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

摘要 化疗的一个常见副作用是不孕不育和女性新近被诊断为癌症或 其他恶性肿瘤通常被建议接受控制性卵巢超刺激作为一种治疗手段 保持生育能力。对于青春期前的女孩或需要立即化疗的妇女，卵巢 超刺激是不可行的，这些患者中的许多人选择冷冻保存卵巢组织 随后进行一次缓解的自体移植。卵巢组织频率的增加 冷冻保存(OTC)预示着未来自体移植需求的激增，但 移植物的存活/功能受到移植后缺血的严重损害。此外，医源性的 化疗药物和/或组织自体存在的炎症环境的影响 移植扰乱了卵泡间的动态平衡，这种动态平衡支配着健康的卵巢生理。我们有 开发了一种利用培养的血管细胞来加速移植卵巢的灌流的方法 组织。此外，我们还证明了一种卵巢特异性分泌因子，抗Müllerian的可能性。 激素(AMH)，以调节卵泡的生长和激活。这项提案的目标是将 在自体移植的背景下，这些技术可以提高组织活力和卵泡产量 和/或减轻化疗药物对原位卵巢的负面影响。该提案旨在 为了解决这一迅速增长的未得到满足的需求：1)通过联合... 移植OTC时分离的患者相合的血管内皮细胞；2)操作 卵巢组织移植时移植部位内抑制早熟卵泡的信号 动员；以及3)通过预适应减轻烷化化疗的性腺毒性影响 卵巢组织中有AMH。在追求这些目标的过程中，该提案将改善数千人的结果 已经或将接受非处方药的女性，同时也旨在放弃未来患者的风险， 非处方药和自体移植的费用、痛苦和不确定性。

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.