Melatonin Ameliorates Ovarian Hyperstimulation Syndrome (OHSS) through SESN2 Regulated Antiapoptosis

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is one of the most severe complications after ovarian stimulation during assisted reproductive technology (ART). However, its pathogenesis still remains unclear. Melatonin is an important antioxidant factor in female reproduction and Sestrin-2 (SESN2) is reported to be involved in cellular response to different stress conditions. Whether or not melatonin and SESN2 are involved in OHSS is still a question to us clinicians. METHODS AND RESULTS: We collected the granulosa cells of OHSS patients and focused on the role of SESN2 in OHSS. We also studied the role and mechanism of melatonin plays in OHSS patients. We found that the expression of SESN2 was increased in the granulosa cells of OHSS patients (n = 24) than those in controls (n = 15). Incubation with angiotensin II (1 μM, 2 μM) in HUVECs and H2O2 (0.1 mM, 0.2 mM) in KGNs increased the generation of ROS concurrent with the increased expression of SESN2, while melatonin treatment partly restored SESN2 levels. The mechanism study demonstrated that SESN2 was deeply involved in the regulation of AMPK and mTOR, whereas melatonin partially restored angiotensin II or H2O2 induced the activation of AMPK phosphorylation and the inhibition of mTOR, 4EBP1 and S6K1 phosphorylation, all of which could trigger cell apoptosis. CONCLUSIONS: These findings indicated that melatonin attenuated ROS-induced apoptosis through SESN2-AMPK-mTOR in OHSS. Thus, melatonin is likely to be a potential and important therapeutic agent for treating and preventing OHSS.