Leucine Promotes Mouse Primordial Follicle Activation Via the PI3K/Akt Signaling Pathway

Premature ovarian insufficiency (POI) patients usually have a few residual dormant primordial follicles that are difficult to activate. We investigated the effects of branched-chain amino acids (BCAAs) on mouse primordial follicle activation. Leucine, but not isoleucine and valine, promoted primordial follicle activation in the cultured neonatal mouse ovaries. Furthermore, leucine significantly elevated the levels of phosphorylated protein kinase B (p-Akt) and phosphorylated forkhead Box O3a (p-FOXO3a), and increased the number of oocytes exhibiting nuclear export of FOXO3a in mouse ovaries. LY294002 and PI3K-IN-1, the inhibitors of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, reversed the promoting effects of leucine on mouse primordial follicle activation. Importantly, intraperitoneal injection of leucine in 3-day-old neonatal mice and oral administration of leucine in 21-day-old mice with or without cyclophosphamide treatment significantly increased the number of growing follicles. Thus, leucine activates mouse primordial follicles through the PI3K/Akt pathway. Leucine may be a potential oral supplement for treating infertility in POI patients with residual dormant primordial follicles.