Title:
In Vitro activation : Development of novel infertility treatment for ovarian dysfunction

 

Speaker:

Kazuhiro Kawamura

Professor

Department of Obstetrics and Gynecology, International University of Health and Welfare School of Medicine

 

Abstract:
Primary ovarian insufficiency (POI) affects about 1% of women in the reproductive age and show severe infertility due to decreasing ovarian reserve and amenorrhea. Although the oocyte donation is promised approach for infertility treatment in POI, there are several concerns to use OD for their infertility treatment. POI patients are infertile due to a lack of follicle growth and ovulation, because residual ovarian follicles in these patients are not responsive to traditional gonadotropin treatments. To induce follicle growth in these remaining dormant follicles, we have developed a method for activation of dormant follicles by using in vitro culture of ovarian fragments treated with PI3K stimulators following disruption of Hippo signaling pathway (IVA, in vitro activation).
Our and previous studies showed the importance of PI3K-Akt-Foxo3 signaling in activation of dormant primordial follicles. We demonstrated the activation of dormant follicles using a PTEN inhibitor and PI3K activator based on a short term (48 hours) in vitro activation protocol in mice and human ovaries, leading to increased primordial follicle number. Furthermore, we generated mature oocytes displaying normal epigenetic regulation in imprinted genes. Following the success of these basic and translational studies, we applied the IVA for clinical study to treat infertility in POI patients. In the clinical study, we removed ovaries and fragmented ovarian cortex into small cubes for tissue culture. After the culture, the ovarian cubes were transplanted beneath the serosa of Fallopian tubes following IVF-ET. This approach included histological analyses to detect residual follicles, which allowed predicting the outcome of follicle growth after IVA. We have reported two deliveries of healthy babies after IVA treatment and the number of babies is increasing. Furthermore, at least seven other pregnancies by three other centers in Spain, China, and Poland have also been achieved.
In this presentation, I will introduce our IVA procedure and update clinical outcome of IVA so far. Furthermore, I will introduce the Drug-free IVA conducting Hippo signal disruption only as a new infertility treatment for patients with ovarian dysfunction.

 

References:
1. Kawamura K, et al. Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. Proc Natl Acad Sci USA. 2013 Oct 22;110(43):17474-9.
2. Hsueh AJ and Kawamura K, et al. Intraovarian control of early folliculogenesis. Endocr Rev. 2015 Feb;36(1):1-24.
3. Kawashima I, Kawamura K. Regulation of follicle growth through hormonal factors and mechanical cues mediated by Hippo signaling pathway. Syst Biol Reprod Med. 2018 Feb;64(1):3-11.