Dr. Victor J. Carrasco Urrutia

Dr. Victor J. Carrasco Urrutia, Endometriosis Specialist

City: Juárez, Chihuahua, Mexico

Philosophy of Endometriosis Care: A Molecular Disease Driven by microRNA Dysregulation, Sublethal Ferroptosis, and Iron-Induced Cellular Reprogramming. (Epigentic and Genetic).

1. Introduction: Rethinking the Origins of Endometriosis– Endometriosis has traditionally been explained by the theory of retrograde menstruation and ectopic implantation of endometrial tissue. However, this paradigm fails to account for the heterogeneity of lesion types, their variable behavior, resistance to hormone therapy, and their presence in distant organs, including in individuals without a uterus. Emerging molecular insights support a paradigm shift: endometriosis is not simply a disorder of misplaced cells but rather a disease of epigenetic reprogramming, sustained by microRNA (miRNA) dysregulation, oxidative damage, and sublethal ferroptosis, all of which collectively transform the phenotype of endometrial cells into persistent, invasive, and inflammatory clones.
2. The Molecular Drivers of Endometriosis – At the core of this transformation is a sustained dysregulation of microRNAs, small non-coding RNAs that regulate gene expression post-transcriptionally. These molecules act as master regulators of apoptosis, inflammation, angiogenesis, immune evasion, and cellular differentiation. In endometriosis, an aberrant expression profile of miRNAs alters the fate of eutopic endometrial cells, making them resistant to apoptosis, responsive to local estrogen production, and capable of invading ectopic environments. This altered transcriptomic and epigenetic landscape allows cells to survive retrograde migration and promotes colonization in ectopic locations. However, survival alone does not explain lesion persistence or progression. A critical second hit occurs through exposure to iron-rich microenvironments, particularly in hemorrhagic lesions and repeated retrograde bleeding, which leads to ferroptosis sublethal stress: a state of iron-driven oxidative damage that damages but does not destroy cells, selecting for those with adaptive survival advantages. This interplay between miRNA-driven transformation and environmental oxidative stress is central to the pathogenesis of all lesion types, yet manifests differently depending on the anatomic and physiological context.
3. Subtype-Specific Pathogenesis – A. Superficial Peritoneal Endometriosis Superficial lesions are typically small (1–5 mm), found on peritoneal surfaces, and historically considered the “earliest” or “mildest” form of the disease. However, from a molecular standpoint, they represent localized populations of reprogrammed endometrial-like cells that have adhered to the mesothelial surface but not yet established a fibrotic niche or deep invasion. • miRNA profile: These lesions show altered miRNA expression consistent with early evasion of apoptosis and enhanced angiogenesis. • Immune environment: Poor immunosurveillance allows their persistence. • Iron exposure: Low to moderate, driven by cyclic retrograde bleeding. Sublethal ferroptosis here may act as a selective pressure for early clonal expansion. These lesions may remain quiescent or evolve depending on iron burden, oxidative stress, and hormonal responsiveness. B. Ovarian Endometriosis (Endometriomas) Ovarian endometriosis is characterized by the formation of chocolate cysts, or endometriomas, which are hemorrhagic cystic structures resulting from repeated bleeding of ectopic endometrial tissue within the ovary. • Iron microenvironment: Endometriomas are iron-saturated niches due to blood accumulation and hemolysis. This creates a sustained ferroptotic microenvironment with massive lipid peroxidation and reactive oxygen species. • Cellular fate: Sublethal ferroptosis in ovarian lesions promotes selection of molecularly damaged but viable cells with enhanced estrogen biosynthesis, progesterone resistance, and immunoevasive behavior. • Epigenetic profile: Extensive methylation changes and miRNA deregulation in endometriomas render these lesions bioactive, hormone-autonomous, and often refractory to standard hormonal suppression. Thus, endometriomas are not passive collections of blood but dynamic bioactive lesions that perpetuate molecular damage and foster disease progression. C. Deep Infiltrating Endometriosis (DIE) Deep lesions extend more than 5 mm below the peritoneal surface and often involve the bowel, bladder, ureters, and pelvic nerves. These are associated with severe pain and significant morbidity. • Molecular profile: These lesions exhibit the highest degree of cellular reprogramming, with profound miRNA dysregulation, immune suppression, neuroangiogenesis, and resistance to apoptosis. • Stromal remodeling: Chronic trauma, bleeding, and local inflammation stimulate fibrosis, nerve infiltration, and neuroinflammation, explaining the severe pain profile. • Oxidative stress: Iron deposition and recurrent hemorrhage promote sustained oxidative stress, contributing to irreversible structural and functional alterations. • Heterogeneity: Each DIE lesion can be genetically and epigenetically distinct, with varying hormonal sensitivity and miRNA signatures. Deep endometriosis may arise from superficial or ovarian lesions subjected to prolonged inflammatory and oxidative stress, leading to a fibrotic, invasive, and neurotrophic phenotype.
4. Endometriosis Beyond the Pelvis- Extrauterine Manifestations Endometriosis has been documented in distant sites including the lungs, diaphragm, kidneys, liver, brain, and even in men. These rare presentations challenge the traditional implantation theory and are better explained through molecular migration hypotheses: • Stem/progenitor cell migration: Endometrial progenitor cells with reprogrammed miRNA profiles may disseminate via lymphovascular routes. • Systemic epigenetic predisposition: The same molecular drivers active in pelvic lesions may operate in ectopic stem niches, particularly under chronic inflammation or hormonal influence. • Iron-independent transformation: In distant sites, local factors (e.g., tissue injury, hormonal crosstalk) may mimic the oxidative and immune environments found in pelvic lesions, allowing ectopic lesions to form without retrograde menstruation. The finding of clonal, progesterone-resistant, estrogen-producing lesions in distant organs supports the notion of systemic disease with localized molecular expressions, not simple mechanical spread.
5. Clinical and Research Implications – This molecular redefinition of endometriosis holds several implications: • Diagnosis: Circulating miRNA panels and iron-sensitive imaging may aid in earlier, non-invasive detection. • Treatment: Approaches should target not only estrogen suppression but also iron metabolism, oxidative stress, and epigenetic reprogramming (e.g., miRNA modulation, ferroptosis regulation). • Phenotype-tailored therapy: Understanding the dominant molecular drivers of each lesion type (e.g., ferroptosis in endometriomas, neuroinflammation in DIE) can guide personalized treatment. Endometriosis is a molecularly dynamic disease that begins with epigenetic and post-transcriptional reprogramming of endometrial cells via microRNA dysregulation. Survival and proliferation of these altered cells are supported by iron-induced sublethal ferroptosis, which perpetuates oxidative stress and drives progressive transformation. Each subtype of endometriosis—superficial, ovarian, and deep—inherits this molecular foundation but diverges based on location-specific environmental conditions. Endometriosis should thus be considered a systemic, clonal, and inflammatory disease, rooted in molecular errors and sustained by a hostile microenvironment that the lesions themselves help to create. This framework provides a unified, mechanistically grounded explanation for the diversity, chronicity, and therapeutic resistance observed in clinical practice. VJCU

 What type of surgery do you perform for endometriosis: Excision

Medication: OCPs, Progestins (dianogest)(including LNG-IUD) – Used for suppression of hormonally responsive lesions, especially after excision. Less effective in progesterone-resistant or estrogen-autonomous lesions like endometriomas. Antioxidants (e.g., N-acetylcysteine,)– Reduce ROS and lipid peroxidation; support ferroptosis modulation and lesion stabilization. Gabapentin, Pregabalin (Lyrica) – Used for central pain desensitization in deep endometriosis and neuroinflammation. Especially useful pre- and post-surgery in patients with chronic pelvic pain or neuropathic pain. Anti-inflammatory & immunomodulators – Target low-grade chronic inflammation and immune dysregulation associated with lesion survival.