Abstract
Studies have shown that melatonin (MLT) can delay ovarian aging, but the mechanism has not been fully elucidated. Here we show that granulosa cells isolated from mice follicles can synthesize MLT; the addition of MLT in ovary culture system inhibited follicle activation and growth; In vivo experiments indicated that injections of MLT to mice during the follicle activation phase can reduce the number of activated follicles by inhibiting the PI3K-AKT-FOXO3 pathway; during the early follicle growth phase, MLT administration suppressed follicle growth and atresia, and multiple pathways involved in folliculogenesis, including PI3K-AKT, were suppressed; MLT deficiency in mice increased follicle activation and atresia, and eventually accelerated age-related fertility decline; finally, we demonstrated that prolonged high-dose MLT intake had no obvious adverse effect. This study presents more insight into the roles of MLT in reproductive regulation that endogenous MLT delays ovarian aging by inhibiting follicle activation, growth and atresia.
Highlights
Studies have shown that melatonin (MLT) can delay ovarian aging, but the mechanism has not been fully elucidated
All the small antral follicle (SAF) constitute a dynamic ovarian follicle reserve (DOR), the size of which determines how many follicles are selected for cyclic recruitment by gonadotrophin (GTH), or eliminated via atresia
The larger the size of DOR, the more SAFs will be eliminated to ensure the stability of fecundity and, more primordial follicles will be activated from preestablished ovarian follicle reserve (PreOR) to replenish the loss of DOR
Summary
Studies have shown that melatonin (MLT) can delay ovarian aging, but the mechanism has not been fully elucidated. The larger the size of DOR, the more SAFs will be eliminated to ensure the stability of fecundity and, more primordial follicles will be activated from PreOR to replenish the loss of DOR. Such vicious cycle will eventually result in a meaningless exhaustion of ovarian follicle reserve[13,17,18]. Studies have demonstrated that shortening the sunshine time can delay reproductive aging, which is considered to be related to MLT31,32; long-term administration of MLT in the drinking water of mice can reduce the production of ROS in the ovary, thereby increasing the number of follicles in middle-aged mice[27,29].
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