Ovarian primordial follicles do not regenerate and proliferate in vivo, and their number decreases with aging as well as with certain pathogeneses. When the number of residual follicles decreases to a threshold level, the initial step of follicle development, namely, the activation of dormant follicles, is disturbed and subsequent follicle growth is suppressed resulting in anovulation and amenorrhea with high gonadotropin levels. If the amenorrhea occurs before 40 years of age, these patients are diagnosed as primary ovarian insufficiency (POI). POI patients show infertility and symptoms caused by estrogen deficiency. So far, donor egg is an only option for effective infertility treatment in patients with POI; we sought to develop a new approach for infertility treatment using their own eggs. Although POI patients still have dormant residual follicles, they are resistant to endogenous signals for activation. Thus, we attempted to activate the residual follicles in vitro. Because the exact mechanisms of the activation of dormant primordial follicles still remain to be determined, we focused on intracellular signaling in the activation process and succeeded in activating those follicles through the activation of PI3K-Akt-Foxo3 pathway (IVA; in vitro activation). Based on the success of IVA, we performed clinical studies to generate mature oocytes from patients with primary ovarian insufficiency, who had few residual follicles in their ovaries, and we have reported successful pregnancies and a birth following IVA. In this chapter, I show our IVA approach and discuss future possibilities for the infertility treatment in patients with diminished ovarian reserve.
In vitro activation Primary ovarian insufficiency Infertility treatment Akt signal Hippo signal
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This work was supported by Grant-In-Aid for Scientific Research (Challenging Exploratory Research: 15K15613, and Innovative Areas, Mechanisms regulating gamete formation in animals: 26114510) and by research funds from the Grant for Fertility Innovation, the Smoking Research Foundation, and the Takeda Science Foundation. None of the authors has a conflict of interest.
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