Human chorionic gonadotropin-induced ovarian hyperstimulation syndrome is associated with up-regulation of vascular endothelial growth factor

Ovarian hyperstimulation syndrome (OHSS), a life-threatening complication occurring in stimulated ovarian cycles, arises from treatment with gonadotropin for induction of follicular maturation in infertile women. Clinical characteristics of OHSS include ascites and pleural effusion induced by increased vascular permeability, where vascular endothelial growth factor (VEGF) was suspected to be the culprit. To test whether the effects of human CG (hCG) on the pathogenesis of OHSS were mediated through the VEGF produced by luteinized granulosa cells, we measured estradiol, VEGF, IGF-II levels in serum, and follicular fluid and analyzed their mRNA expression in luteinized granulosa cells obtained from 101 women (58 with OHSS and 43 controls) who underwent in vitro fertilization and embryo transfer. This study presents the first evidence that hCG up-regulated VEGF expression of granulosa cells in the OHSS, not the control groups, and that follicular VEGF worked through an autocrine mechanism using its kinase insert domain-containing receptor, not the fms-like tyrosine kinase receptor. We calculated total follicular production of VEGF, by multiplying follicular concentrations by follicular volumes, and verified that an increase in total follicular production of VEGF accounted for elevated serum levels of VEGF, which was associated with the development of OHSS. These findings demonstrate that through up-regulation of VEGF, hCG plays a significant role in the pathogenesis of OHSS.