Turin, 10126 Turin, Italy
Sci2026, 8(7), 167;https://doi.org/10.3390/sci8070167
This article belongs to the Section Clinical Medicine and Healthcare
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Abstract

(1) Background: Chronic endometritis (CE) is a chronic disease of the endometrium characterized by inflammatory infiltration into the endometrial stroma. The diagnosis of CE is complex. Clinical examination and transvaginal ultrasound are not specific for CE. Biopsy is an indispensable tool. Two specific populations can be analyzed at the endometrial level: CD138 positive plasma cells and CD56 positive Natural Killer cells. (2) Methods: Our narrative review was based on an online search with a focus on the last ten years of literature in the English language. (3) Results: Twenty studies on CD138 positive plasma cells and 16 articles on CD56 positive Natural Killer cells highlighted the correlations of CE with diagnostic possibilities and reproductive outcomes. (4) Conclusions: The etiological pathway and management of CE require further scientific studies and investigations. Hysteroscopy is the diagnostic gold standard, but other blind biopsy techniques (i.e., Perma, Pipelle, Novak, etc.) and molecular procedures may help in the diagnosis of chronic endometritis.

1. Introduction

Infertility is defined as the inability to conceive after unprotected sexual intercourse. Guidelines recommend initiating a diagnostic workup after 12 months of unsuccessful conception in women under 35 years of age and after 6 months in women over 35 years of age. However, in women over 40 years of age, a more immediate evaluation may be considered [1].
The extent of investigations depends on multiple factors, including the patient’s age, personal and reproductive history, duration of infertility, and the couple’s preferences.
It is estimated that in 40% of infertile couples, the woman is the sole or contributing cause of infertility; in another 40% of cases, infertility is attributable to the male partner, and in the remaining 20% of cases, there are no identifiable causes.
Transvaginal ultrasound is a fundamental first-line tool for evaluating uterine and adnexal pathologies and for studying ovarian reserve. It allows for the analysis of the number and size of ovarian follicles, especially when performed during the luteal phase [2]. Uterine pathologies account for approximately 16% of the causes of female infertility. They include both more common acquired conditions, such as endometrial polyps, uterine fibroids, and adhesions, as well as congenital pathologies, including bicornuate uterus, septate uterus, or other congenital uterine anomalies [3].
Hysteroscopy, on the other hand, represents a diagnostic but also therapeutic method for intrauterine pathologies [4].
The balance between reproductive difficulties and achieving a pregnancy is very delicate. Another potential cause of recurrent miscarriages or implantation failure is genital infection, connecting intestinal dysbiosis and endometritis. Several microorganisms, including Ureaplasma, Mycoplasma, and Chlamydia [5,6], that cause bacterial vaginosis, also appear to be implicated in first- and second-trimester miscarriages [7].
More recently, increasing attention has been paid to the role of the immune system in reproductive function, particularly the altered inflammatory and immune status of the endometrium, which can lead to unexplained infertility and recurrent miscarriages: this condition is called chronic endometritis (CE).
Chronic endometritis is a chronic inflammatory disease of the endometrium characterized by plasma cell infiltration into the endometrial stroma (Figure 1). The diagnosis of CE is complex. Clinical examination and transvaginal ultrasound are not specific for CE; endometrial biopsy is fundamental. Several diagnostic methods have been suggested for the diagnosis of chronic endometritis, the most widely used of which is hysteroscopy, allowing the identification of the classic signs of endometritis:
Figure 1. Impaired immunological function, endometritis and infertility.
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Focal or diffuse hyperaemia (the “strawberry” appearance);
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Stromal edema;
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Micro-polyps (small growths < 1 mm, a highly predictive sign of endometritis).
Moreover, the endometrial biopsy is fundamental for studying these diagnostic populations: CD138 plasma cells and CD56 Natural Killer cells.
Immunohistochemistry for the plasma cell marker CD-138 at the endometrial histological level is currently the most reliable and rapid diagnostic method for CE. However, this technique has several limitations [8,9].
Endometrial epithelial cells can express CD-138 on the basolateral side of their plasma membrane, potentially leading to misdiagnosis. Therefore, additional specific staining techniques for CE would be useful. CE may represent a substrate for the development of proliferative endometrial lesions, including endometrial polyps [8]. Furthermore, CE may impair endometrial receptivity to the embryo, resulting in infertility and recurrent miscarriages. Unfortunately, the exact mechanisms underlying chronic endometritis-related infertility are still unknown, potentially involving other cells, such as Natural Killer (NK) CD56+ [8,9]. The risk of CE may also be significantly related to the presence of endometrial polyps: it appears more likely in women with polypoid endometrium, as well as in those with three or more endometrial formations compared to those with a single one [8,9]. Available evidence in premenopausal women suggests that this condition may represent two consecutive phases of a common pathological process, which requires further study to fully clarify its role in infertility [8,9].
In most cases, patients are asymptomatic or present with nonspecific symptoms such as pelvic pain, dyspareunia, leukorrhea, and dysmenorrhea [8].
Chronic endometritis compromises the uterine environment by altering cytokine production, reducing the expression of implantation-related genes, and promoting stromal fibrosis [9].
Our aim is to summarize the updated literature known so far about the topic to deepen our understanding of the diagnostic criteria and management in infertility.

