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This version published online on August 10, 2006
Endocrinology, doi:10.1210/en.2006-0657
A more recent version of this article appeared on November 1, 2006
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Submitted on May 16, 2006
Accepted on July 27, 2006

Low dose dopamine agonist administration blocks VEGF mediated vascular hyperpermeability without altering VEGFR-2 dependent luteal angiogenesis in a rat ovarian hyperstimulation model

Raul Gomez*, Miguel Gonzalez-Izquierdo, Ralf C. Zimmermann, Edurne Novella-Maestre, Isabel Alonso-Muriel, Jose Sanchez-Criado, Jose Remohi, Carlos Simon, and Antonio Pellicer

Department of Obstetrics and Gynaecology, Columbia University, New York, NY (R.G), (R.Z); University Institute IVI, University of Valencia, Valencia, SPAIN (R.G), (E.NM), (I.AM), (J.R), (C.S), (A.P); Hospital Dr Peset, Valencia, SPAIN (M.GI), (A.P); Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain (J.SC); Instituto Valenciano de Infertilidad (IVI), Valencia, SPAIN (J.R), (C.S), (A.P)

* To whom correspondence should be addressed. E-mail: rg2278{at}columbia.edu.

No specific treatment is available for ovarian hyperstimulation syndrome (OHSS), the most important complication in infertile women treated with gonadotropins. OHSS is caused by increased vascular permeability (VP) through ovarian hypersecretion of VEGF activating VEGFR-2.

We previously demonstrated in an OHSS rodent model that increased VP was prevented by inactivating VEGFR-2 with a receptor antagonist (SU5416). However due to its toxicity (thromboembolism), and disruption of VEGFR-2 dependent angiogenic processes critical for pregnancy, this kind of compounds cannot be used clinically to prevent OHSS. Dopamine receptor 2 (Dp-r2) agonists, used in the treatment of human hyperprolactinemia including pregnancy, inhibit VEGFR-2 dependent VP and angiogenesis when administered at high doses in animal cancer models.

To test whether VEGFR-2 dependent VP and angiogenesis could be segregated in a dose dependent fashion with the Dp-r2 agonist cabergoline, a well established OHSS rat model supplemented with prolactin was used. A 100 µg/kg low dose Dp-r2 agonist cabergoline reversed VEGFR-2 dependent VP without affecting luteal angiogenesis through partial inhibition of ovarian VEGFR-2 phosphorylation levels. No luteolytic effects (serum progesterone levels and luteal apoptosis unaffected) were observed. Cabergoline administration also did not affect VEGF/VEGFR-2 ovarian mRNA levels. Results in the animal model and the safe clinical profile of Dp-r2 agonists encouraged us to administer cabergoline to oocyte donors at high risk for developing the syndrome. Prophylactic administration of cabergoline (5-10 µg/kg/day) decreased the occurrence of OHSS from 70% (controls) to 15% (treatment). Therefore, a specific, safe treatment for OHSS is now available.
Key words: OHSS • vascular permeability • VEGF • VEGFR-2 • dopamine agonists




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