In Vitro Activation of Follicles for Treatment of Ovarian Insufficiency

Abstract

Introduction: Due to delayed childbearing being the current norm, ovarian dysfunction is rapidly emerging in women. Premature ovarian insufficiency (POI) shows severe ovarian dysfunction exhibiting infertility and symptoms caused by estrogen deficiency. In contrast to the recent development of assisted reproductive technology, POI and diminished ovarian reserve (DOR) are still difficult to have their genetically linked offspring, and oocyte donation is the only established approach for successful pregnancies. This article aims to introduce the procedures of in vitro activation (IVA) and drug-free IVA as potential new infertility treatments for ovarian dysfunction patients. Methods: Based on the findings demonstrating the activation of dormant primordial follicles by the stimulation of Akt signaling pathway in both mice and human ovaries, our group developed a new infertility treatment, in vitro activation (IVA). The IVA includes laparoscopic ovary removal and subsequent ovarian cortical tissue culture with Akt stimulator drugs followed by autotransplantation of activated tissues. During the development of IVA, we also found that ovarian fragmentation disrupted Hippo signaling pathway to increase the expression of downstream growth factors, leading to secondary follicle growth, and then recently developed the drug-free IVA omitting the tissue culture step, which enables DOR patients to conceive using their own eggs by stimulation of residual early follicles by Hippo signal disruption only. Results: With the combination of ovarian fragmentation and Akt stimulation, the IVA approach has resulted in successful follicle growth and live births in POI patients. Also, the drug-free IVA succeeded in achieving a higher number of antral follicle numbers as well as a higher number of retrieved oocytes as compared with previous in vitro fertilization treatment outcomes before the IVA approach, leading to successful pregnancies and deliveries. Conclusions: The implementation of VA and drug-free IVA could increase the potential to conceive genetically related children for patients with ovarian dysfunction. KeywordsAkt stimulationDiminished ovarian reserveDrug-free IVAHippo signalIn vitro activation (IVA)Ovarian fragmentationPremature ovarian insufficiency