Gatekeepers of ovarian fate: the molecular landscape of diminished ovarian reserve

Diminished ovarian reserve (DOR) is a major reproductive disorder characterised by accelerated follicular depletion and impaired ovarian responsiveness, yet its molecular basis remains incompletely understood. This review integrates current evidence across the major biological processes that determine ovarian reserve and follicular competence. Primordial follicle activation governed by PI3K–AKT–FOXO3/PTEN–mTOR, Hippo–YAP, KIT/KITL and AMH signaling represents an upstream determinant of follicle-pool consumption, while bidirectional oocyte–granulosa cell communication and the stromal microenvironment sustain follicular development. Genomic instability, defective DNA repair, chromatin remodeling and epigenetic dysregulation further compromise cellular integrity and reproductive longevity. Mitochondrial bioenergetic failure, mtDNA instability, altered mitochondrial dynamics and oxidative stress form a central mechanistic hub linking metabolic dysfunction to follicular damage. Emerging evidence additionally highlights the autophagy–mitophagy–lysosome system, including stress-granule clearance and lysosomal proteostasis, as a context-dependent quality-control network rather than an intrinsically lethal pathway. Downstream cell-fate responses, particularly granulosa-cell apoptosis, cellular senescence and ferroptosis, together with immune–inflammatory and endocrine disturbances, further promote follicular attrition. Importantly, the strength of evidence varies substantially across mechanisms, with direct human DOR data available for only a subset of pathways and many proposed mechanisms remaining dependent on animal or cellular models. Clinically, AMH and antral follicle count remain the principal reserve markers, whereas molecular biomarkers and targeted interventions are largely investigational. By organizing these mechanisms into an integrated framework, this review identifies key evidence gaps and priorities for mechanistically informed biomarker development and therapeutic translation in DOR.