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 o...

Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome

“…Cytokines and growth factors (interleukins IL-2, IL-6, IL-8, IL-10, IL-18, VEGF) are known to be implicated in the inflammatory processes associated with late follicular maturation, ovulation, corpus luteum function and embryo implantation, as these molecules are present in the aforementioned fluids in women with OHSS. Other substances, such as histamine, prolactin, prostaglandins and renin-angiotensin, have been proposed as participants in OHSS pathophysiology (Rizk et al, 1997) (Table III).…”

“…It has been demonstrated that the ovary is the main source of VEGF and other cytokines produced during hyperstimulation (Rizk et al, 1997;Schenker, 1999), and that increased capillary permeability and ascites are phenomena predominantly related to the ovaries (Blumenfeld et al, 1997). Furthermore, parameters of ovarian activity during stimulation (E 2 levels and number of oocytes retrieved) correlate closely with VEGF gene expression (Doldi et al, 1997).…”

The Role of Angiogenesis in the Accumulation of Peritoneal Fluid in Benign Conditions and the Development of Malignant Ascites in the Female

“…Serum VEGF levels and clinical biological characteristics of this condition (including capillary leakage and leukocytosis), were significantly correlated [35]. VEGF is present in ascitic fluid of women who develop ovarian hyperstimulation syndrome following exogenous gonadotropin stimulation [36,37].…”

Ovarian hyperstimulation syndrome: pathophysiology and prevention

“…A number of cytokines are associated with the inflammatory process that takes place during the late follicular maturation, ovulation, corpus luteum function, and embryo implantation [11]. Some interleukins may be found in elevated concentration in patients with OHSS, and increased expression of interleukin 6, for example, is associated with increased vascular permeability, hemoconcentration, elevated plasma estradiol concentration, and inhibition of hepatic albumin production [12].…”