2. Materials and Methods

Our study aims to conduct a narrative review of the literature on CD138+ plasma cells and CD56+ NK cells, focusing on endometritis and reproductive outcomes such as abortion/pregnancy rate/recurrent implantation failure, etc., using searches from PubMed, Scholar, Embase, Scopus, etc.
The identification of the articles in the English language was based on the keywords:
  • (“Infertility” [MeSH Terms]) AND (“CD138” [Title/Abstract] OR “syndecan-1” [Title/Abstract] OR “plasma cells” [MeSH Terms]),
  • (“Infertility” [MeSH Terms]) AND (“Natural Killer Cells” [MeSH Terms] OR “NK cells” [Title/Abstract]).
Literature from the last 10 years (2016–2026) was then filtered, according to the scientific research evidence (based on strength of evidence, sample size, quality of studies, etc.). Our narrative review is written following the Equator Guidelines [10] (Figure 2).
Figure 2. Flow-chart of the literature evaluation.
Inclusion and Exclusion Criteria
-Inclusion Criteria:
  • Observational studies (cohort, case–control, cross-sectional) and clinical trials (randomized or otherwise) evaluating the role of CD138+ plasma cells and/or NK cells in patients with infertility.
  • Studies that included an assessment of CD138+ (by immunohistochemistry) or CD56+ NK cells (using flow cytometry, immunohistochemistry, or endometrial biopsy).
  • Comparative studies with fertile control groups or pre-/post-treatment designs.
-Exclusion Criteria:
  • Preclinical studies using animal models or in vitro cell lines.
  • Abstracts without full text available.
  • Case reports, editorials, letters to the editor, and narrative reviews.
  • Studies not directly related to infertility (e.g., oncology).
Gemini AI 3.5 Flash was used to create Figure 1 (Branch • CD56, CD138 and implantation failure—Google Gemini https://gemini.google.com/app/b2888b43343800b0?hl=it), accessed online on 29 May 2026.

3. Results

The initial identification of 77 articles was based on the keywords and scientific evidence; 36 articles in the English language were then filtered according to the last 10 years of production for table description.

