The role of vascular endothelial growth factor and interleukins in the pathogenesis of severe ovarian hyperstimulation syndrome

Abstract

Ovarian hyperstimulation syndrome (OHSS) is a dramatic complication of ovulation induction. In its most severe form, OHSS is characterized by massive cystic enlargement of the ovaries associated with third space fluid shift, resulting in the formation of ascites and pleural effusion. Ascites developes because of increased peritoneal capillary permeability. In this study we examined the role of vascular endothelial growth factor (VEGF) and interleukins in the pathogenesis of increased capillary permeability. VEGF is a member of the family of heparin binding proteins that act directly on endothelial cells to induce proliferation and angiogenesis. VEGF mRNA and protein are expressed by human ovarian granulosa and theca cells late in follicular development and subsequent to ovulation by granulosa and theca cells. Therefore, VEGF is ideally positioned to provoke the increased permeability of theca blood vessels that occurs shortly before ovulation. Hybridization studies in the rat and primate ovary have demonstrated VEGF mRNA expression predominantly after the luteinizing hormone (LH) surge known to be essential for OHSS. The gonadotrophin-releasing hormone antagonist results in a decreased mRNA expression, implying such expression is dependent on LH. The expression of VEGF mRNA has been recently shown to be enhanced by human chorionic gonadotrophin (HCG) in a dose- and time-dependent fashion. These studies confirm the timely association between VEGF and HCG that has been clinically known for many years to be integral in the development of OHSS. VEGF concentrations in serum, peritoneal fluid and follicular fluid of patients at risk for OHSS have been shown to be significantly related to the development of the syndrome. Furthermore, the kinetics of VEGF in the plasma of patients who actually develop severe OHSS are closely correlated with the clinical course of the syndrome and with certain biological characteristics of OHSS and of capillary leakage, such as leukocytosis and increased hematocrit. Studies on ascitic fluid from patients with sever OHSS have proved that VEGF is the major capillary permeability agent. Incubation with VEGF antiserum decreased the vascular permeability activity by 70%. Interleukin-2 (IL-2) is the first of a series of lymphocytotrophic hormones to be recognized as pivotal for the regulation of immune response. However, hard data to confirm its central role in the pathogenesis of OHSS are still lacking, despite the fact that some preliminary studies suggest a positive association between the pooled follicular fluid IL-2 concentration and the development of OHSS. IL-6 is a mediator of the acute phase response to injury, a systemic reaction characterized by leukocytosis, increased vascular permeability and increased synthesis of acute phase proteins by the liver. Significantly higher serum and ascites IL-6 concentrations were seen in OHSS patients. The immunohistochemical localization pattern suggested that IL-6 is LH or HCG dependent. However, the use of IL-6 as a predictor for the occurrence of OHSS has not been successful. The kinetics of IL-6 in patients with severe OHSS are correlated with the clinical symptoms and the biochemical parameters known to be associated with the severity of the syndrome, suggesting a possible role for IL-6. Further molecular biology studies similar to those performed on VEGF are needed to confirm if this interleukin is central in the cascade of events. IL-8 is a chemoattractant, activating cytokine and a potent angiogenic agent. The peritoneal fluid levels is increased in patients with severe OHSS; its concentration in peritoneal fluid is increased inpatients with severe OHSS. The place of this interleukin in the cascade of events is as yet undetermined and further studies are needed. In conclusion, molecular biology and clinical studies strongly suggest that VEGF is the principal mediator by which HCG might increase capillary permeability in OHSS.