INSERM Unité 1185, Faculté de Médecine Paris-Sud, Université Paris Saclay, Le Kremlin Bicêtre, France; and.
Department of Reproductive Medicine and Fertility Preservation, Hôpital Antoine Béclère, Clamart, France.
FASEB J. 2019 Jan;33(1):1278-1287. doi: 10.1096/fj.201801089R. Epub 2018 Aug 16.
The follicular ovarian reserve, constituted by primordial follicles (PMFs), is established early in life, then keeps declining regularly along reproductive life. The maintenance of a normal female reproductive function implies the presence of a vast amount of dormant PMFs. This process involves a continuous repression of PMF activation into early growing follicle through the balance between factors activating the initiation of follicular growth, mainly actors of the PI3K signaling pathway, and inhibiting factors such as anti-Müllerian hormone (AMH). Any disruption of this balance may induce follicle depletion and subsequent infertility. It has been recently proposed that cyclophosphamide (Cy), an alkylating agent commonly used for treating breast cancer, triggers PMF activation, further leading to premature ovarian insufficiency. Preventing chemotherapy-induced ovarian dysfunction might represent an interesting option for preserving optimal chances of natural or medically assisted conceptions after healing. The aim of the present study was to evaluate, in a model of Cy-treated pubertal mice, whether AMH administration might restrain PMF depletion. The counting of the total PMF number within mouse ovaries showed that recombinant AMH prevented Cy-induced PMF loss. Western blot analysis revealed activation of PI3K signaling pathway after Cy administration. After AMH injection, FOXO3A phosphorylation, a main actor of PMF activation, was significantly decreased. Taken together, these results support a protective role of AMH against Cy-induced follicular loss. We also provide evidence for a possible role of autophagy in the preservation of follicular pool reserve. Therefore, concomitant recombinant AMH administration during chemotherapy might offer a new option for preserving young patients' fertility.-Sonigo, C., Beau, I., Grynberg, M., Binart, N. AMH prevents primordial ovarian follicle loss and fertility alteration in cyclophosphamide-treated mice.
卵泡卵巢储备，由原始卵泡（PMFs）构成，在生命早期建立，然后沿着生殖寿命定期持续下降。正常女性生殖功能的维持意味着存在大量休眠的 PMFs。这个过程涉及通过激活起始卵泡生长的因素（主要是 PI3K 信号通路的因子）和抑制因子（如抗苗勒管激素（AMH））之间的平衡，持续抑制 PMF 向早期生长卵泡的激活。这种平衡的任何破坏都可能导致卵泡耗竭和随后的不孕。最近有人提出，环磷酰胺（Cy），一种常用于治疗乳腺癌的烷化剂，可触发 PMF 激活，进一步导致卵巢早衰。预防化疗引起的卵巢功能障碍可能是在治愈后保留自然或医学辅助受孕最佳机会的一个有趣选择。本研究的目的是在 Cy 治疗的青春期小鼠模型中评估 AMH 给药是否可以抑制 PMF 耗竭。对小鼠卵巢中总 PMF 数量的计数表明，重组 AMH 可防止 Cy 诱导的 PMF 损失。Western blot 分析显示 Cy 给药后 PI3K 信号通路被激活。AMH 注射后，PMF 激活的主要因子 FOXO3A 磷酸化显著降低。总之，这些结果支持 AMH 对 Cy 诱导的卵泡丢失具有保护作用。我们还提供了自噬在卵泡池储备保护中的可能作用的证据。因此，在化疗期间同时给予重组 AMH 可能为保护年轻患者的生育能力提供新的选择。-Sonigo，C.，Beau，I.，Grynberg，M.，Binart，N. AMH 可防止环磷酰胺处理的小鼠原始卵泡丢失和生育力改变。
