Infertility is defined as the inability to be pregnant within one year of unprotected intercourse and its incidence has reached to 10–15% in recent years.[Maya et al.,2012]. It has become not only a medical concern, but 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). OHSS is not uncommon. Studies reported that the presence of its moderate and severe form was up to 10% of all IVF cycles [Asch et al.,1991]. The true incidence of OHSS is probably much underestimated since the symptoms of mild OHSS are easy to be ignored [Ryan et al.,2014]. The symptoms of OHSS in its mild form can be untypical such as nausea, vomiting, however, the moderate and severe OHSS may result in oliguria, hydrothorax, ascite, hepatorenal failure, acute respiratory distress syndrome, hemorrhage from ovarian rupture, thromboembolism even ultimately, death [Mocanu et al., 1997]. 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.
The precise cause of OHSS remains currently the subject of controversy. Nevertheless, high estradiol levels in the presence of human chorionic gonadochotropin (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[McDonough 2003]. The vascular endothelium is then deteriorated by these imbalanced free radicals that cannot be antagonized by free radical scavengers, consequently, high vascular permeability occures and finally results in the aggravation of OHSS [Gomez et al.,2010].
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) [Brzezinski et al.1987]. 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[Hattori et al.,2007]. 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 [Zavodnik et al.,2006; Kang et al.,2009]. Recently, more and more attention has been paid to the importance of melatonin in female reproduction [Tamura et al.,2008].
Sestrins are highly conserved and stress-inducible metabolic regulators which are ubiquitously expressed at different levels in all adult tissues [Velasco-Miguel et al., 1999; Qyerfyrtg et ak,,2010]. The physiological functions of sestrins have not been fully elucidated yet. The critical roles of sestrins in mammalian metabolism have been revealed by the deletion of these proteins which is incompatible with the survive of mice[Peng et al.,2014].Previous studies have also suggested that sestrins have close relationship with age and oxidative stress associated diseases such as Alzeimer’s disease, Parkinson’s disease, diabetes, etc and have a favorable profile as potential therapeutic targets for these diseases[Schapira et al.,2010; Lee et al., 2010]. Sestrin-2 (SESN2) belongs to the sestrins family and functions as a suppressor of ROS accumulation as well as a neuroprotector [Wullschleger et al.,2006]. The overexpression of SESN2 reduces ROS levels whereas SESN2 knockdown in cultured cells or mice increases ROS content[Budanov et al.2001;Kopnin et al.,2001]. Moreover, any condition that leads to ROS accumulation induces SESN2 expression[Lee et al.,1999]. Therefore, the increased ROS levels in OHSS may increase the expression of SESN2. Most previous studies on SESN2 have been focused on nervous system and cardiovascular system, these studies have shown that SESN2 played an important role in preventing ROS damage, repairing mitochondria deterioration and maintaining the stability of inner environment [Zhou et al.,2013; Chen et al.,2017]. However, there are very few studies on the expression and the function of SESN2 in human reproduction. Since OHSS is closely associated with the excessive production of ROS and melatonin is supposed to be a powerful radical scanvenger, therefore, 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.