Vascular Endothelial Growth Factor Production by Circulating Immune Cells Is Elevated in Ovarian Hyperstimulation Syndrome

Among the most serious complications when using gonadotropins to induce ovulation is ovarian hyperstimulation syndrome (OHSS), an iatrogenic disorder characterized by enlarged ovaries, increased permeability of peritoneal capillaries, and massive ascites. Vascular endothelial growth factor (VEGF), which promotes angiogenesis and vascular permeability, is viewed as playing a major role in developing OHSS, but its mechanism of action remains incompletely understood. This study tested the hypothesis that immune cells produce VEGF and contribute to increased capillary permeability in OHSS. Peripheral blood mononuclear cells (PBMCs) and plasma were collected from 14 healthy nonpregnant women in the proliferative phase of the cycle and 13 in the secretory phase. Samples were also taken from several groups of patients undergoing in vitro fertilization (IVF): 16 in the secretory phase without OHSS; 13 pregnant women without OHSS; 12 women with early-onset OHSS; and 7 with late-onset OHSS. PBMCs were cultured for 48 hours. Blood levels of progesterone and estradiol were estimated by radioimmunoassay, and of VEGF by enzyme-linked immunosorbent assay. Plasma concentrations of VEGF in patients with early or late-onset OHSS were significantly higher than those in nonpregnant patients without OHSS, pregnant patients without OHSS, and nonpregnant women in either the proliferative or secretory phase of the cycle. Increased VEGF production was also noted in cultured PBMCs. Oocyte retrieval rates were comparable in all groups. In patients with OHSS there was no correlation between VEGF production by PBMCs and plasma VEGF concentrations. In addition, no significant correlation was found between VEGF production by PBMCs or plasma VEGF concentrations and either estradiol or progesterone levels. The finding that production of VEGF by PBMCs is significantly increased in women with OHSS suggests that circulating immune cells have a pathogenetic role in this disorder. The lack of significant correlation between VEGF production by PBMCs and plasma VEGF concentrations points to possible heterogeneity in the pathogenesis of OHSS.