3.1. Plasma Cells CD138 (Table 1)

CD138+ plasma cells (Syndecan-1) are the main diagnostic marker of chronic endometritis. Although immunohistochemical detection of CD138+ plasma cells is now globally accepted as the best marker for diagnosing CE, there is no consensus on the cut-off that is considered statistically significant. This variability may be due to the different methods used to quantify CD138+ cells. The most common approach is to count CD138+ cells per high-power field (HPF). The study by Chen et al. recommends a cutoff of >5 CD138+ cells/HPF [11]. Bouet et al. [12] proposed a minimum of five plasma cells in 10 non-overlapping HPFs as the diagnostic threshold for chronic endometritis; Kitaya et al. [13] instead suggested a cutoff of >5 cells in 20 non-overlapping HPFs.
These above-mentioned studies, however, do not definitively correlate the number of CD138+ cells with adverse reproductive outcomes.
The optimal diagnostic window is also still unclear regarding the optimal timing for endometrial sampling, and results are controversial. Furthermore, Li et al.’s research [9] evaluated 716 women highlighting that a number of CD138+ cells ≥ 5 in at least one of 30 HPFs was statistically significantly associated with adverse pregnancy outcomes. In this study, endometrial biopsies were performed during the proliferative phase, highlighting how the result may vary depending on the phase of the menstrual cycle in which the sampling was performed [9].
Previous studies have suggested the follicular phase as the best time to perform biopsy, as the luteal phase may show inflammatory infiltration, leading to false positives [14].
Selmi et al.’s study on 249 patients found no statistically significant differences in the detection of CE between the proliferative and secretory phases in patients with RIF (recurrent implantation failure) and RPL (recurrent pregnancy loss), suggesting that this is a persistent rather than cyclical condition [15].
A prospective study from 2021 [16] observed that the mean CD138+ score (calculated as the number of CD138/HPF cells) was significantly altered in women with full-term pregnancies compared to those with infertility and recurrent miscarriages. Women with >16 CD138/HPF had a significantly higher risk of miscarriage.
The rate of chronic endometritis in infertile women undergoing in vitro fertilization (IVF) reaches 30–40%, decreasing to approximately 10% after antibiotic and probiotic therapy [16].
Table 1. Literature review about plasma cells CD138+ and infertility.

