Even though our understanding of CE has advanced, there are still research gaps. Chronic endometritis is not consistently recognized and managed in different clinical settings due to the inconsistency in existing diagnostic techniques⁽³⁾. Furthermore, studies are still being conducted to determine the exact role of the endometrial microbiome in the pathophysiology of CE. As our understanding of the microbiome expands, future studies should evaluate the potential of probiotics and other microbiome-based therapies as adjunctive therapy for chronic endometritis. To agree on treatment protocols, diagnostic standards and the use of microbiome-modulating medications, large-scale, multicenter trials are necessary⁽⁵⁾.

Materials and method

This review aims to consolidate the current understanding of chronic endometritis, encompassing its etiology, clinical manifestations, diagnostic challenges, treatment options, and implications for reproductive health.

Data were collected from the existing literature, utilizing the keywords “chronic endometritis (CE)”, “infertility”, “recurrent pregnancy loss (RPL)”, “endometrial biopsy”, and “hysteroscopy”. The focus was directed towards randomized controlled trials and observational studies, with inclusion limited to publications in the English language. A comprehensive list of all references utilized is provided in the reference section.

Pathophysiology

Microbial factors: changes in the endometrial microbiome’s number and composition, which are marked by an overabundance of different bacteria, appear to be linked to the formation of CE. These are represented by intracellular and Gram-negative bacteria, including Mycoplasma, Ureaplasma, Chlamydia, Escherichia coli, Enterococcus faecalis, and some Streptococcus species. This supports the notion of an infectious origin for CE, as numerous studies have shown that targeted antibiotic treatment can effectively resolve the condition in most patients. In certain regions, Mycobacterium tuberculosis is prevalent, accounting for 40-75% of infertility cases, primarily because of its disruption of implantation. This occurs by altering the immune response in the endometrium, leading to hormonal imbalances and the release of antiphospholipid antibodies. It is now widely acknowledged that the uterus is not a sterile environment, and the mere presence of microorganisms does not necessarily indicate inflammation^(3-6). Several researchers have reported the asymptomatic presence of bacteria in the endometrial cavity, through transcervical samples or cultures obtained from post-hysterectomy specimens^(4,5).

Endometrial inflammation: plasma cells found in endometrial tissue are the ones that determine CE. Both implantation and the course of pregnancy are negatively impacted by this ongoing inflammation, which interferes with the endometrium’s natural receptivity⁽³⁾. Autoimmune mechanisms: in certain cases, chronic endometritis may arise from autoimmune disorders, where the immune system mistakenly targets the endometrial tissue, leading to chronic inflammation⁽³⁾. The Di Pietro et al. study examined the expression levels of 25 genes linked to apoptosis, cellular proliferation, and inflammation in the endometrial tissue during the window for implantation. In contrast to a control group of ten healthy women, this study included 16 women who had been diagnosed with CE after hysteroscopy and histological investigation. The results showed that gene expression had changed significantly. B-cell CLL/lymphoma 2, BCL2-associated X protein, and insulin-like growth factor binding protein 1 showed notable increases. On the other hand, IL-11, chemokine ligand 4, insulin-like growth factor 1, and caspase 8 expression were decreased. Both the development of endometrial hyperplastic lesions and embryonic implantation may be impacted by these changes in gene expression⁽⁷⁾.

Etiology

Microorganisms that climb from the cervix and vaginal vault into the uterine lining are typically the cause of endometritis. Depending on the kind of endometritis, several microorganisms may be implicated, and it can frequently be difficult to identify them⁽¹⁾.

Acute endometritis. Research shows that more than 85% of infections in cases of acute endometritis are linked to sexually transmitted diseases (STDs). Acute endometritis is mostly caused by Chlamydia trachomatis, followed by Neisseria gonorrhoeae and bacteria linked to vaginal infections, in contrast to chronic and postpartum endometritis, which can involve many pathogens⁽⁸⁾. Acute endometritis has been linked to several risk factors. These include those who are younger than 25 years old, have a history of STIs, engage in high-risk sexual behaviors like having multiple partners, or have undergone specific gynecological procedures such as endometrial biopsies or the implantation of intrauterine devices. In particular populations, these factors significantly increase the likelihood of getting this illness^(9-11).

