Human Reproduction Update Advance Access published online on April 2, 2008
Human Reproduction Update, doi:10.1093/humupd/dmn008
Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome
1 Instituto Valenciano de Infertilidad, IVI Lisboa—Av. Infante Dom Henrique, 333-H, 1800–282 Lisbon, Portugal 2 Instituto Universitario IVI, Universidad de Valencia—Plaza de la Policía Local, 3, 46015 Valencia, Spain 3 Instituto Valenciano de Infertilidad, IVI Madrid— Santiago de Compostela, 88, 28035 Madrid, Spain 4 Hospital Universitario Dr. Peset, Valencia, Spain
To whom correspondence should be addressed at: 5 Correspondence address. E-mail: apellicer{at}ivi.es
BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) typically occurs when ovaries are primed with FSH/LH and subsequently exposed to hCG. The ultimate pathophysiological step underlying this clinical picture is increased vascular permeability (VP).
METHODS: A search of the literature was carried out using PubMed and the authors’ files.
RESULTS: In rodents and humans, the expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR-2) mRNA increases during ovarian stimulation. With the administration of hCG, the expression of each rises to a maximum. Expression of VEGF/VEGFR-2 mRNAs correlates with enhanced VP, with both peaking 48 h following an injection of hCG. Immunohistochemistry shows the presence of VEGF and VEGFR-2 proteins in the granulosa-lutein and endothelial cells of the entire corpus luteum. Increased VP may be mediated through adhesion molecules such as VE-cadherin, which is involved in the loosening of endothelial intercellular junctions. These findings regarding the pathophysiology of OHSS suggest that the syndrome can be prevented by inducing ovulation with LH or GnRH analogues, which prevent VEGF overexpression. Also, co-administration of a dopamine agonist inhibits phosphorylation of the receptor VEGFR-2. In a trial of 69 oocyte donors, the incidence of moderate OHSS was 20% with the dopamine agonist cabergoline and 44% with a placebo (P = 0.04).
CONCLUSIONS: The pathophysiological mechanisms involved in OHSS suggest potential preventive approaches, but larger trials are necessary for evaluating the efficacy and safety of the pharmaco-prevention of OHSS.
Key words: vascular endothelial growth factor / ovarian hyperstimulation syndrome / vascular permeability / dopamine agonist / pathophysiology
Received on October 9, 2007; revised January 28, 2008; accepted on February 7, 2008