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Similarly, dysregulation of the PI3KAktFOXO3 axis drives premature awakening of dormant primordial follicles: activating mutations in PIK3CA or loss of PTEN propel unrestrained follicle recruitment, exhausting the reserve [108,109,110]

This finding has direct implications for research protocol design: most published and structured study designs incorporate a rest period following the active phase to allow receptor sensitivity to normalize before any subsequent research cycle, rather than using continuous, uninterrupted administration

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