Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:

1. Identify signs and standard criteria for diagnosis of chronic endometritis.

2. Describe changes within the endometrium in patients with chronic endometritis.

3. Explain treatment for chronic endometritis and the impact on reproductive outcomes.

Endometrium

The uterus is a soft-tissue organ with 3 layers: a thin external serosal layer, a wide middle myometrial layer, and an inner endometrial layer. The endometrium, a 2-layer mucosal membrane containing both glands and stroma, is composed of an inner stratum basale and an outer stratum functionale. Unlike the stratum basale, which minimally changes during the menstrual cycle and does not desquamate during menstruation, the stratum functionale responds to altering ovarian corticosteroid hormone levels. The stratum functionale is thought to be further subdivided into the lower layer providing strength and the upper layer metabolically preparing for possible blastocyst implantation. Microscopic changes within the endometrium can impact reproductive outcomes.

Endometritis

Endometritis refers to a process involving inflammation of the endometrial layer. It can be classified as either acute or chronic, typically based on histopathology. Acute endometritis is noted to have neutrophils or microabscess formation on histology. In contrast, chronic endometritis is characterized by plasma cells in the stroma, increased stromal density, edema, and disconnected maturation of epithelial cells and stroma fibroblasts.1,2

Although most commonly thought of as an obstetric disease, acute endometritis can also occur in the nonobstetric population as a manifestation of pelvic inflammatory disease (PID) or an invasive gynecologic procedure. On the contrary, chronic endometritis is poorly understood and is not thought to typically occur due to a transition from the acute to chronic phase. Patients with chronic endometritis are most commonly asymptomatic, and thus the true prevalence of chronic endometritis in the general population is difficult to identify.

Based on biopsies from hysterectomy specimens obtained from patients undergoing surgery for unrelated, benign gynecologic disorders, the prevalence of chronic endometritis is estimated to be about 10% to 11%.1-3 In the minority of patients who experience symptoms attributed to chronic endometritis, they are generally nonspecific and include abnormal uterine bleeding (AUB; intermenstrual spotting, postcoital bleeding, and amenorrhea), pelvic pain, dysmenorrhea, dyspareunia, leucorrhea, urinary symptoms, and infertility.1,2,4

Chronic endometritis is commonly diagnosed in women experiencing reproductive failure. The quoted incidence of chronic endometritis ranges from 2% to 56% of infertile women; the prevalence also appears to be quite high in patients with recurrent pregnancy loss, fetal demise, repeated implantation failure, and unexplained infertility.5-13 The wide range of prevalence in these conditions reflects the uncertainty about the nature of the diagnosis. In the past, chronic endometritis was believed to be a benign condition, but there has been growing interest in the relationship of this finding to adverse reproductive outcomes in view of these emerging data.

Pathophysiology

The ovarian and menstrual cycles occur in coordination with the immune system to facilitate the formation of a successful pregnancy. During the proliferative phase of the menstrual cycle, as estradiol levels rise, the number of glands and stromal cells increases, and the stratum functionale grows in thickness. In the secretory phase, progesterone works to stabilize the thickened lining by influencing the vascular network and differentiation of glands and stromal cells. Furthermore, the ovarian cycle impacts endometrial leukocytes as seen through their cyclical fluctuation.6,14 It is hypothesized that chronic endometritis (and its immune response) leads to disruption of the normal communication between ovarian corticosteroid hormones and the endometrium.

Expression of sex corticosteroid hormone receptors within the endometrium changes throughout the menstrual cycle. Chronic endometritis has been found to change estrogen and progesterone receptor (ER and PR, respectively) expression. Using immunohistochemistry, Wu et al15 demonstrated that patients with chronic endometritis had significantly stronger staining for ER and PR in glands and stromal cells in the mid-secretory phase as compared with those without chronic endometritis.4,6 It is hypothesized that these variations are more consistent with what is expected in the proliferative phase rather than the secretory phase. This observation potentially supports the alteration in endometrial receptivity, which may be seen in chronic endometritis.

