Abstract :
[en] Cancer therapies such as chemotherapy, while increasingly effective, can severely impair ovarian function, leading to premature ovarian failure and infertility. Ovarian tissue cryopreservation and transplantation (OTCTP) is currently the only viable fertility preservation strategy for prepubertal girls and women requiring immediate treatment. Despite its clinical success, OTCTP is limited by excessive follicle loss after grafting, largely driven by ischemia, apoptosis, and primordial follicle (PMF) hyperactivation.
To address this, we first developed a novel, minimally invasive heterotopic transplantation model, between the skin and cartilage of the ear, which allows for localized post-grafting pharmacological treatment. Comparison with the conventional but invasive kidney capsule model showed that PI3K inhibition with LY294002 produced similar effects on follicle activation at both sites, validating the new model’s utility for testing pharmacological interventions.
Building on prior ex vivo findings with the mTOR inhibitor rapamycin, we aimed to improve follicle preservation during the transplantation process. Rapamycin addition during the cryopreservation process maintained follicle quiescence and improved fertility restoration in vivo, resulting in more offspring with higher live birth rates compared to controls. However, rapamycin treatment triggered feedback activation of the Akt pathway.
We therefore investigated BEZ235, a dual PI3K/mTOR inhibitor. Its addition during cryopreservation significantly preserved the PMF pool and suppressed follicle activation more effectively than single-pathway inhibitors, both in vitro and in vivo. Post-grafting VEGF/G-CSF injections, intended to enhance vascularization, did not further enhance PMF preservation when combined with BEZ235.
In conclusion, while rapamycin supports follicle dormancy and fertility restoration, dual inhibition of PI3K/mTOR with BEZ235 more effectively reduces post-grafting follicle loss. As fertility preservation is becoming increasingly important for young cancer patients, such strategies may help extend their reproductive lifespan and quality of life post-treatment.
