Endocrine and Molecular Mechanisms of Oocyte Aging: From Gonadotropin Signaling to Metabolic and Microenvironmental Dysfunction.

Ovarian aging and oocyte aging are closely interconnected but distinct components of reproductive aging. Whereas ovarian aging encompasses progressive follicular depletion and changes in ovarian endocrine and somatic-cell function, oocyte aging refers more specifically to the age-associated deterioration in the molecular, cellular, and developmental competence of the oocyte. This deterioration contributes to increased aneuploidy, impaired embryonic development, implantation failure, and early pregnancy loss. This narrative review synthesizes current evidence on the endocrine, cellular, and molecular mechanisms underlying oocyte aging and their potential interactions, and examines emerging strategies for preserving oocyte competence. Age-related dysregulation of the hypothalamic-pituitary-ovarian axis, altered gonadotropin signaling, and changes in intraovarian endocrine and paracrine communication may disrupt follicular development and the follicular microenvironment. These changes may compromise functional interactions between the oocyte and surrounding somatic cells. These alterations may converge with mitochondrial dysfunction, oxidative stress, mtDNA abnormalities, impaired energy metabolism, alterations in telomere biology, and epigenetic dysregulation, ultimately compromising oocyte meiotic competence and developmental potential. Experimental strategies, including antioxidant supplementation, restoration of NAD+ metabolism, mitochondrial transfer, and exosome-based interventions, have shown potential to ameliorate features of oocyte aging, primarily in animal and preclinical models. However, none of these interventions has been shown to delay physiological oocyte aging in women, and evidence supporting their clinical effectiveness and long-term safety remains insufficient. Understanding how endocrine dysregulation interacts with metabolic, genomic, and epigenetic alterations and changes in the follicular microenvironment may facilitate the identification of biomarkers and the development of targeted approaches to preserve oocyte quality during reproductive aging.