Endometrial contractility patterns have been studied in nonobstetric patients. It is proposed that elimination of menstrual fragments is expedited through contractility from the fundus to the cervix (anterograde) during the menstrual phase. Migration of spermatozoa is facilitated through contractility from the cervix to the fundus (retrograde) during the late proliferative phase. It is speculated that implantation is enhanced by the absence of such contractions during mid-secretory phase.4,16 In chronic endometritis, Pinto et al17 observed altered uterine contraction patterns, including decreased retrograde contractility during the periovulatory window. These authors theorized that this effect was due to a disruption in endometrial paracrine signaling from altered immune function. Not only would this observation help to explain impaired fertility in chronic endometritis, but it also might provide insight into the symptoms of pelvic pain and dysmenorrhea.

Immune cells within the endometrium not only protect against pathogens but also generate immune tolerance toward sperm and embryos. Certain endometrial immune cells undergo cyclic changes, but this needs to be further investigated.14 Natural killer cells are a part of innate immunity, but their role in the endometrium requires further elucidation. A subset of low cytotoxic natural killer cells, which are thought to influence the success of a pregnancy by playing a role in immune tolerance, are found to increase in concentration in the late-secretory phase in women without chronic endometritis.18 However, in those with chronic endometritis, these natural killer cells decrease in concentration, which might change the receptivity of the endometrial lining.4,7 In this manner, chronic endometritis has the capacity to disrupt the immunologic environment necessary for the physiologic changes associated with the menstrual cycle and a successful pregnancy.

B cells are found in less than 1% of all endometrial immune cells within the inner stratum basale layer, and they do not change with the endometrial cycle.2,4,14 However, in chronic endometritis it is hypothesized that alterations in adhesion molecules and chemokines leads to an influx of B cells within the stratum functionale, next to stromal cells and within the glandular lumen.19 Plasma cells are differentiated B cells; thus, it is suspected that the influx of B cells is associated with the presence of plasma cells in chronic endometritis.

The ovarian cycle governs the production of corticosteroid hormones, which influences the endometrium and immune cross-talk. Chronic endometritis leads to a dysynchrony between the ovarian and menstrual cycles, thereby affecting proliferation, cell migration, and apoptosis on the microscopic level. Further investigation is needed to fully understand this interaction.

Etiology

Previously, the uterine cavity was thought to be a sterile environment, and it was speculated that chronic endometritis resulted from an ascending infection from the cervix to the endometrium leading to an inflammatory reaction. More recent studies have shown that not only have microorganism been detected in endometrial samples with no signs of pathology, but now the existence of a uterine microbiome is hypothesized.4,20,21 This observation undermines the more traditional theory of ascending uterine infection. The dominant microorganisms within the uterine microbiome may differ between patients. What seems clear is that it is the adverse interaction between the endometrial immune cells and the organisms, which lead to the clinical sequelae, not merely the presence of the bacteria.4

Interestingly, microorganisms are still assumed to be the main cause of chronic endometritis because antibiotic treatment is believed to be an effective treatment.5,9 No single pathogen predominates as the major cause of chronic endometritis. Common microorganisms found in chronic endometritis include Staphylococcus spp, Streptococcus spp, Escherichia coli, Enterococcus faecalis, Mycoplasma spp, Klebsiella pneumoniae, and Candida spp.22 However, the prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae is relatively low in patients with chronic endometritis.1,2,4,22 Furthermore, endometrial microorganisms do not always correlate with the microorganisms found on vaginal or endocervical cultures.22,23 The origin of these microorganisms found in chronic endometritis is not fully understood, but they may not always represent ascending infections from the urogenital tract; hematogenous spread from inflamed mucosal surfaces in the gastrointestinal tract or gums has also been implicated.1

Chronic granulomatous endometritis is commonly due to endometrial tuberculosis, a well-known sequela of Mycobacterium tuberculosis, and is a common cause of infertility and AUB in countries with a high prevalence of tuberculosis.24,25 It alters the ovarian and endometrial cycle and the immune response, which in return disrupts the endometrial cycle and its receptivity. Similarly, infections with other bacteria and subsequent interactions with the immune system are suspected to lead to the disease process seen in chronic endometritis.

