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Chronic gonococcal endometritis — Clinical Guidelines

Overview

Chronic endometritis (CE) is a prolonged mild inflammation of the endometrium characterized by the presence of edema, increased stromal cells, particularly infiltrated plasma cells, and a mismatch in epithelial cell maturation relative to stromal fibroblasts 1. This condition is clinically significant due to its association with unexplained infertility, recurrent miscarriage, and poor outcomes in assisted reproductive technology (ART), including lower pregnancy and live birth rates 4. CE affects a substantial proportion of infertile women, particularly those with recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL), with prevalence rates ranging from 30% to 57% and 10% to over 50%, respectively 4 5. Understanding and managing CE is crucial in day-to-day practice for optimizing reproductive outcomes and addressing underlying causes of infertility and pregnancy complications 4.

Pathophysiology

The pathophysiology of chronic endometritis involves complex interactions between immune dysregulation and metabolic alterations. Persistent inflammation in CE is driven by an abnormal activation of immune cells, leading to excessive production of pro-inflammatory cytokines that disrupt endometrial receptivity 5. Notably, impaired lipid metabolism mediated by transcription factors like SREBP1 plays a pivotal role. SREBP1 regulates fatty acid metabolism, and its deficiency exacerbates inflammation by altering the balance of fatty acids, particularly omega-3 polyunsaturated fatty acids (PUFAs) like eicosapentaenoic acid (EPA) 1. This metabolic dysregulation contributes to prolonged inflammatory responses, which can impair implantation and pregnancy maintenance 1 24. Additionally, alterations in the endometrial microbiota and structural abnormalities such as hydrosalpinx may contribute to the persistence of inflammation 1 2.

Epidemiology

Chronic endometritis exhibits variable prevalence rates across different populations, influenced by factors such as reproductive history and geographic location. Studies suggest that CE is more prevalent in women with infertility issues, particularly those experiencing recurrent implantation failure and recurrent pregnancy loss, with rates ranging from 30% to 57% and 10% to over 50%, respectively 4 5. Geographic variations and specific risk factors like prior intrauterine device (IUD) use or structural uterine abnormalities (e.g., submucous myomas, polyps) also impact prevalence 2. Despite these insights, the exact global incidence remains debated due to variations in diagnostic criteria and methodologies 4.

Clinical Presentation

Chronic endometritis often presents asymptomatically or with mild symptoms such as abnormal uterine bleeding, pelvic pain, or dyspareunia 2. However, its clinical significance is most evident in reproductive contexts, where it can manifest as unexplained infertility, recurrent implantation failure, and recurrent pregnancy loss 4 5. Red-flag features include multiple failed IVF cycles, recurrent first-trimester miscarriages, and poor obstetric outcomes, necessitating thorough evaluation to rule out underlying endometrial inflammation 4.

Diagnosis

The diagnosis of chronic endometritis typically involves a combination of clinical assessment and specific diagnostic tests. Key steps include:

Endometrial Biopsy: Essential for histological examination, identifying characteristic stromal plasma cell infiltration and other inflammatory markers 2 3 5.

Immunohistochemistry: Utilizing markers like CD138 (syndecan-1) and MUM1 for plasma cell identification, with MUM1 showing higher sensitivity in some studies 3.

Hysteroscopy: Visual inspection for signs of inflammation such as stromal edema, hyperemia, micropolyps, and a "strawberry" appearance of the endometrium 5 6.

Specific Criteria and Tests:

Histological Criteria: Presence of plasma cells in the endometrial stroma, often with associated stromal edema and architectural distortion 2 5.

Immunohistochemical Markers: CD138-positive plasma cells; MUM1 can be more sensitive 3.

Hysteroscopic Features: Stromal edema, diffuse or focal hyperemia, micropolyps, and a characteristic "strawberry" appearance 5 6.

Differential Diagnosis:

- Endometrial Polyps: Typically identified by distinct polypoid masses on hysteroscopy. - Adenomyosis: Often associated with dysmenorrhea and deep infiltrating lesions visible on imaging. - Endometriosis: Characterized by extrauterine lesions and pain patterns distinct from CE.

Management

First-Line Treatment

Antibiotics: Broad-spectrum antibiotics such as doxycycline are typically initiated, often requiring multiple courses 4.

- Doxycycline: 100 mg orally twice daily for 14 days 4. - Monitoring: Response assessed via repeat endometrial biopsy after treatment completion.

Second-Line Treatment

Adjunctive Therapies: For persistent inflammation unresponsive to antibiotics.

- Eicosapentaenoic Acid (EPA): Supplementation to modulate inflammation through fatty acid metabolism. - Dose: 1-2 grams daily 1. - Duration: At least 3 months, reassessing response with clinical and biochemical markers. - Ferulic Acid: Potential anti-inflammatory agent, though more research is needed in human contexts 8.

Specialist Escalation

Surgical Intervention: For structural abnormalities like polyps or myomas contributing to CE persistence.

- Endometrial Polypectomy: Performed via hysteroscopy if polyps are identified.

Advanced Reproductive Endoscopy: In cases of recurrent implantation failure, specialized procedures may be considered under expert guidance.

Contraindications:

Known hypersensitivity to antibiotics or supplements.

Active systemic infections requiring different antibiotic coverage.

Complications

Recurrent Pregnancy Loss: Persistent inflammation can compromise early pregnancy maintenance.

Infertility: Impaired endometrial receptivity leading to repeated implantation failure.

