Calcitriol is involved in maintaining primordial follicle reserve through the inhibition of the PI3K/Akt signaling pathway

BACKGROUND: In mammals, precise regulation of primordial follicle activation is essential for maintaining the female reproductive lifespan. In this study, we demonstrated that the vitamin D receptor (VDR) is expressed in both pre-granulosa cells and oocytes within primordial follicles of mice and humans. METHODS: The VDR ligand, calcitriol, was tested through ovarian culture and intraperitoneal injection experiments in neonatal mice. In addition, oral administration of the calcitriol precursor VD3 was performed in mice. Calcitriol was also tested on cultured human ovarian fragments. RESULTS: Calcitriol inhibited the activation of primordial follicles in neonatal mice. Moreover, calcitriol promoted the formation of the VDR-RXR-p85α complex, thereby stabilizing the PI3K heterodimer (p85α/p110) and inhibiting activation of the PI3K/Akt signaling pathway. This resulted in reduced phosphorylation of FOXO3a in the ovaries and decreased nuclear export in oocytes of primordial follicles, thereby suppressing the activation of primordial follicles. Oral administration of VD3 significantly decreased the number of growing follicles and prolonged the reproductive age in mice compared with controls. Importantly, calcitriol also inhibited human primordial follicle activation and reduced p-Akt levels in cultured ovarian fragments. CONCLUSION: Thus, calcitriol inhibits the activation of both mouse and human primordial follicles by suppressing the VDR-mediated PI3K/Akt signaling pathway. As an oral medication, the calcitriol precursor VD3 may be used to maintain the primordial follicle reserve and extend the reproductive age in women.