Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome.
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.
Soares
Sérgio Reis
SR
Instituto Valenciano de Infertilidad, IVI Lisboa-Av. Infante Dom Henrique, 333-H, 1800-282 Lisbon, Portugal.
Gómez
Raúl
R
Simón
Carlos
C
García-Velasco
Juan Antonio
JA
Pellicer
Antonio
A
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D000818:Animals; D000077465:Cabergoline; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D018491:Dopamine Agonists / Q000627:therapeutic use; D004873:Ergolines / Q000627:therapeutic use; D004958:Estradiol / Q000494:pharmacology / Q000627:therapeutic use; D004967:Estrogens / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D016471:Ovarian Hyperstimulation Syndrome / Q000378:metabolism / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D011758:Pyrroles / Q000627:therapeutic use; D051381:Rats; D012102:Reproductive Control Agents / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism* / Q000502:physiology
D006063:Chorionic Gonadotropin; D018491:Dopamine Agonists; D004873:Ergolines; D004967:Estrogens; D007211:Indoles; D011758:Pyrroles; D012102:Reproductive Control Agents; D042442:Vascular Endothelial Growth Factors; D004958:Estradiol; C116890:Semaxinib; D000077465:Cabergoline