What question did this study set out to answer?

This study aims to explore the molecular differences in ovarian responses during in vitro fertilization, focusing on oxidative stress and signaling pathways.

April 21, 2026

Molecular Extremes of Ovarian Response: Divergent PI3K / AKT / mTOR Signaling and Oxidative Stress Patterns in Low and High Responders Undergoing In Vitro Fertilization

Key Points

This study aims to explore the molecular differences in ovarian responses during in vitro fertilization, focusing on oxidative stress and signaling pathways.
Stratified women into poor, normal, and high responders for in vitro fertilization
Analyzed oxidative stress markers and signaling pathways in granulosa cells
Used immunohistochemistry and immunofluorescence for pathway assessment
Both poor and high responders showed increased oxidative stress compared to normal responders
Granulosa cells in poor responders exhibited reduced antioxidant levels and increased apoptosis markers
PI3K/AKT/mTOR signaling was reduced in poor responders but enhanced in high responders compared to normal responders

Abstract

ABSTRACT 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.

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Cite This Study

Korkmaz et al. (Sun,) studied this question.

synapsesocial.com/papers/69e7138bcb99343efc98d14b https://doi.org/https://doi.org/10.1002/biof.70102

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