Lithium treatment promotes the activation of primordial follicles through PI3K/Akt signaling

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.

Dietary lithium stimulates female fecundity in Drosophila melanogaster

“…Nonetheless, we are positive that our investigations are directional towards a better understanding of the putative role of lithium in female fecundity and its potential molecular targets. According to the most recent literature, it is evident that lithium affects the activities and fate of mammalian stem cells and that this trace element is also capable of stimulating the maturation of murine and human primordial oocytes 26,98 . Remarkably, these in vitro and in vivo observations were made applying similar lithium concentrations that were found to significantly increase Drosophila egg production in the present study, that are, 0.1–3 mM (see Figure S1).…”

“…According to the most recent literature, it is evident that lithium affects the activities and fate of mammalian stem cells and that this trace element is also capable of stimulating the maturation of murine and human primordial oocytes. 26,98 Remarkably, these in vitro and in vivo observations were made applying similar lithium concentrations that were found to significantly increase Drosophila egg production in the present study, that are, 0.1-3 mM (see Figure S1). 4,26,[95][96][97] Hence, it is possible that the observation made in this study may also account for higher organisms.…”

“…26,98 Remarkably, these in vitro and in vivo observations were made applying similar lithium concentrations that were found to significantly increase Drosophila egg production in the present study, that are, 0.1-3 mM (see Figure S1). 4,26,[95][96][97] Hence, it is possible that the observation made in this study may also account for higher organisms. We therefore intend to determine the cause of the lithium-induced stimulation of egg production and its potential relevance to other species in the future.…”

“…[22][23][24][25] Most recently, it was demonstrated that lithium activates murine and human primordial follicles. 26 Based on this outcome, the authors proposed lithium to be a promising agent in the treatment of premature ovarian insufficiency.…”

“…In summary, lithium was shown to affect levels of luteinizing hormone, estradiol‐associated activities, the formation of the corpus luteum, luteal steroidogenesis, the production of prostaglandin E2 as well as the number of mature oocytes in mammalian in vivo ad in vitro models 22–25 . Most recently, it was demonstrated that lithium activates murine and human primordial follicles 26 . Based on this outcome, the authors proposed lithium to be a promising agent in the treatment of premature ovarian insufficiency.…”