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24 July 2022 Lithium treatment promotes the activation of primordial follicles through PI3K/Akt signaling
Biao Li, Weiyong Wang, Yingying Huang, Lincheng Han, Jia Li, Nana Zheng, Zhanying Wu, Xiaodan Zhang, Xuelan Li, Ling Deng, Min Lin, Xin Chen, Meijia Zhang
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Abstract

In mammals, dormant primordial follicles represent the ovarian reserve throughout reproductive life. In vitro activation of dormant primordial follicles has been used to treat patients with premature ovarian insufficiency (POI). However, there remains a lack of effective strategies to stimulate follicle activation in vivo. In this study, we used an in vitro ovarian culture system and intraperitoneal injection to study the effect of lithium treatment on primordial follicle activation. Lithium increased the number of growing follicles in cultured mouse ovaries and promoted pre-granulosa cell proliferation. Furthermore, lithium significantly increased the levels of phosphorylated protein kinase B (Akt) and the number of oocytes with forkhead Box O3a (FOXO3a) nuclear export. Inhibition of the phosphatidylinositol 3 kinase (PI3K)/Akt pathway by LY294002 reversed lithium-promoted mouse primordial follicle activation. These results suggest that lithium promotes mouse primordial follicle activation by the PI3K/Akt signaling. Lithium also promoted primordial follicle activation and increased the levels of p-Akt in mouse ovaries in vivo and in human ovarian tissue cultured in vitro. Taken together, lithium promotes primordial follicle activation in mice and humans by the PI3K/Akt signaling. Lithium might be a potential oral drug for treating infertility in POI patients with residual dormant primordial follicles.

Summary Sentence

Lithium contributes to the activation of primordial follicles via PI3K/Akt signaling in mouse and human ovarian tissue cultured in vitro, or intraperitoneal injection for mice.

Graphical Abstract

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© The Author(s) 2022. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Biao Li, Weiyong Wang, Yingying Huang, Lincheng Han, Jia Li, Nana Zheng, Zhanying Wu, Xiaodan Zhang, Xuelan Li, Ling Deng, Min Lin, Xin Chen, and Meijia Zhang "Lithium treatment promotes the activation of primordial follicles through PI3K/Akt signaling," Biology of Reproduction 107(4), 1059-1071, (24 July 2022). https://doi.org/10.1093/biolre/ioac150
Received: 26 December 2021; Accepted: 17 July 2022; Published: 24 July 2022
KEYWORDS
Lithium
PI3K/AKT signaling
POI
primordial follicle activation
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