Department of Obstetrics and Gynecology and Department of Advanced Reproductive Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216-8511, Japan.
Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17474-9. doi: 10.1073/pnas.1312830110. Epub 2013 Sep 30.
Primary ovarian insufficiency (POI) and polycystic ovarian syndrome are ovarian diseases causing infertility. Although there is no effective treatment for POI, therapies for polycystic ovarian syndrome include ovarian wedge resection or laser drilling to induce follicle growth. Underlying mechanisms for these disruptive procedures are unclear. Here, we explored the role of the conserved Hippo signaling pathway that serves to maintain optimal size across organs and species. We found that fragmentation of murine ovaries promoted actin polymerization and disrupted ovarian Hippo signaling, leading to increased expression of downstream growth factors, promotion of follicle growth, and the generation of mature oocytes. In addition to elucidating mechanisms underlying follicle growth elicited by ovarian damage, we further demonstrated additive follicle growth when ovarian fragmentation was combined with Akt stimulator treatments. We then extended results to treatment of infertility in POI patients via disruption of Hippo signaling by fragmenting ovaries followed by Akt stimulator treatment and autografting. We successfully promoted follicle growth, retrieved mature oocytes, and performed in vitro fertilization. Following embryo transfer, a healthy baby was delivered. The ovarian fragmentation-in vitro activation approach is not only valuable for treating infertility of POI patients but could also be useful for middle-aged infertile women, cancer patients undergoing sterilizing treatments, and other conditions of diminished ovarian reserve.
原发性卵巢功能不全 (POI) 和多囊卵巢综合征是导致不孕的卵巢疾病。虽然 POI 尚无有效治疗方法，但多囊卵巢综合征的治疗方法包括卵巢楔形切除术或激光打孔以诱导卵泡生长。这些破坏性手术的潜在机制尚不清楚。在这里，我们探讨了保守的 Hippo 信号通路的作用，该通路有助于维持器官和物种之间的最佳大小。我们发现，小鼠卵巢的碎裂促进了肌动蛋白聚合并破坏了卵巢 Hippo 信号，导致下游生长因子的表达增加，促进了卵泡生长，并产生了成熟的卵母细胞。除了阐明卵巢损伤引起的卵泡生长的机制外，我们还进一步证明，当卵巢碎裂与 Akt 刺激剂治疗联合使用时，卵泡生长会增加。然后，我们通过破坏 Hippo 信号，随后进行 Akt 刺激剂治疗和自体移植，将结果扩展到 POI 患者的不孕治疗中。我们成功地促进了卵泡生长，取回了成熟的卵母细胞，并进行了体外受精。胚胎移植后，成功分娩了一个健康的婴儿。卵巢碎裂-体外激活方法不仅对治疗 POI 患者的不孕有价值，而且对中年不孕妇女、接受绝育治疗的癌症患者以及其他卵巢储备减少的情况也可能有用。