Chronic endometritis. CE’s precise cause is frequently unknown. According to research, noninfectious causes of endometrial inflammation include submucosal fibroids, endometrial polyps, and intrauterine devices (IUDs)⁽¹²⁾. When a polymicrobial infectious agent is discovered, it usually consists of organisms that are frequently present in the vaginal canal. Furthermore, genital tuberculosis can lead to chronic granulomatous endometritis, especially in developing regions. Unlike acute endometritis, chronic cases are not primarily linked to Chlamydia trachomatis or Neisseria gonorrhoeae⁽¹⁰⁾.

Chronic endometritis frequently manifests with mild symptoms, making it difficult to accurately gauge its true prevalence. In patients experiencing recurrent pregnancy loss, certain studies suggest that the incidence may reach nearly 30%. However, this figure can vary within the same research, depending on the menstrual phase during which endometrial biopsies are performed^(12,13).

Clinical presentation

Chronic endometritis often lacks distinctive clinical symptoms and manifests nonspecifically in serological and culture assessments. As a result, a definitive diagnosis generally necessitates histological or hysteroscopic evaluation. The presence of plasma cells in the endometrial stroma, which can be identified using the CD138 immunohistochemical marker or standard staining techni­ques, is usually investigated by an endometrial biopsy⁽¹²⁾. Interestingly, there is still disagreement among experts on the bare minimum of endometrial stromal plasma cells (ESPCs) needed to make a definitive diagnosis^(10,13,14).

The International Working Group for Standardization of CE Diagnosis has established precise criteria for reaching a definitive diagnosis. Histological confirmation is considered positive when CD138 staining detects clusters of less than 20 plasma cells or when one to five stromal plasma cells are visible in each high-power area⁽¹⁵⁾. Additionally, several hysteroscopic traits observed during the follicular phase are recognized as CE diagnostic indicators:

• Endometrial micropolyposis is characterized by small elevations on the endometrial surface that measure between 1 and 2 millimeters.
• Stromal edema causes the endometrium to appear thickened and lighter during the follicular phase, rather than the usual secretory phase.
• There are distinct areas of redness within the endometrial tissue, characterized by irregular, well-defined edges.
• Extensive areas of reddened endometrial tissue feature white spots at the center.
• Focal areas of increased blood flow^(13,15,16).

Diagnosis

Histopathological examination. A tissue biopsy is usually used to confirm the diagnosis of CE by detecting the stromal plasma cells present in the endometrium.

Since these plasma cells are important markers of the illness, CD138 labeling must be used to properly differentiate them. To determine the best diagnostic cutoff point for chronic endometrial inflammation, researchers performed a systematic review in a 2023 paper titled “The Role of Plasma Cells as a Marker of CE”. The results showed a strong correlation between the detection of at least five plasma cells per high-power field (HPF) and adverse reproductive outcomes, including a higher risk of miscarriage. This cut­off point has the potential to greatly improve diagnostic precision and its relevance in fertility evaluations^(17-19).

A 2023 study titled “Histological Diagnostic Criterion for CE” underscores the significance of detecting at least one plasma cell in every 10 high-power fields (HPFs) as a key factor in diagnosing CE. Because it offers a more precise method of diagnosing the illness and enhancing reproductive health outcomes, this criterion is especially crucial for women who are experiencing infertility^(20-22).

Hysteroscopy. The endometrium can be visually examined with hysteroscopy, a minimally invasive treatment. Micropolyps, areas of increased blood flow, and endometrial surface abnormalities are among the specific results that can be found with this approach in CE instances. These visual clues facilitate quicker diagnosis confirmation, which leads to more precise CE management and treatment^(23,24). The usefulness of hysteroscopy in treating chronic endometritis is examined in “The Role of Hysteroscopy in Diagnosing CE”. The study cla­ims that hysteroscopy makes it easier to spot important features such as endometrial micropolyps, regions that are prone to hyperemia, and surface abnormalities⁽²⁴⁾.

Microbial cultures and PCR. When combined with histological analysis, microbial cultures, and PCR testing are helpful techniques for identifying specific infections associated with chronic endometritis⁽²⁵⁾. Moreno et al. found that PCR testing outperformed traditional diagnostic methods like histology, hysteroscopy, and microbiological cultures in detecting CE. The study showed that PCR has a high sensitivity for identifying bacteria that are hard to grow or only present in tiny numbers. Histology, hysteroscopy and microbiological cultures all improved overall diagnosis accuracy, but PCR continuously beat these methods in terms of precision^(26-29). The relationship between chronic endometritis and uterine microbiota was examined in a 2023 study, specifically to RPL and recurrent implantation failure (RIF). Researchers found a higher incidence of Lactobacillus iners using 16S rRNA gene sequencing⁽²⁹⁾.