3.2. Natural Killer CD56+

Natural Killer (NK) cells are potentially linked to reproduction in a significant way [35]. The literature provides varied data regarding the connection between Natural Killer cells, endometritis, and infertility (Table 2) [36,37,38,39,40,41,42,43,44,45,46,47,48,49,50].
Uterine NK cells represent the major leukocyte population in the normal endometrium and also play a fundamental role in angiogenesis and trophoblast invasion [51]. Their presence varies physiologically during the different phases of the menstrual cycle, likely due to the recruitment of NK cells from peripheral blood or their proliferation in the uterus. They represent 40% of total leukocytes during the proliferative phase and increase to 60% during the secretory phase [52].
There are two subgroups of CD56+ NK cells, depending on the density of CD56 on the cell surface, which can be distinguished into CD56bright (high expression) and CD56dim (low expression) cells. CD56bright cells are primarily immunomodulatory and cytokine-producing, while CD56dim cells are highly cytotoxic and represent the mature and predominant phase in peripheral blood [53].
In peripheral blood, 90% of NK cells are CD56+/CD16+ and CD56−/CD16+ cells. CD56+/CD16− cells constitute 70–90% of lymphocytes present in the secretory phase of the endometrium and are less cytotoxic [54,55]. Both peripheral blood NK cells (pNKs) and uterine NK cells (uNKs) display CD56 on their surface but differ in both phenotype and function. A total of 90% of pNK cells are CD56dim/CD16+, while 80% of uNK cells are CD56bright/CD16+.
Several studies have attempted to correlate pNK levels with recurrent miscarriages, but the literature to date has yielded conflicting results (Table 2).
The study by Azargoon et al. observed a significantly higher mean percentage of CD56+ cells in infertile women compared to fertile women (p-value 0.007). However, no significant differences were found in the total number of CD56+ cells between women with recurrent miscarriages and the control group [56].
The study by Fukui et al. showed, using immunophenotypic analysis, a higher percentage of CD16+/CD56dim cells and a lower percentage of CD16−/CD56bright cells in women with infertility who miscarried following in vitro fertilization, compared to women who carried their pregnancies to term [57].
Lachapelle et al. also observed a prevalence of CD16+/CD56dim cells and a reduction in CD16−/CD56bright cells in women with recurrent miscarriages compared to controls [58].
The study by Junovich et al. found an increase in the number of CD16+ endometrial NK cells in patients with unexplained infertility, correlated with a reduction in IL-6 and VEGF levels in the endometrium [59].
It can therefore be hypothesized that an increase in CD16+ NK cells may create an unfavourable environment for implantation, likely by producing pro-inflammatory cytokines and secreting cytotoxic factors in response to trophoblast cells [59].
Repeated implantation failure is typically defined as three failed Intra-Cytoplasmic Sperm Injection (ICSI) cycles, although this definition varies, and the literature often uses a number of failed cycles of ≥2. The IVF success rate is 40.1% in women under 35 years of age, while it is 20.6% in women over 40 years of age. Pregnancy failure is due to implantation failure in more than 50–75% of cases [60].
During the implantation window, the number of endometrial NK cells increases significantly, from 30% in the proliferative phase to 70% in the secretory phase [39]. The increase in NK cells is likely involved in preparing the endometrium for embryo implantation, angiogenesis, trophoblast invasion, decidualization, and immunological tolerance through the production of various cytokines [61].
Several studies have investigated the impact of NK cells on the success or failure of IVF procedures (Table 2).