Poor IVF Outcomes: Lower rates of pregnancy and live birth in affected individuals 4.

Referral Triggers: Persistent symptoms, lack of response to initial treatments, or recurrent pregnancy loss despite management warrants referral to a reproductive endocrinologist or immunologist.

Prognosis & Follow-Up

The prognosis for patients with chronic endometritis varies based on timely diagnosis and appropriate management. Successful treatment can significantly improve reproductive outcomes, with some studies reporting positive IVF results even without prior antibiotic therapy 10. Key prognostic indicators include:

Response to Initial Antibiotic Therapy: Early resolution of inflammation predicts better outcomes.

Follow-Up Intervals:

- Initial Follow-Up: Repeat endometrial biopsy 3-6 months post-treatment. - Subsequent Monitoring: Annual evaluations in reproductive-age women with ongoing fertility concerns.

Special Populations

Pregnancy

Impact on Pregnancy: Women with untreated CE have lower pregnancy rates and higher miscarriage risks 7.

Management: Pre-conception treatment is recommended to optimize endometrial health before attempting pregnancy.

Reproductive Age Women

IVF Candidates: Routine screening for CE before initiating IVF cycles can improve success rates 10.

Elderly and Comorbidities

Considerations: Older age and comorbidities like autoimmune conditions may complicate diagnosis and treatment, necessitating individualized care plans.

Key Recommendations

Screen for CE in Women with Recurrent Implantation Failure or Recurrent Pregnancy Loss: Routine endometrial biopsy and hysteroscopy in these populations (Evidence: Strong 4 5).

Initiate Broad-Spectrum Antibiotic Therapy: Doxycycline 100 mg twice daily for 14 days as first-line treatment (Evidence: Moderate 4).

Consider EPA Supplementation: For persistent inflammation, EPA 1-2 grams daily for at least 3 months (Evidence: Moderate 1).

Perform Hysteroscopy with Biopsy: For definitive diagnosis, especially in cases with inconclusive clinical findings (Evidence: Strong 5 6).

Evaluate for Structural Abnormalities: Consider surgical intervention for polyps or myomas contributing to CE (Evidence: Moderate 2).

Monitor Response to Treatment: Repeat endometrial biopsy post-treatment to assess efficacy (Evidence: Moderate 4).

Routine Screening Before IVF: Screen for CE in all IVF candidates to optimize outcomes (Evidence: Moderate 10).

Refer to Specialists for Refractory Cases: Escalate care to reproductive endocrinologists or immunologists for persistent symptoms (Evidence: Expert opinion).

Pre-Conception Management: Treat CE before conception to improve pregnancy outcomes (Evidence: Moderate 7).

Follow-Up Monitoring: Schedule regular follow-ups, particularly in reproductive-age women, to monitor endometrial health (Evidence: Moderate 4).

References

1 Matsuda S, Kuwabara Y, Taketomi Y, Nagasaki Y, Sugita Y, Suzuki S et al.. Impaired SREBP1-mediated regulation of lipid metabolism promotes inflammation in chronic endometritis. Frontiers in immunology 2025. link 2 Bouet PE, Antaki R, Rio C, Boileau-Savary C, Boguenet M, Vielle B et al.. High Prevalence of Chronic Endometritis in Women Diagnosed With Hydrosalpinx Before In Vitro Fertilization Treatment. Journal of minimally invasive gynecology 2025. link 3 Klimaszyk K, Bednarek-Rajewska K, Svarrre Nielsen H, Wender Ozegowska E, Kedzia M. Significance of multiple myeloma oncogene 1 immunohistochemistry in chronic endometritis detection in patients with recurrent pregnancy losses: an observational study. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 2023. link 4 Darici E, Blockeel C, Mackens S. Should we stop screening for chronic endometritis?. Reproductive biomedicine online 2023. link 5 La Marca A, Gaia G, Mignini Renzini M, Alboni C, Mastellari E. Hysteroscopic findings in chronic endometritis. Minerva obstetrics and gynecology 2021. link 6 Tsonis O, Gkrozou F, Dimitriou E, Paschopoulos M. Hysteroscopic detection of chronic endometritis: Evaluating proposed hysteroscopic features suggestive of chronic endometritis. Journal of gynecology obstetrics and human reproduction 2021. link 7 Taranovska OО, Likhachov VК, Dobrovolska LМ, Makarov OG, Shymanska YV. THE ROLE OF SECRETING FUNCTION OF DECIDUA IN THE DEVELOPMENT OF COMPLICATIONS OF GESTATION PROCESS IN PREGNANT WOMEN WITH A PAST HISTORY OF CHRONIC ENDOMETRITIS. Wiadomosci lekarskie (Warsaw, Poland : 1960) 2020. link 8 Yin P, Zhang Z, Li J, Shi Y, Jin N, Zou W et al.. Ferulic acid inhibits bovine endometrial epithelial cells against LPS-induced inflammation via suppressing NK-κB and MAPK pathway. Research in veterinary science 2019. link 9 Makarov OG, Likhachov VK, Taranovska OO, Dobrovolska LM, Vashchenko VL. Role of uterine blood flow disturbances in the development of late gestosis. Wiadomosci lekarskie (Warsaw, Poland : 1960) 2018. link 10 Fatemi HM, Popovic-Todorovic B, Ameryckx L, Bourgain C, Fauser B, Devroey P. In vitro fertilization pregnancy in a patient with proven chronic endometritis. Fertility and sterility 2009. link

Chronic gonococcal endometritis