Precision Therapeutic and Preventive Molecular Strategies for Endometriosis-Associated Infertility

Abstract

Endometriosis, a chronic estrogen-dependent disorder defined by ectopic endometrial-like tissue growth, causes pelvic pain and infertility in reproductive-age women. Despite its prevalence, the underlying mechanisms driving lesion persistence and reproductive impairment remain unclear. This review synthesizes recent pathophysiological advances, highlighting how hormonal dysregulation, immune dysfunction, epigenetic alterations, and oxidative stress collectively foster lesion persistence and treatment resistance. Critically, these molecular disturbances disrupt critical reproductive functions-including oocyte quality, endometrial receptivity, and embryo implantation. We further explore emerging non-hormonal therapeutic strategies, including MAPK and PI3K/AKT inhibitors as well as epigenetic agents targeting HOXA10 methylation and microRNA modulation, which offer fertility-sparing alternatives to conventional hormonal suppression. To enhance clinical translation, we propose a multi-level prevention framework-encompassing at the primary level, risk reduction; at the secondary level, biomarker-guided intervention; and at the tertiary level, fertility preservation-to anticipate disease progression and personalize reproductive care. By delineating shared pathways between endometriosis and infertility, this work advances precision medicine approaches for affected patients.

Keywords: biomarkers; endometriosis-associated infertility; epigenetics; prevention; therapeutics.

Figure 1

Aberrant vascular remodeling in endometriosis: integration of canonical and non-canonical angiogenic signals. Hypoxia and oxidative stress stabilize HIF-1α, inducing VEGF-A and disorganized neovascularization. Additional non-canonical pathways—including Slit2/ROBO1, PROK1/PROKR1, and Notch/Dll4 suppression—disrupt vessel architecture and branching. The resulting leaky and unstable vasculature facilitates stromal invasion, immune cell infiltration, and neural ingrowth, contributing to a self-perpetuating inflammatory microenvironment.

Figure 2

Interconnected mechanisms driving infertility in endometriosis.

Figure 3

Molecular landscape of non-hormonal therapies in endometriosis.

Figure 4

Endometriosis and fertility: molecular complexity and emerging precision approaches. Graphical representation of the multifactorial nature of endometriosis, highlighting key molecular alterations (hormonal imbalance, oxidative stress, inflammation, epigenetic reprogramming), their impact on fertility, and emerging strategies for personalized, fertility-preserving care. Abbreviations: ERβ: estrogen receptor beta; cfDNA: cell-free DNA; PRS: polygenic risk score; ROS: reactive oxygen species.