Treatment

Reducing chronic inflammation, improving reproductive results, and curing the underlying condition are the main goals of CE treatment. Broad-spectrum antibiotics are typically used as part of the standard treatment regimen. Doxycycline, which is commonly given at a dose of 200 mg daily for 14 days, has been demonstrated to be effective against common bacteria associated with CE, such as Mycoplasma and Ureaplasma^(31,32).

When doxycycline by itself is insufficient to produce the desired effects, a combination therapy may be used. Drugs that target a wider variety of anaerobic and aerobic bacteria, including ciprofloxacin and metronidazole or ofloxacin and metronidazole, may be used in this situation⁽³²⁾.

Even when a particular pathogen is not present, empirical antibiotic treatment is recommended for individuals who are experiencing RPL or implantation failure. Many people have experienced symptomatic improvement as a result of this method⁽³³⁾.

In one study, Johnston-MacAnanny et al. assessed doxy­cycline’s efficacy in treating patients with CE. The re­sults showed that plasma cells that tested positive for CD138, a marker of chronic endometritis, were cleared 70% of the time after a 14-day treatment with 200 mg/day of doxycycline⁽³⁴⁾. Research on probiotic therapy’s poten­tial as a CE treatment is also ongoing. This approach aims to restore a healthy microbial balance in the vaginal and uterine environment. Research is still in progress, but the theory is that promoting the growth of beneficial bacteria or restoring them may lessen chronic inflammation caused by toxic or unbalanced microbiota⁽³⁵⁾. According to recent studies, probiotic medicine may be a helpful strategy for treating chronic endometritis and for enhancing reproductive outcomes, particularly when combined with antibiotic therapy^(35-37).

Complications

Infertility and repeated miscarriages have been intimately linked to chronic endometritis, especially when the underlying causes are still unknown. This conversation will offer a thorough examination of how CE affects particular reproductive disorders.

Infertility

Endometrial receptivity, which is essential for a successful embryo implantation, may be negatively impacted by chronic endometritis. In cases when the underlying causes are yet unknown, CE has been closely associated with infertility and recurrent miscarriages. A detailed analysis of the relationship between chronic endometritis and several reproductive problems will be provided in this discussion. Endometrial receptivity, which is essential for successful embryo implantation, may be negatively impacted by chronic endometritis which is associated with chronic inflammation that alters the uterine lining, decreasing its capacity to promote implantation in multiple ways, by altering the equilibrium of immune cells and cytokines in the endometrium and, so, inflammation impairs the uterus’ capacity to receive a fertilized egg^(38,39). Endometrial inflammation frequently prevents embryos from implanting properly, leading to infertility or unproductive pregnancies⁽³⁹⁾. According to studies, women with CE usually have poorer success rates with IVF and other assisted reproductive technologies, and frequently struggle to conceive naturally^(38,39).

Recurrent pregnancy loss (RPL)

Recurrent miscarriages are closely associated with chronic endometritis. The endometrial environment is disturbed by the ongoing inflammatory process in multiple significant ways. One of them is impaired placental development where prolonged inflammation may prevent the placenta from developing and attaching, which may lead to early pregnancy loss⁽⁴⁰⁾. The elevated risk of miscarriage is another way. Research indicates that women with CE are more likely than those without the illness to experience repeated miscarriages.

It has been demonstrated that treating chronic endometritis with antibiotics improves pregnancy outcomes for RPL-affected women^(40,41).

Adhesions and Asherman’s syndrome

When scar tissue (adhesions) develops inside the uterus and/or cervix, it can lead to Asherman’s syndrome, also known as intrauterine adhesions or intrauterine synechiae, which is a serious complication⁽⁴²⁾. Because they might not notice or care about the symptoms, women who are not attempting to conceive may not know they have Asherman’s syndrome. These ladies might experience hypomenorrhea. As a result, Asherman’s syndrome may go undiagnosed because it is typically not noticeable during standard exams or diagnostic tests like ultrasound scans⁽⁴²⁾. To remove the adhesions and restore the uterus’s capacity to support a pregnancy, this syndrome usually necessitates surgical interventions, which further complicate the fertility treatments^(42,43). In order to show the adhesions, Asherman’s syndrome is more frequently assessed initially using saline sonography or hysterosalpingography, even though two-dimensional sonography may indicate adhesive illness. However, the diagnostic sensitivity of these modalities is still only 75%. The gold standard for determining the severity of the illness and enabling concurrent therapy is still hysteroscopy. When there is complete obliteration of the uterine cavity, an MRI is required⁽⁴³⁾.