Interestingly, some research has observed a paradoxical association between normal uNK cell counts and poor reproductive outcomes, leading to functional hypotheses of exhaustion or inappropriate receptor–ligand interactions. Killer Cell Immunoglobulin-like Receptors (KIRs) and their interactions with HLA-C ligands on trophoblasts could potentially determine the immunological “compatibility” between mother and embryo, influencing implantation success [30,52,62].
The study by Mardanian et al. demonstrated a significantly higher level of CD56dimCD16+ cells in peripheral blood in the IVF-failure group compared to the IVF-successful group (p < 0.0001), while the level of CD56brightCD16− cells did not show statistically significant differences (p = 0.28) [63].
Other data have found a higher percentage of CD56dim NK cells in the peripheral blood of women with repeated implantation failure compared to fertile controls, such as the study by Sacks et al. (p < 0.001) [64].
The relationship between NK cells in the peripheral blood and implantation failure remains highly controversial. It is believed that increased NK cell activity may be involved in the immune response of “fetal rejection” by preventing invasion of the trophoblast in the endometrium [65].
However, updated studies evaluating the presence and impact of endometrial NK cells on infertility are few or with a small sample size and are not always conclusive.
Chen et al. [66] showed a significantly higher percentage of CD56+ cells in the endometrium in cases of repeated implantation failure (p-value < 0.001). A more in-depth investigation of the NK cell population showed a significantly higher percentage of both CD56+CD16+ and CD56+CD16− cells in women with repeated implantation failure compared to the control group.
In the retrospective study by Ekemen et al. [36], endometrial samples were collected during the secretory phase of the cycle. In 74.3% of cases with two or more IVF failures, elevated CD56+ cells were found in patients. These patients were then treated with cortisone and intralipid therapy. In 85.5% of cases, a successful pregnancy was achieved following treatment.
Functional profiling of uNK cells at the transcriptomic level reveals a dual phenotype. While CD56bright uNK cells express angiogenic factors, aberrant populations exhibit increased transcripts for cytotoxic mediators. Research using single-cell RNA sequencing has identified uNK subpopulations with divergent roles, supporting implantation or mediating immune rejection. At the proteomic level, excessive activation correlates with the secretion of granzyme B, perforin, and IFN-γ, which can disrupt trophoblast invasion and endometrial vascular remodelling [30,57]. CD56bright CD16− endometrial NK cells are present in large numbers at the implantation site where they come into contact with trophoblast cells, and transcriptomic studies suggest that this cell phenotype expresses proangiogenic factors [53,67].
The mechanism by which trophoblast cells escape endometrial NK cells is unclear. It is hypothesized that increased NK cell activity may lead to trophoblast cell suppression and thus miscarriage [68].
A new area of interest is the interaction between CD138+ plasma cells and endometrial NK cells. Some studies, such as that of Kitaya et al. in 2018, suggest that chronic inflammation and an altered innate immune response may together create a uterine environment unfavourable to implantation [69].
Preliminary studies suggest altered levels of metabolites involved in oxidative stress, which could alter immune tolerance and local cytokine production. These alterations could modulate the cytotoxic threshold of NK cells and plasma cell survival, compromising embryo implantation [70].
CD138+ plasma cells and NK cells have shown a particularly important role in IVF, where the lack of endogenous immunomodulation by the corpus luteum could increase susceptibility to immune dysfunction. This is a possible explanation why antibiotic therapy for chronic endometritis and/or corticosteroid and intralipid therapy in cases of high numbers of cytotoxic NK cells in the peripheral blood are associated with increased implantation success [67].
Table 2. Literature review about Natural Killer CD56+ and infertility.