Other causes of chronic endometritis include radiation therapy, structural pathology (polyps, submucosal fibroids, incomplete abortion, or retain products of conception), or foreign bodies (intrauterine device, pessaries).2

Diagnosis

It is difficult to identify chronic endometritis through symptomatology. Most women are asymptomatic, or they may report a variety of nonspecific symptoms such as AUB, pelvic pain, dyspareunia, or leucorrhea. There are no uniformly accepted criteria for diagnosing chronic endometritis, but presence of plasma cells on endometrial biopsy is widely accepted for diagnosis. The follicular phase has been suggested as a better time to perform the endometrial biopsy to best facilitate detection of chronic endometritis.26 Typically, immunostaining for CD138 (syndecan-1) is used to better identify plasma cells compared with a hematoxylin and eosin (H&E) stain. As previously discussed, histologic changes such as increased stromal density, edema, and disconnected maturation of epithelial cells and stroma fibroblasts can also be seen.1,2

With no uniformly accepted criteria to diagnose chronic endometritis, investigators have found that variation in technique can lead to inconsistency in detection of chronic endometritis. This includes the way samples are stained for CD138 (temperature of sample, dilution of stain, incubation time, etc), number of plasma cells identified in samples (>1 vs >5), and method of endometrial biopsy (uterine location, amount of tissue collected, and endometrial cycle stage at time of collection).4 Ultimately, this could also contribute to the discrepancy in the prevalence of chronic endometritis in the general population and those struggling with infertility; standard criteria need to be established to diagnose chronic endometritis.

There are other methods of identifying chronic endometritis. On hysteroscopy, chronic endometritis is detected by visualizing micropolyps (defined as <1 mm vascularized and pedunculated protrusions), stromal edema (pale and thick), and hyperemia (accentuated vascular network).9,22,27,28 Additionally, endometrial cultures at the time of endometrial biopsy can facilitate detection of a specific microorganism for targeted treatment.

Treatment

Due to the aberrant response of the endometrial environment to microorganisms seen in chronic endometritis, antibiotics are generally prescribed. There are no set therapeutic guidelines for antibiotic regimens to cure chronic endometritis. It is widely accepted to treat chronic endometritis with doxycycline as a first-line agent. Typically, patients are prescribed 100 mg of doxycycline every 12 hours for 14 days, as this agent is active against common pelvic bacteria and mycoplasma.9,13,29 Recommended second-line regimens for those women failing to respond to doxycycline alone include ciprofloxacin and metronidazole, ofloxacin and metronidazole, doxycycline and metronidazole, ciprofloxacin and amoxicillin/clavulanate, etc.5 If presumptive antibiotic therapy does not work, providers could consider using drug sensitivities from repeated endometrial biopsy/cultures to select targeted therapy for 14 days.9 Previous studies have demonstrated a cure rate up to 100% after a second course of antibiotics.4,5 If there is no success after targeted therapy, it is reasonable to try broad-spectrum antibiotic therapy as recommended for PID (per Centers for Disease Control and Prevention guidelines).

