Anti-Mullerian hormone for preserving ovarian function before administration of gonadotoxic therapies or after transplantation of cryopreserved tissue.

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Abstract A frequent side effect of chemotherapy is infertility and female patients newly diagnosed with cancer or other malignancies are routinely counseled to undergo controlled ovarian hyper-stimulation as a means of fertility preservation. For pre-pubertal girls or women requiring immediate chemotherapy, ovarian hyperstimulation is unavailable and many of these patients opt to cryopreserve ovarian tissue with subsequent auto-transplantation once in remission. The increasing frequency of ovarian tissue cryopreservation (OTC) portends a surge in future demand for auto-transplantation, yet the viability/function of grafts is significantly undermined by post-transplant ischemia. Moreover, the iatrogenic influence of chemotherapeutic agents and/or the inflammatory milieu present following tissue auto- transplantation upsets the inter-follicular homeostasis that governs healthy ovarian physiology. We have developed an approach that utilizes cultured vascular cells to accelerate perfusion of transplanted ovarian tissue. In addition, we have demonstrated the potential for an ovary-specific secreted factor, anti-Müllerian hormone (AMH), to modulate follicular growth and activation. The goals of this proposal are to combine these technologies to enhanced tissue viability and follicular output in the context of auto-transplantation and/or mitigate the negative influence of chemotherapeutic agents on the ovary in situ. The proposal aims to address this burgeoning unmet need by: 1) improving viability and output of ovarian tissue grafts by co- transplanting patient-matched vascular endothelial cells isolated at the time of OTC; 2) manipulating signaling within the graft site at the time of ovarian tissue transplantation to repress premature follicular mobilization; and 3) mitigating the gonadotoxic influence of alkylating chemotherapy via pre-conditioning of ovarian tissue with AMH. In pursuing these goals, the proposal stands to improve outcomes for thousands of women who have undergone or will undergo OTC, while also aiming to forego in future patients the risk, expense, pain, and uncertainty of OTC and auto-transplantation.