3.3. Endometrial Sampling Methods

Regarding different diagnostic methods, hysteroscopy is still the gold standard, but the 2025 study by Falahy et al. showed no statistically significant differences between hysteroscopic curettage and the Pipelle probe sampling [71].
An innovative and less invasive diagnostic tool still under investigation is the aspiration of uterine fluid (“endometrial lavage”) as a method to assess the immune status of the endometrium through the search for immune markers. Some preliminary studies suggest that soluble forms of CD138 and NK cell-associated cytokines (e.g., IL-15, IFN-γ) can be quantified in endometrial secretions and may correlate with endometrial tissue findings [72].
These blind techniques would facilitate repeated monitoring of the immune profile over time and in response to potential treatment [30,72].
As shown in Table 1 and Table 2, several studies highlight the potential clinical utility of tools such as pipettes in outpatient settings.

3.4. Treatment

The treatment of chronic endometritis is predominantly antibiotic, given the primarily bacterial etiology of the disease. In recent years, several studies have shown that adequate treatment of chronic endometritis is associated with significant improvements in in vitro fertilization outcomes [51,67].
Currently, antibiotic therapy represents the gold standard for the treatment of this condition, often combined with the use of prednisone [73] or, in more experimental settings, supported by immunoglobulin treatment [74].
The study by Cicinelli et al. [51] compared the pregnancy rate and live birth rate between patients undergoing antibiotic treatment with subsequent histological confirmation of disease resolution and patients with persistent endometritis after treatment. The results showed a significantly higher live birth rate in group 1 compared to group 2 (61% vs. 13%, p-value 0.02).
Similarly, Cheng et al. [75], through a systematic review and meta-analysis, evaluated the impact of antibiotic therapy on IVF outcomes. The results showed a statistically significant increase in several outcomes, such as implantation rate, ongoing pregnancy rate, and live birth rate in patients with successfully treated chronic endometritis, compared to both patients with persistent CE and those without an initial diagnosis of chronic endometritis. This benefit was demonstrated exclusively in cases where histological confirmation of endometritis resolution was present.
Similar results were also reported in the meta-analysis by Vitagliano et al. [67], which highlighted a significant increase in clinically confirmed pregnancy and live birth rates in patients with histologically confirmed resolved chronic endometritis compared to patients with persistent endometritis after treatment. Conversely, no statistically significant differences were found between patients who did not receive antibiotic treatment and those who did, but without histological confirmation of treatment success.
Several studies have also investigated the role of corticosteroid therapy, given the importance of immunological factors in embryo implantation processes due to the involvement of uterine NK cells in regulating embryo implantation [76].
The 2022 [77] study by Giulini et al., conducted on patients with repeated implantation failure, evaluated the impact of combined therapy with prednisone (10 mg/day) and doxycycline (100 mg twice daily for 14 days) in patients with endometrial biopsies positive for CD138 plasma cells and CD56 cells vs. corticosteroid therapy alone in cases positive exclusively for CD56. The results showed improved reproductive outcomes, with a live birth rate of 22.2% after treatment. Specifically, treatment with prednisone was more effective in patients with severe endometritis (CD56 > 10%), with a live birth rate of 29.4%, compared to patients with mild forms of endometritis, where the therapy was less effective (live birth rate of 10%). The 2018 study by Lédée et al. [78], conducted on 55 patients with RIF, showed a reduction in CD56+ cell expression in approximately half of the patients after treatment with prednisone.
Cooper et al. (2019) observed a significant reduction in uterine NK cell concentration following prednisone therapy, but did not demonstrate a statistically significant difference in pregnancy outcomes [79].
More recently, the study by Zou et al. [80] reported a significant increase in key reproductive outcomes, such as implantation rate, clinically confirmed pregnancy rate with heartbeat, and ongoing pregnancy rate, in the group treated with the combination of doxycycline and prednisone compared to the group treated with doxycycline alone. Furthermore, treatment with doxycycline alone also showed a significant improvement in reproductive outcomes compared to no treatment, confirming the role of antibiotic treatment.
An emerging area of interest concerns the intrauterine therapeutic approach.
A 2023 [81] study compared pregnancy outcomes between patients treated with oral antibiotic therapy (doxycycline and metronidazole) combined with intrauterine perfusion with gentamicin and dexamethasone and patients treated with oral therapy alone. Comparing the group receiving oral therapy alone with the cohort receiving the combined treatment, significantly higher rates of clinically proven pregnancy (30% vs. 50%, p < 0.001), ongoing pregnancy (33.33% vs. 45.45%, p < 0.0001), and live births (33.33% vs. 45.45%, p < 0.0001) were reported. A statistically significant decrease in the rate of early spontaneous abortions was also observed (6.667% vs. 4.545%, p = 0.0068).
The work by Zhang [82] et al. evaluated the efficacy of intrauterine infusion of a targeted antibiotic against the identified microorganism in combination with dexamethasone 5 mg. Patients in whom treatment resulted in resolution of chronic endometritis showed a significantly higher rate of implantation and clinically confirmed pregnancy, both compared to patients with RIF without evidence of chronic endometritis and those with persistent chronic endometritis [82]. Finally, restorative medicine could have a role. Mesenchymal stem cells introduced into the uterus may actively repair damaged endometrial tissue. Regenerative therapies utilize immunomodulation to calm persistent uterine inflammation and tissue damage. Transplanted stem cells secrete critical growth factors to trigger natural cellular healing processes. These cellular approaches stimulate angiogenesis, forming new blood vessels to improve tissue circulation. For example, cell-free therapies utilize exosomes to deliver regenerative genetic material directly to the tissue, and advanced therapies successfully restore lost endometrial glands crucial for early embryo implantation. By reducing fibrosis and boosting lining thickness, these alternatives could restore fertility after chronic infection [83].

