Retinoic acid maintains the primordial follicle reserve by inhibiting PI3K/Akt signaling

In female mammals, nonrenewable primordial follicles are orderly activated to maintain reproductive lifespan. However, the initiating regulator(s) of primordial follicle maintenance and activation remain poorly characterized. RA synthesis enzymes were mainly expressed in the pre-granulosa cells, and RA receptors (RARs) were mainly expressed in the oocytes of human and mouse primordial follicles. RAR signaling was downregulated during the transition from primordial follicles to primary follicles. RA inhibited primordial follicle activation in neonatal mouse ovaries and human ovarian cortex tissue. Furthermore, RA promoted the formation of the RAR-p85α complex to stabilize the phosphoinositide 3-kinase (PI3K) heterodimer p85α/p110, resulting in the suppression of PI3K/Akt signaling and the nuclear export of Forkhead box O3 (FOXO3a) in the oocytes of primordial follicles. Rarα and Rarγ double-knockout ( Rarα / γ -dKO) mice exhibited excessive primordial follicle depletion and shortened reproductive lifespan. Meanwhile, PIP3-activated Akt signaling was markedly enriched and the proportion of primordial follicle oocytes was decreased in Rarα / γ -dKO oocyte cluster, accompanied by disrupted developmental trajectories and increased oocyte apoptosis. RA oral administration delayed mouse primordial follicle activation and extended reproductive lifespan. Taken together, RA maintains primordial follicle quiescence in humans and mice by inhibiting RAR-mediated PI3K/Akt signaling, suggesting its potential as an oral drug to preserve follicle reserve and prolong women’s reproductive lifespan.