Molecular Extremes of Ovarian Response: Divergent PI3K/AKT/mTOR Signaling and Oxidative Stress Patterns in Low and...

Ovarian response extremes are associated with distinct alterations in the follicular microenvironment, yet the underlying molecular mechanisms remain incompletely understood. This study investigated oxidative stress, antioxidant responses, apoptosis, and PI3K/AKT/mTOR signaling in granulosa cells from women undergoing intracytoplasmic sperm injection, stratified into poor (POR), normal (NOR), and high ovarian response (HOR) groups (n = 30). Follicular fluid oxidative stress markers, antioxidant systems, and regulatory factors were analyzed, while intracellular reactive oxygen species, DNA fragmentation, and chromatin integrity were evaluated in granulosa cells. In addition, PI3K/AKT/mTOR pathway activity was assessed using immunohistochemistry and immunofluorescence. Compared with NOR, both POR and HOR groups exhibited increased oxidative stress, reflected by elevated MDA levels (p < 0.05), accompanied by divergent antioxidant responses, including reduced GSH levels in POR and a progressive increase in SOD activity from NOR to HOR (p < 0.05). Although melatonin and TGF-β levels did not differ significantly, melatonin showed a trend toward lower levels in POR and higher levels in HOR. Granulosa cell ROS production and apoptosis-related markers were significantly increased in both response extremes, particularly in POR (p < 0.05). Consistently, PI3K/AKT/mTOR signaling displayed differential regulation, with reduced activation in POR and enhanced activation in HOR compared to NOR (p < 0.05). Overall, NOR appears to reflect a balanced redox and molecular state, whereas both poor and high responses are characterized by oxidative stress, cellular damage, and dysregulated PI3K/AKT/mTOR signaling. These findings suggest that deviation from physiological equilibrium, rather than response magnitude alone, is a key determinant of granulosa cell dysfunction and impaired follicular competence.