Implications of Nonphysiological Ovarian Primordial Follicle Activation for Fertility Preservation

Abstract

In recent years, ovarian tissue cryopreservation has rapidly developed as a successful method for preserving the fertility of girls and young women with cancer or benign conditions requiring gonadotoxic therapy, and is now becoming widely recognized as an effective alternative to oocyte and embryo freezing when not feasible. Primordial follicles are the most abundant population of follicles in the ovary, and their relatively quiescent metabolism makes them more resistant to cryoinjury. This dormant pool represents a key target for fertility preservation strategies as a resource for generating high quality oocytes. However, development of mature, competent oocytes derived from primordial follicles is challenging, particularly in larger mammals. One of the main barriers is the substantial knowledge gap regarding the regulation of the balance between dormancy and activation of primordial follicles to initiate their growing phase. In addition, experimental and clinical factors also impact dormant follicle demise, while the mechanisms involved remain largely to be elucidated. Moreover, most of our basic knowledge of these processes comes from rodent studies and should be extrapolated to humans with caution, considering the differences between species in the reproductive field. Overcoming these obstacles is essential to improving both the quantity and the quality of mature oocytes available for further fertilization, and may have valuable biological and clinical applications, especially in fertility preservation procedures. This review provides an update on current knowledge of mammalian primordial follicle activation under both physiological and non-physiological conditions, and discusses implications for fertility preservation and priorities for future research.

HGF Secreted by Mesenchymal Stromal Cells Promotes Primordial Follicle Activation by Increasing the Activity of the PI3K-AKT Signaling Pathway

“…The proper balance between primordial follicle quiescence and activation is essential for the maintenance of fertility. While overactivation of primordial follicles leads to premature depletion of the ovarian reserve, inactivation of primordial follicles adversely affects the establishment of the growing follicle pool [37]. Therefore, artificial methods of primordial follicle activation would be valuable for fertility interventions.…”

Ovarian toxicity of carboplatin and paclitaxel in mouse carriers of mutation in BRIP1 tumor suppressor gene

“…The administration of cisplatin and doxorubicin have been also shown to activate the PTEN/Akt/FOXO3 pathway in mice resulting in exhaustion of the ovarian reserve 33 , 37 . The PI3K/AKT/mTOR pathway is an intrafollicular signalling pathway that has been described as a regulator of physiological and chemotherapy-induced primordial follicular activation 38 . Several growth factors activate the PI3K signalling in the follicles, including KL.…”

Pharmacological inhibition of the PI3K/PTEN/Akt and mTOR signalling pathways limits follicle activation induced by ovarian cryopreservation and in vitro culture

“…However, when p-Akt staining in the whole ovarian section was considered, a decreased staining density was observed in cryopreserved ovaries cultured with inhibitors compared to the control condition. This difference could be explained by the fact that stromal and follicle cells are communicating to trigger follicle activation [ 66 ]. The reduced staining density of p-Akt in the whole ovarian section is therefore probably related to stromal cells.…”