Clinical studies demonstrate associations between chronic endometritis and infertility, recurrent implantation failure and recurrent miscarriage. Cicinelli et al12 demonstrated chronic endometritis in the majority of women with unexplained infertility (56.8%) via endometrial biopsy and CD138 staining. Song et al26 recognized that there was an overall prevalence of 24.4% via endometrial biopsy and CD138 staining in those with AUB or reproductive failure. Several studies have also demonstrated a higher prevalence of chronic endometritis in those with recurrent implantation failure (14%-57.5%)9,30 or recurrent pregnancy loss (8.9%-56.1%).5,10,30

Conversely, Kasius et al11 identified chronic endometritis in only a small percentage (2.8%) of asymptomatic infertile patients via hysteroscopic guided endometrial biopsy and H&E staining with additional CD138 staining if needed. In addition, this study demonstrated comparable live birth rates between asymptomatic infertile patients with and without chronic endometritis over the course of 3 years.11 The large variability in the incidences of chronic endometritis in these populations with reproductive issues paints an unclear picture and could be somewhat explained that associations between chronic endometritis and fertility disorders are needed.

Treatment of chronic endometritis may improve reproductive outcomes. Cicinelli et al12 observed higher pregnancy and live birth rates in those with unexplained fertility who had been treated successfully for chronic endometritis. Studies of women with recurrent implantation failure after in vitro fertilization (IVF) embryo transfers have shown significant improvements of pregnancy outcomes after successful antibiotic treatment for chronic endometritis. A recent systematic review and meta-analysis by Vitagliano and colleagues described higher implantation rates, pregnancy rates, and ongoing pregnancy/live birth rates in those women with recurrent implantation failure who were successfully treated for chronic endometritis.31

Furthermore, in those with recurrent pregnancy loss, McQueen et al5 demonstrated significant improvement in live birth rate in those treated for chronic endometritis. Overall, studies suggest that antibiotic treatment for chronic endometritis not only eliminates plasma cells, but also results in higher rates of implantation and lower rates of miscarriage.2,4 Unfortunately, there are no prospective randomized clinical trials to address the effects of the treatment of chronic endometritis on reproduction. Yang et al32 compared pregnancy outcomes in women with recurrent implantation failure and histologic chronic endometritis who chose antibiotic treatment versus those who refused antibiotics. They found marginal improvements in ongoing pregnancy rates in the next IVF cycle in the antibiotic-treated women (29.4 % vs 25.0%, nonsignificant difference). It is important to note that in this study, the decision to undertake antibiotic treatment was not randomized but rather patient choice.32 Kitaya et al29 also studied women with recurrent implantation failure (defined as 3 or more failed IVF transfers with good-quality embryos) and compared those treated for chronic endometritis with patients who did not have chronic endometritis on histologic analysis. They also noted nonsignificantly improved live birth rates in the antibiotic-treated chronic endometritis group (38.8% vs 27.9%, nonsignificant difference). Both studies are somewhat underpowered.29 Well-designed, larger studies are needed to understand further the relationship between chronic endometritis and infertility.

Conclusion

Chronic endometritis may affect endometrial receptivity and embryo implantation through modifications in the immune response to the endometrial environment. Although often asymptomatic (or associated with mild, nonspecific symptoms), chronic endometritis has been linked to endometrial dysfunction and a variety of reproductive issues. Clinicians should have a low threshold to perform an endometrial biopsy or hysteroscopy to diagnose this condition. Standard antibiotic regimens are usually successful and may improve clinical outcomes. Large, well-designed studies would be helpful to better understand the clinical impact of chronic endometritis on reproductive outcome.

Practice Pearls

* Patients with chronic endometritis are often asymptomatic or have nonspecific symptoms (AUB, pelvic pain, dyspareunia, and leucorrhea).

* Microorganisms are assumed to be the main source of chronic endometritis, but no single pathogen has been identified to cause chronic endometritis.

* Chronic endometritis leads to dysfunction between the ovarian and menstrual cycle and immune cross-talk.

* Identifying plasma cells on endometrial biopsy via immunostaining for CD138 is widely accepted for diagnosis and can correlate to specific hysteroscopic findings.

* Antibiotics should be prescribed for treatment, and it is widely accepted to use doxycycline 100 mg every 12 hours for 14 days.

* Treatment has the potential to improve implantation, pregnancy, and live birth rates, and lower rates of miscarriage in those struggling with fertility issues.

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