Activation of primordial follicles.

Abstract

Primordial follicle activation represents the pivotal and rate-limiting transition that governs the size and longevity of the ovarian reserve, thereby shaping female reproductive lifespan. Although the vast majority of primordial follicles remain quiescent, a small fraction is periodically activated through tightly regulated signaling events. Emerging evidence reveals that dormancy is not a passive state, but an actively maintained program orchestrated by intrinsic oocyte pathways, surrounding pre-granulosa cells, and the ovarian microenvironment. Key intracellular regulator PI3K-Akt-FOXO3 signaling establishes the oocyte's threshold for activation, and pre-granulosa cell cues, including KITL-KIT interactions, mechanical constraints, and extracellular matrix dynamics, modulate this core signaling. Additionally, paracrine signals from stromal cells, local hypoxia, and biomechanical forces contribute to the spatial patterning of activation within the ovary. Integration of these inputs ensures both the lifelong preservation of a dormant pool and the continuous supply of follicles entering the growth phase. Recent advances in single-cell technologies, imaging, and lineage tracing systems have begun to redefine the temporal and spatial complexity of primordial follicle activation. Dysregulation of this system underlies a spectrum of reproductive disorders, from premature ovarian insufficiency to diminished ovarian reserve and aberrant follicle recruitment. Understanding the molecular logic of activation not only illuminates the biology of ovarian aging but also informs emerging therapeutic strategies, including targeted modulation of signaling pathways, ovarian tissue engineering, and fertility preservation interventions. This chapter describes current knowledge of the mechanisms governing primordial follicle activation and highlights key gaps that will shape future research in ovarian biology.