Mammalian ovaries consist of follicles as basic functional units. The total number of ovarian follicles is determined early in life, and the depletion of this pool leads to reproductive aging. During initial recruitment of follicles, unknown intraovarian mechanisms stimulate or release a small number of primordial follicles to initiate growth, whereas the rest of the follicles remain quiescent for months or years. Once entering the growing pool, ovarian follicles continue to grow until the early antral stage with minimal loss. For those follicles not recruited, the default pathway is to remain dormant. Although the exact mechanisms underlying the initial recruitment of dormant follicles is unknown, recent studies using mutant mice indicated that oocyte-specific deletion of the PTEN (Tumor-suppressor phosphatase with TENsin homology) gene promoted the growth of all primordial follicles in neonatal animals, leading to the exhaustion of the entire follicle pool and subsequent premature ovarian failure. The PTEN gene encodes a phosphatase enzyme that negatively regulates the phosphatidylinositol 3-kinase (PI3K) and PKB/Akt signalling pathway important for cell cycle regulation. Deletion of PTEN in the oocyte stimulates PI3K activity and allows the activation of all dormant primordial follicles. Taking advantage of the availability of PTEN inhibitors, we obtained preliminary data showing the activation of primordial follicles in neonatal mice. Neonatal ovaries exposed transiently to PTEN inhibitors in vitro showed marked increases in follicle growth after transplantation into the kidney capsule of FSH-treated adult recipients. We propose to refine the present model of in vitro PTEN inhibitor treatment, followed by in vivo ovarian transplantation, to demonstrate the efficacy and safety of this follicle activation model for the derivation of preovulatory oocytes and healthy offspring. Although fertility is compromised in patients with premature ovarian failure and peri-menopausal women, their ovaries still contain small number of primordial follicles. The present transient and ovary-specific exposure to PTEN inhibitors in vitro, followed by in vivo transplantation, could provide a new approach to retrieve functional preovulatory oocytes for infertility treatment.
The present application deals with the use of an enzyme inhibitor to initiate the growth of dormant ovarian primordial follicles for subsequent maturation into preovulatory follicles. Once optimized, the present treatment protocol could benefit patients with premature ovarian failure and infertile women during peri-menopausal transition.
|Li, Jing; Kawamura, Kazuhiro; Cheng, Yuan et al. (2010) Activation of dormant ovarian follicles to generate mature eggs. Proc Natl Acad Sci U S A 107:10280-4|