Melatonin potential and important therapeutic agent for treating and preventing OHSS
Infertility is defined as the inability to be pregnant within one year of unprotected intercourse. It has become not only a medical concern but9 also a social issue with increasing prevalence in both developed and developing countries. In vitro fertilization (IVF) is wildly accepted over the past 35 years as an effective treatment for infertility during which controlled ovarian stimulation (COH) is almost always employed to retrieve more oocytes. Although COH might improve IVF outcome, it also increases the risk of an iatrogenic complication: ovarian hyperstimulation syndrome (OHSS). Further OHSS is not uncommon.
The true incidence of OHSS is probably much underestimated since the symptoms of mild OHSS are easy to be ignored. The symptoms of OHSS in its mild form can be untypical such as nausea and vomiting; however, moderate and severe OHSS may result in oliguria, hydrothorax, ascites, hepatorenal failure, acute respiratory distress syndrome, hemorrhage from ovarian rupture, thromboembolism, and ultimately, even death. Although OHSS increases the physical, psychological, and economic burden of the patients and their families, its pathogenesis is not completely understood and no specific therapy is available for this syndrome. Therefore, prevention of OHSS becomes a crucial issue since its treatment is largely tamping down symptoms, rather than addressing causes. So far, several strategies including cycle cancellation, coasting, in vitro oocyte maturation have been used in practice to prevent OHSS.
The precise cause of OHSS remains currently the subject of controversy. Nevertheless, high estradiol levels in the presence of human chorionic gonadotropin (hCG) increase the vascular endothelium permeability, leading to a massive shift of intravascular fluid into the third space. There are also evidences that during the pathogenesis of this iatrogenic complication, large amounts of angiotensin II, vascular endothelial growth factor (VEGF), interleukins (ILs), nitric oxide (NO), tumor necrosis factor-a (TNF-a), and other molecules are excessively produced, causing the overproduction of reactive oxygen species (ROS) which results in oxidant-antioxidant imbalance. The vascular endothelium is then deteriorated by these imbalanced free radicals that cannot be antagonized by free radical scavengers; consequently, high vascular permeability occurs and finally results in the aggravation of OHSS.
Melatonin is mainly secreted by pineal glands in human beings and is regulated by circadian rhythms. However, higher levels of melatonin are found in human follicular fluid than in plasma because melatonin is not only derived from the general circulation but also synthesized in the ovary (mainly by the granulosa cells). Melatonin has a significant impact on female reproduction. It is considered essential for folliculogenesis, steroid production. There are also evidences that melatonin takes part in the control of pubertal onset, ovulation, sexual maturation and pregnancy protection. Melatonin as well as its metabolites has been proved to be a powerful radical scavenger. It reduces ROS levels in the ovary through receptor dependent and independent pathways. Recently, more and more attention has been paid to the importance of melatonin in female reproduction.
Sestrins are highly conserved and stress-inducible metabolic regulators which are ubiquitously expressed at different levels in all adult tissues. The physiological functions of sestrins have not been fully elucidated yet. Sestrin-2 (SESN2) belongs to the sestrins family and functions as a suppressor of ROS accumulation as well as a neuroprotector. The overexpression of SESN2 reduces ROS levels whereas SESN2 knockdown in cultured cells or mice increases ROS content. Moreover, any condition that leads to ROS accumulation induces SESN2 expression. Therefore, the increased ROS levels in OHSS may increase the expression of SESN2. Since OHSS is closely associated with the excessive production of ROS and melatonin is supposed to be a powerful radical scavenger, the objective of this study was to investigate whether SESN2 are induced in OHSS and whether melatonin can alleviate oxidative stress in OHSS as well as the potential role of SESN2 in OHSS.
Authors collected the granulosa cells of OHSS patients and focused on the role of SESN2 in OHSS. They also studied the role and mechanism of melatonin plays in OHSS patients. They 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.
In this study, authors demonstrated that SESN2 level was increased in the granulosa cells of OHSS patients and was involved in the oxidative stress of OHSS by regulating the apoptosis of endothelium cells. Incubation with angiotensin II in cultured HUVECs and H2O2 in cultured KGNs induced augmented ROS generation and increased SESN2 expression, both of which were restored by the treatment of melatonin. These beneficial effects of melatonin could be explained partly by regulating antiapoptosis through SESN2- AMPK-mTOR.
The results described herein help us understand the beneficial effects of melatonin in OHSS patients. The antioxidative and antiapoptotic properties of melatonin seem to produce positive effects on OHSS. Considering the safety of exogenous melatonin has been testified in many studies, the present findings will provide the potential for clinical application of melatonin to prevent OHSS and define the most appropriate timing when the administration of melatonin should be effectively carried. This is the very initial step of study and the results may not be adapted to OHSS patients without large-scale clinical studies.
Source: Min Zheng et al; Hindawi Obstetrics and Gynecology International Volume 2023, Article ID 1121227, 10 pages
https://doi.org/10.1155/2023/1121227