4. Discussion

Chronic endometritis is a persistent inflammation of the endometrial stroma. Unlike the acute form, it is often oligosymptomatic or completely asymptomatic, manifesting clinically only through infertility. The role of CE has been linked to miscarriages and recurrent implantation failures. The local balance required for pregnancy establishment is very delicate, and many factors may intervene, albeit in ways that are still unknown. For this reason, the ESHRE guidelines also highlight the evaluation of the endometrium as a potential resource for the diagnosis of CE. Since there are no definitive data, this step is among the suggested ones, which is why it is necessary to increase scientific research in this direction [84].
Standard histological diagnosis is based on the identification via biopsy of inflammatory infiltrates. Plasma cells should not be abundant in a normal endometrium. The CD138 marker is the surface antigen of choice, identified using techniques such as immunohistochemistry [24]. This dramatically increases diagnostic sensitivity compared to simple hematoxylin–eosin staining, where plasma cells can be confused with stromal fibroblasts. There is still no universal consensus, but the presence of ≥5 plasma cells per high-power field (HPF) is commonly used to define positivity (Table 1).
Uterine NK cells are different from peripheral ones. Although they are not direct markers of infection, their count can be crucial. Excessive activation or density of CD56+ cells is often associated with a pro-inflammatory state resulting from endometritis, contributing, for example, to trophoblast rejection.
Hysteroscopy is the visual “gold standard,” but biopsy remains essential for confirmation to study these cell populations.
In addition to direct under vision biopsy, other techniques are available, such as Fluid Biopsy (Uterine Liquid Biopsy) with the analysis of endometrial fluid to detect bacterial DNA or inflammatory cytokines and blind sampling techniques, such as Pipelle, Perma, and Novak [5].
The future of diagnosis is shifting from cellular observation to molecular biology. While CD138+ plasma cell evaluation remains the operational standard, it suffers from high inter-observer variability and epithelial false positives. As CE heavily impacts reproductive success, integrating emerging molecular and microbial approaches could be clinically vital. Other new markers are being studied for their potential diagnostic reliability [30,57], e.g., MUM1 [29], cytokine profile in uterine fluid (IL-6, IL-1beta and TNF-α), and transcriptomic indicators. Molecular techniques, like Real-Time PCR and Next-Generation Sequencing (NGS), provide objective and quantifiable data. Alternative cellular markers like MUM1/IRF4 reduce diagnostic ambiguity by offering cleaner staining with lower background noise [29]. Concurrently, 16S rRNA gene sequencing has redefined CE from a simple infection into a complex microbiome dysbiosis. Mapping the uterine cavity into Lactobacillus-dominated or non-dominated environments allows for personalized, targeted therapies. Techniques are becoming increasingly precise, such as microbiome analysis (Real-Time PCR, NGS), e.g., tests such as ALICE (Analysis of Infectious Chronic Endometritis), allowing the identification of specific pathogens responsible for inflammation, overcoming the limitations of traditional procedures (many endometrial bacteria are difficult to grow in vitro) [85].
Furthermore, evaluating advanced immune biomarkers highlights the true inflammatory burden harming endometrial receptivity. Measuring uterine Natural Killer (uNK) cell density and pro-inflammatory cytokines (IL-6, IL-1β) maps local immune disruption.
Together, these multi-omic approaches transform CE from a poorly defined finding into a highly characterized condition. Expanding the narrative to include these diagnostic vectors could be essential to optimize treatments and improve reproductive outcomes.
Due to their practicality and ease of use, the outpatient use of other devices (e.g., Pipelles, Perma, etc.) could be beneficial [71]. Despite the lack of visual support, this could streamline waiting lists for hysteroscopic procedures and provide a rapid clinical approach in targeted cases.
The strength of this study is its updated summary of the topic, identifying the most relevant recent literature. This work also attempted to highlight the quantitative aspects of diagnostics in the two most well-known populations in CE and, for the first time, underscored the value of blind endometrial sampling techniques for clinical speed and patient comfort. Limitations include that studies generally involve heterogeneous, limited sample sizes of patients undergoing search for offspring, with different reproductive outcomes.

5. Conclusions

The evolution of various sampling techniques could significantly impact future reproductive outcomes. The diagnosis of chronic endometritis may provide a response to the many implantation failures that still exist in assisted reproduction. It is necessary to further investigate the possibility of increasingly personalized management of the couple seeking pregnancy [29], as well as with some drugs in the context of other infertility disorders [86], with:
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Faster and more painless sampling techniques- even during the gynecological examination (e.g., Perma, Pipelles) [71,87].
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Targeted Antibiotic Therapy—moving from empiric protocols (often based on doxycycline) to therapies guided by molecular PCR results to combat antibiotic resistance.
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Immunomodulation—in addition to antibiotics, the use of vaginal/uterine probiotics to restore a Lactobacillus-dominant microbiome and the use of specific anti-inflammatories [88].
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AI in Hysteroscopy—the development of artificial intelligence algorithms capable of recognizing CE patterns during endoscopic examinations in real time, eliminating operator subjectivity.
In conclusion, the diagnosis of chronic endometritis and its treatment in case of a positive result require further scientific studies and investigations to determine the most valid and appropriate strategy for each specific case.

Author Contributions

Conceptualization, C.I.A. and D.S.; methodology, C.I.A. and D.S.; validation, C.I.A., S.C., R.T. and D.S.; formal analysis, C.I.A., A.L. and D.S.; investigation, C.I.A., A.L. and D.S.; resources, R.B. and S.C.; data curation, C.I.A., A.L. and D.S.; writing—original draft preparation, C.I.A., A.L. and D.S.; writing—review and editing, C.I.A. and D.S.; visualization, C.I.A. and D.S.; supervision, S.C. and D.S.; project administration, C.I.A. and D.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

During the preparation of this manuscript, the authors used Gemini AI to create Figure 1 (https://gemini.google.com/app/b2888b43343800b0?hl=it, accessed on 29 May 2026). The authors have reviewed and edited the output and take full responsibility for the content of this publication.

Conflicts of Interest

The authors declare no conflicts of interest.

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