The Expression Of GDF-15 In Follicular Fluid And Its Correlation With Ovarian Hyperstimulation Syndrome

Ovarian hyperstimulation syndrome(OHSS)is one of the most serious iatrogenic complications caused by ovulation induced by exogenous gonadotropin and human chorionic gonadotropin during in vitro fertilization.The main symptoms of OHSS include enlarged ovary,ascites and pleural effusion.In severe cases,hypovolemia,renal failure,venous embolism,and even death may occur.In theory,OHSS could happen to any woman who receives superovulation.However,some known risk factors for OHSS have been identified,such as youth,low BMI,ovarian polycystic degeneration and previous history of ovarian hyperresponsiveness.At present,The specific pathogenesis of OHSS is not clear,but its core lies in increased permeability and ovarian neovascularization,fluid leakage from blood vessels into the third cavity,leading to a variety of pathological and clinical manifestations of OHSS.Vascular endothelial growth factor(VEGF)is a highly specific mitogen of vascular endothelial cells.it has a strong effect of promoting endothelial proliferation,angiogenesis and vascular permeability by binding to specific receptors of vascular endothelial cells.IL-6 is the mediator of acute phase of injury and a systemic reaction,which is characterized by leukocytosis,increased vascular permeability and increased synthesis of acute phase proteins in the liver.Motro et al proposed as early as 1990 that IL-6mRNA can be produced during follicular neovascularization and may enhance vascular permeability during ovulation.Subsequently,a number of studies have shown that the concentration of IL-6 in serum,follicular fluid,ascites and pleural effusion is significantly increased in patients with OHSS,suggesting that IL-6 can be used as a marker of OHSS.In addition,it was also found that the increase of IL-6 concentration in follicular fluid during egg extraction could predict the occurrence of early OHSS in high responders.Immunohistochemical localization suggests that IL-6 is luteinizing hormone(LH)or HCG dependent,while IL-6 can up-regulate the expression of VEGF and is an effective hepatic albumin production inhibitor,which can aggravate the disease of OHSS.Growth differentiation factor-15 is a member of the transforming growth factor-β(TGF-β)family,which acts as a secretory protein.A number of studies have confirmed that,as a multi-functional reactive molecule,GDF-15 has a strong role in promoting inflammation,tumor,angiogenesis and so on.However,it was not until the end of 2017 that its endogenous specific receptor GFRAL was discovered.After binding to the functional receptor tyrosine kinase(Ret),it plays a role in metabolic regulation and pregnancy vomiting.Studies have shown that GDF-15 can be synthesized and secreted into follicular fluid by normal ovarian granulosa cells,but it is not clear whether GDF-15 plays a role in the pathogenesis of OHSS.ObjectionBased on the fact that GDF-15 is closely related to nutritional metabolism,immune cells and inflammatory factors,and has been confirmed to exist in follicular fluid and granulosa cells of women of childbearing age,and has a promoting effect on angiogenesis,we speculate that GDF-15 may induce OHSS by participating in inflammatory response and/or promoting angiogenesis.At present,there is no expression level of GDF-15 in follicular fluid of patients with OHSS and its correlation with IL-6 and VEGF.Therefore,we investigated the levels of GDF-15,IL-6 and VEGF in follicular fluid of patients with OHSS and their correlation,and preliminarily understood whether GDF-15 was involved in the pathogenesis of OHSS;so as to provide new ideas and theoretical basis for clinical prevention of OHSS.Materials and methodsThe clinical data of 27 patients who underwent in vitro fertilization and embryo transfer in the College of Reproduction and Genetics of the first affiliated Hospital of Zhengzhou University were collected.According to the diagnostic criteria of OHSS,13 patients in the OHSS group and 14 patients in the control group were selected.The follicular fluid was collected on the day of egg collection.The concentrations of GDF-15,IL-6 and VEGF in the follicular fluid were measured by enzyme-linked immunosorbent assay(ELISA),the baseline data,clinical ovulation induction data and laboratory data of the patients were recorded.The differences in baseline data and clinical and laboratory data between the two groups were compared,and the level of GDF-15 in follicular fluid of patients with OHSS and its correlation with IL-6 and VEGF were analyzed.Result1.The E2 level(5635.08± 1305.90 vs 3065.07±1693.99),the number of oocytes obtained(22.54±6.86 vs 12.14±3.42),the number of MⅡ oocytes(17.38± 4.84 vs 10.86±3.30),the number of 2PN fertilized(12.85±4.98 vs 7.14±2.93)and the number of 2PN cleavage(12.31±4.94 vs 7.07±3.00)in the OHSS group were significantly higher than those in the control group(P<0.05),the rate of MⅡ oocytes was significantly lower than that of the control group(78.86±13.01 vs 89.20±11.20,P<0.05).There was no significant difference in the number of transferable embryos,the number of high quality embryos,the cleavage rate of 2PN and the rate of high quality embryos between the two groups(P>0.05).3.The levels of GDF-15 in follicular fluid of OHSS group were significantly higher than those of control group(7.52±1.59 vs 5.75±1.17,P=0.003).The level of GDF-15 in follicular fluid of patients with OHSS was positively correlated with IL-6(r=0.896,P<0.001)and VEGF(r=0.629,P=0.021).4.The levels of GDF-15(r=0.655,P<0.05),IL-6(r=0.830,P<0.05)and VEGF(r=0.582,P<0.05)in follicular fluid of patients with OHSS were positively correlated with the number of oocytes,while VEGF was negatively correlated with the rate of MⅡ oocytes(r=-0.655,P<0.05).Conclusion1.GDF-15 exists in the follicular fluid of normal people,and it is highly expressed in OHS S patients,and is positively correlated with IL-6 and VEGF respectively,suggesting that it may participate in the pathogenesis of OHSS.2.There may be some connection between GDF-15,IL-6 and VEGF in the follicular fluid of OHSS patients,which leads to the decrease of oocytes maturation rate in OHSS patients.