Fertility Preservation Research Laboratory, IVF Unit, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel.
Sci Transl Med. 2013 May 15;5(185):185ra62. doi: 10.1126/scitranslmed.3005402.
Premature ovarian failure and infertility are major side effects of chemotherapy treatments in young cancer patients. A more thorough understanding of the mechanism behind chemotherapy-induced follicle loss is necessary to develop new methods to preserve fertility in these patients. We show that the alkylating agent cyclophosphamide (Cy) activates the growth of the quiescent primordial follicle population in mice, resulting in loss of ovarian reserve. Despite the initial massive apoptosis observed in growing, though not in resting, follicles of Cy-treated mice, differential follicle counts demonstrated both a decrease in primordial follicles and an increase in early growing follicles. Immunohistochemistry showed that granulosa cells were undergoing proliferation. Analysis of the phosphatidylinositol 3-kinase signaling pathway demonstrated that Cy increased phosphorylation of proteins that stimulate follicle activation in the oocytes and granulosa cells. Coadministration of an immunomodulator, AS101, reduced follicle activation, thereby increasing follicle reserve and rescuing fertility after Cy, and also increased the efficacy of Cy against breast cancer cell lines. These findings suggest that the mechanism in Cy-induced loss of ovarian reserve is accelerated primordial follicle activation, which results in a "burnout" effect and follicle depletion. By preventing this activation, AS101 shows potential as an ovarian-protective agent, which may be able to preserve fertility in female cancer patients.
卵巢早衰和不孕是年轻癌症患者化疗治疗的主要副作用。为了开发新的方法来保护这些患者的生育能力，有必要更深入地了解化疗引起卵泡损失的机制。我们表明，烷化剂环磷酰胺（Cy）激活了小鼠静止原始卵泡群体的生长，导致卵巢储备减少。尽管在 Cy 处理的小鼠生长卵泡中观察到最初大量的细胞凋亡，但但在休眠卵泡中没有观察到这种凋亡，差异卵泡计数显示原始卵泡减少，早期生长卵泡增加。免疫组化显示颗粒细胞正在增殖。对磷脂酰肌醇 3-激酶信号通路的分析表明，Cy 增加了刺激卵母细胞和颗粒细胞中卵泡激活的蛋白的磷酸化。免疫调节剂 AS101 的共同给药减少了卵泡激活，从而增加了卵泡储备，并在 Cy 后恢复了生育能力，并且还增加了 Cy 对乳腺癌细胞系的疗效。这些发现表明，Cy 诱导的卵巢储备丧失的机制是加速原始卵泡激活，导致“耗竭”效应和卵泡耗竭。通过防止这种激活，AS101 显示出作为卵巢保护剂的潜力，它可能能够保护女性癌症患者的生育能力。