Prevention and future directions for CE

Early diagnosis and screening: one of the primary strategies for preventing CE is early detection, particularly in women who exhibit risk factors such as unexplained infertility or RPL. By screening women facing reproduc­tive issues with techniques like hysteroscopy, endometrial biopsy, or advanced diagnostic methods such as PCR for pathogen identification, chronic endometritis can be identified at an early stage, facilitating prompt and effective treatment⁽⁴³⁾.

Antibiotic prophylaxis: research indicates that administering prophylactic antibiotics to women undergoing procedures like in vitro fertilization may help decrease the risk of developing CE by preventing infections that could result in chronic inflammation of the endometrium^(43,44).

Minimizing invasive procedures: reducing the frequ­ency of invasive uterine procedures, including repeated dilation and curettage, and exercising caution during surgeries such as hysteroscopy can significantly lower the risk of infection and scarring, which may lead to chronic endometritis⁽⁴⁴⁾.

Prevention: it has been shown that significantly better results can be obtained from routinely screening for CE in women who are experiencing recurrent miscarriages or unexplained infertility. Timely intervention is made possible by early discovery which may help prevent major reproductive issues⁽⁴⁵⁾. More research aimed at enhancing diagnostic methods and determining the best antibiotic regimens is desperately needed. Fur­ther research options include examining the role of the microbiome in chronic endometritis and assessing the efficacy of probiotic treatments^(39,40,44).

Discussion

Female fertility is severely hampered by chronic endometritis, especially when it comes to infertility and the prevalence of repeated miscarriages. This section seeks to highlight the most important findings, evaluate their clinical relevance, and compare them to previ­ous studies⁽²¹⁾. Evidence suggests a strong connection between CE and negative reproductive outcomes. The inflammation caused by chronic endometritis can impair endometrial receptivity, so it will make it harder for embryos to implant and increase the risk of miscarriage. Prompt administration of antibiotics has been shown to eliminate plasma cells, improving fertility outcomes^(21,46,47). The findings presented are consistent with prior research that highlights the association between CE and unexplained infertility. Nevertheless, there are notable differences in the recommended diagnostic methods. Although conventional histology methods provide insightful information, using PCR and metagenomic sequencing could greatly increase the precision of diagnosis^(37,38). Regular screening for chronic endometritis is vital for women facing infertility or recurrent pregnancy loss. Employing advanced diagnostic methods, such as hysteroscopy and PCR testing, enables early intervention that will substantially improve outcomes⁽⁴⁸⁾. The latest studies underscore the significance of prompt diagnosis in enhancing reproductive health for those who suffer from chronic endometritis⁽⁴³⁾. Studies suggest that implementing antibiotic prophylaxis throughout reproductive procedures may reduce the risk of developing complications. However, we have to keep in mind that many current studies are limited by small sample sizes and retrospective designs that may limit how far their findings can be applied⁽⁴⁹⁾. Additionally, the lack of standardized diagnostic criteria throughout various studies complicates the development of universally accepted treatment guidelines^(37-39).

In the future, our main focus should be on the significance of carrying out bigger, multicenter studies to standardize CE treatment and diagnostic procedures. Furthermore, investigating the role of the endometrial microbiome and evaluating how well probiotic therapies work present worthwhile chances to improve therapeutic approaches^(46,47).

Conclusions

Even while chronic endometritis is often asymptomatic, it nonetheless poses a serious risk to women’s reproductive health, especially with infertility that cannot be explained and recurrent miscarriages. There is little doubt that chronic endometritis has been associated with lower fertility.

It has been shown that prompt diagnosis and proper use of antibiotics are useful tools when trying to improve reproductive outcomes. To better understand the wider effects of chronic endometritis on women’s health, fur­ther research is also needed to develop novel diagnostic techniques and implement therapeutic strategies like probiotic use and microbiome.   

CORRESPONDING AUTHOR: Aniela-Roxana Nodiţi E-mail: aniela.noditi@umfcd.ro

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.