AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy

作者：Motohiro Kano, Amanda Sosulski, LiHua Zhang, Hatice D. Saatcioglu, Dan Wang, Nicholas Nagykery, Mary E. Sabatini, Guangping Gao, Patricia K. Donahoe, David Pépin · 发表于：Proceedings of the National Academy of Sciences · 年份：2017 · DOI：10.1073/pnas.1620729114 · 被引用次数：206 · 研究领域：Ovarian function and disorders、Reproductive Biology and Fertility、Ovarian cancer diagnosis and treatment

The ovarian reserve represents the stock of quiescent primordial follicles in the ovary which is gradually depleted during a woman's reproductive lifespan, resulting in menopause. Müllerian inhibiting substance (MIS) (or anti-Müllerian hormone/AMH), which is produced by granulosa cells of growing follicles, has been proposed as a negative regulator of primordial follicle activation. Here we show that long-term parenteral administration of superphysiological doses of MIS, using either an adeno-associated virus serotype 9 (AAV9) gene therapy vector or recombinant protein, resulted in a complete arrest of folliculogenesis in mice. The ovaries of MIS-treated mice were smaller than those in controls and did not contain growing follicles but retained a normal ovarian reserve. When mice treated with AAV9/MIS were paired with male breeders, they exhibited complete and permanent contraception for their entire reproductive lifespan, disrupted vaginal cycling, and hypergonadotropic hypogonadism. However, when ovaries from AAV9-MIS-treated mice were transplanted orthotopically into normal recipient mice, or when treatment with the protein was discontinued, folliculogenesis resumed, suggesting reversibility. One of the important causes of primary ovarian insufficiency is chemotherapy-induced primordial follicle depletion, which has been proposed to be mediated in part by increased activation. To test the hypothesis that MIS could prevent chemotherapy-induced overactivation, mice were give...