褪黑素调控垂体LβT2细胞分泌模式及其对卵巢功能影响的机制探索

昼夜节律紊乱是现代社会的普遍现象，研究表明昼夜节律紊乱与女性月经异常和生育力下降密切相关，但具体机制尚不清楚。褪黑素是一种神经内分泌胺类激素，主要参与人体昼夜节律的调控，已经证实昼夜节律紊乱可导致褪黑素分泌异常。本项目成功构建了体外细胞灌流系统，发现在高频率脉冲的促性腺激素释放激素（GnRH）刺激下，褪黑素显著抑制小鼠垂体LβT2细胞表达黄体生成素β亚基（LHβ），直接参与垂体激素的调控。为此，我们推测褪黑素可能通过调节垂体促性腺激素的分泌模式，进而影响卵巢功能，导致女性生育功能的下降。本项目拟在前期研究基础上，利用体外细胞灌流系统，深入研究褪黑素对垂体LβT2细胞分泌促性腺激素模式的影响和作用机制，并通过建立小鼠昼夜节律紊乱模型，探索褪黑素对小鼠促性腺激素分泌及卵巢功能的影响，为阐明昼夜节律紊乱引起女性生殖内分泌异常及生育力下降的发生机制，以及褪黑素改善生育的临床应用提供理论依据。

Circadian rhythm disorder is a common phenomenon in modern society. Studies have shown that disturbed circadian rhythm is closely related to aberrant menstruation and decreased fertility in women, but the specific mechanism remains unclear. Melatonin is a neuroendocrine amine hormone, which is mainly involved in the regulation of human circadian rhythm. It has been confirmed that the disturbance of circadian rhythm can lead to aberrant secretion of melatonin. In our pilot study, we have successfully constructed an in vitro cell perfusion system that simulates the stimulation of pulsed gonadotropin-releasing hormone (GnRH) at different frequencies in vivo. It was found that melatonin could significantly inhibit the expression of luteinizing hormone β subunit (LHβ) under the high frequency GnRH stimulation in the mouse pituitary LβT2 cells, which was directly involved in the regulation of pituitary hormone. Therefore, we speculate that melatonin may affect ovarian function by regulating the secretion pattern of pituitary gonadotropin, thus leading to the decline of female reproductive function. Based on our previous work, we intend to use the in vitro cell perfusion system to deeply study the effects and regulatory mechanisms of melatonin on the gonadotropin secretion pattern of pituitary LβT2 cells and ovarian function, and further explore the effects of melatonin on gonadotropin secretion and ovarian function in mice by establishing the mice model of circadian rhythm disturbance. This study is expected to provide a theoretical basis for elucidating the mechanisms of the decline in female fertility caused by circadian rhythm disturbances and female reproductive endocrine abnormalities, as well as the clinical application of melatonin to improve female fertility.