Endometriosis-associated infertility: From pathophysiology to tailored treatment Original paper

What was reviewed?

This paper is a detailed review of the current knowledge on endometriosis-associated infertility, synthesizing recent advances in understanding the pathophysiology, diagnosis, and management of this complex and multifactorial condition. The review highlights that endometriosis is not only a localized pelvic disease but also a systemic condition with pleiotropic effects on reproductive health. The review scrutinizes the interactions between inflammation, hormonal dysregulation, altered pelvic anatomy, diminished ovarian reserve, impaired endometrial receptivity, and systemic immune changes, all of which collectively contribute to infertility in women with endometriosis. The authors further discuss animal models, molecular mechanisms, including genetic and epigenetic influences, and the role of stem cells and microRNAs in disease pathogenesis and clinical presentation.

Who was reviewed?

The review focuses on women of reproductive age affected by endometriosis, with particular attention to those experiencing infertility. It draws from a heterogeneous population including both clinical and experimental (animal) models, and examines evidence from diverse phenotypes, ranging from women with minimal, mild, or advanced disease to those with specific subtypes such as ovarian, peritoneal, or deep infiltrating endometriosis. The paper also reviews findings from meta-analyses, randomized controlled trials, cohort studies, and basic science research, ensuring a broad and representative scope of current evidence.

What were the most important findings?

Endometriosis-associated infertility is multifactorial, with the most important mechanisms involving a persistent pro-inflammatory microenvironment, hormonal imbalances, particularly estrogen dominance and progesterone resistance, and anatomical disruption from adhesions and fibrosis. The review underscores that only half of women with endometriosis-associated infertility have typical macroscopic lesions, which contributes to underdiagnosis and delays in treatment. A core finding is that chronic inflammation, stemming from elevated cytokines and immune cell dysfunction, distorts the follicular and endometrial microenvironments, ultimately impairing ovulation, fertilization, embryo development, and implantation. Diminished ovarian reserve, especially in women with ovarian endometriomas, is linked to oxidative stress, stromal fibrosis, and accelerated follicular depletion, which can be exacerbated by surgical interventions.

At the molecular level, the review identifies major microbial associations (MMA) and signatures such as dysregulation of specific genes (e.g., HOXA10, PR isoform B), aberrant DNA methylation, and microRNAs that alter gene expression and promote disease progression. The immune signature of the eutopic endometrium in affected women is notably pro-inflammatory, with increased type I macrophages and impaired regulatory T cell function. Stem cell trafficking and inappropriate differentiation play significant roles in lesion formation at both pelvic and extra-pelvic sites. On the diagnostic front, the review highlights promising advances in non-invasive biomarkers, particularly panels of serum-derived miRNAs with high sensitivity and specificity for disease detection. Treatment recommendations are increasingly individualized, combining surgical, medical, and assisted reproductive strategies tailored to disease severity, ovarian reserve, age, and patient preferences. Novel molecular diagnostic tools, such as transcriptomic-based endometrial receptivity assays and BCL6 testing, are emerging as potential game-changers for clinical decision-making.

What are the greatest implications of this review?

This review has major implications for clinical practice. It clarifies that endometriosis-associated infertility cannot be addressed with a single, uniform approach; rather, it demands individualized, multidisciplinary care informed by an understanding of both systemic and local pathophysiology. The integration of molecular and microbiome signatures into diagnostic and therapeutic protocols holds promise for earlier detection and more precise interventions. The review also calls attention to the significant impact of diagnostic delays, emphasizing the need for validated, non-invasive tests such as miRNA panels for timely diagnosis and intervention. The authors advocate for collaborative, specialized care in referral centers, incorporating both reproductive surgery and assisted reproductive technologies (ART). The review also recognizes the ongoing need for research to further elucidate molecular mechanisms, optimize biomarker panels, and refine therapeutic algorithms, particularly as new insights into the microbiome, genetics, and immune modulation emerge.