THE ROLE OF VASCULAR ENDOTHELIAL GROWTH-FACTOR AND INTERLEUKINS IN THE PATHOGENESIS OF SEVERE OVARIAN HYPERSTIMULATION SYNDROME

Ovarian hyperstimulation syndrome (OHSS) is a dramatic complication of ovulation induction. In its most severe form, OHSS is characterized b y massive cystic enlargement of the ovaries associated with third spac e fluid shift, resulting in the formation of ascites and pleural effus ion. Ascites develops because of increased peritoneal capillary permea bility. In this study we examined the role of vascular endothelial gro wth factor (VEGF) and interleukins in the pathogenesis of increased ca pillary permeability. VEGF is a member of the family of heparin bindin g proteins that act directly on endothelial cells to induce proliferat ion and angiogenesis. VEGF mRNA and protein are expressed by human ova rian granulosa and theca cells late in follicular development and subs equent to ovulation by granulosa and theca cells. Therefore, VEGF is i deally positioned to provoke the increased permeability of theca blood vessels that occurs shortly before ovulation. Hybridization studies i n the rat and primate ovary have demonstrated VEGF mRNA expression pre dominantly after the luteinizing hormone (LH) surge known to be essent ial for OHSS. The gonadotrophin-releasing hormone antagonist results i n a decreased mRNA expression, implying such expression is dependent o n LH. The expression of VEGF mRNA has been recently shown to be enhanc ed by human chorionic gonadotrophin (HCG) in a dose- and time-dependen t fashion. These studies confirm the timely association between VEGF a nd HCG that has been clinically known for many years to be integral in the development of OHSS. VEGF concentrations in serum, peritoneal flu id and follicular fluid of patients at risk for OHSS have been shown t o be significantly related to the development of the syndrome. Further more, the kinetics of VEGF in the plasma of patients who actually deve lop severe OHSS are closely correlated with the clinical course of the syndrome and with certain biological characteristics of OHSS and of c apillary leakage, such as leukocytosis and increased haematocrit. Stud ies on ascitic fluid from patients with severe OHSS have proved that V EGF is the major capillary permeability agent. Incubation with VEGF an tiserum decreased the vascular permeability activity by 70%. Interleuk in-2 (IL-2) is the first of a series of lymphocytotrophic hormones to be recognized as pivotal for the regulation of immune response. Howeve r, hard data to confirm its central role in the pathogenesis of OHSS a re still lacking, despite the fact that some preliminary studies sugge st a positive association between the pooled follicular fluid IL-2 con centration and the development of OHSS. IL-6 is a mediator of the acut e phase response to injury, a systemic reaction characterized by leuko cytosis, increased vascular permeability and increased synthesis of ac ute phase proteins by the liver. Signifitcantly higher serum and ascit es IL-6 concentrations were seen in OHSS patients. The immunohistochem ical 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 OHS S are correlated with the clinical symptoms and the biochemical parame ters known to be associated with the severity of the syndrome, suggest ing a possible role for IL-6. Further molecular biology studies simila r to those performed on VEGF are needed to confirm if this interleukin is central in the cascade of events. IL-8 is a chemoattractant, activ ating cytokine and a potent angiogenic agent. The peritoneal fluid lev els is increased in patients with sever OHSS; its concentration in per itoneal fluid is increased inpatients with severe OHSS. The place of t his interleukin in the cascade of events is as yet undetermined and fu rther studies are needed, In conclusion, molecular biology and clinica l studies strongly suggest that VEGF is the principal mediator by whic h HCG might increase capillary permeability in OHSS.