Background: Chronic endometritis (CE) is one of the most frequent and potentially reversible causes of implantation failure and unexplained infertility. Current diagnostic and therapeutic strategies are largely focused on bacterial pathogens. However, many patients with persistent reproductive failure demonstrate no evidence of bacterial dysbiosis, suggesting the presence of alternative inflammatory triggers. The role of viral persistence in the endometrium remains poorly investigated and may represent a missing etiological link in so-called “idiopathic” infertility.

Objective: To comprehensively evaluate the uterine microbiome, viral colonization, and local immune remodeling in infertile women and to determine whether viral infection contributes to chronic endometrial inflammation and implantation failure.

Methods: In this prospective study, infertile patients underwent Pipelle endometrial biopsy (n = 142).

Endometrial microbiota was assessed using molecular profiling (Femoflor-16 panel). Viral DNA/RNA from the Herpesviridae family (including cytomegalovirus, CMV) and human papillomavirus (HPV) was detected by multiplex PCR. Local immune markers, including α-defensin and TGF-β1, were quantified by ELISA. In women with idiopathic repeated implantation failure, viral testing was additionally performed in follicular fluid.

Results: Microbiome analysis demonstrated that overt bacterial dysbiosis was uncommon: only 13% of patients exhibited non-lactobacillus flora, whereas 39% showed Lactobacillus dominance and 36% mixed lactobacillus microbiota. Thus, bacterial imbalance alone could not explain persistent endometrial inflammation or infertility.

In contrast, viral agents were frequently detected. Viral DNA was identified in 16% of the overall cohort and increased to 31.3% among women undergoing extended molecular evaluation. HPV accounted for 66% of infections and Herpesviridae for 34%.

Viral presence was independently associated with:

• dominance of Lactobacillus iners or depletion of protective Lactobacillus spp.,
• elevated α-defensin levels,
• decreased TGF-β1 concentrations, indicating impaired tissue homeostasis and chronic inflammatory remodeling.

Importantly, viruses were detected not only in the endometrium but also in follicular fluid in patients with idiopathic repeated failures, suggesting that viral persistence may affect both implantation and oocyte competence.

Novelty: To our knowledge, this is the first integrated clinical study demonstrating that chronic endometritis can be driven by viral persistence even in the absence of bacterial dysbiosis, providing evidence for a distinct viral-associated inflammatory phenotype of CE.

Clinical implications: These findings challenge the traditional bacteria-only concept of chronic endometritis and support routine viral screening of the endometrium. Diagnostic algorithms and targeted treatment strategies addressing both bacterial and viral endometrial infection will be presented, proposing a new personalized management approach for patients with unexplained infertility and ART failure.

Conclusions: Chronic endometritis should not be considered exclusively bacterial. Viral persistence represents a significant, previously underestimated, and potentially treatable cause of endometrial dysfunction, impaired receptivity, and reproductive failure. Recognition of a viral-associated CE phenotype may substantially improve diagnostic accuracy and clinical outcomes.

Keywords: chronic endometritis; viral infection; HPV; Herpesviridae; uterine microbiome; implantation failure; infertility; reproductive immunology.

Natalia I. Tapilskaya, MD, Dr. Sci. (Med.), is a leading expert in obstetrics, gynecology, and reproductology in Russia. She holds a doctor of medical sciences degree and the academic title of professor. Since 2023, she has served as the Head of the department of reproductology at the prestigious D.O. Ott Research Institute of Obstetrics, Gynecology, and Reproductology in St. Petersburg. Concurrently, she continues her role as a leading research scientist at the institute's department of assisted reproductive technologies, a position she has held since 2018. She combines intensive research with academic work. Since 2018, she has been a professor at the department of obstetrics and gynecology at the St. Petersburg State Pediatric Medical University, mentoring future generations of specialists. She possesses extensive, hands-on experience in clinical research as a principal investigator and coordinator for numerous national and international trials in gynecology, focusing on infertility, endometriosis, uterine fibroids, inflammatory diseases, and menopausal disorders. Her expertise is further solidified by regular certifications in Good Clinical Practice (GCP). She is a prolific author of over 260 scientific publications and a contributor to the development of national clinical guidelines, shaping modern standards of care in her field. Her work is dedicated to advancing reproductive medicine and improving patient outcomes.