Reply of the Authors

Abstract

We thank Dr. Orvieto for the interest in our recent publication on the etiology of ovarian hyperstimulation syndrome (OHSS) and the use of dopamine agonists (1Soares S.R. Etiology of OHSS and use of dopamine agonists.Fertil Steril. 2012; 97: 517-522Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). In his letter, Dr. Orvieto expresses his belief in the absence of significant evidence to ascribe to vascular endothelial growth factor (VEGF) a key role in the genesis of the syndrome. To support this view, a 1997 study is quoted in which women of advanced reproductive age and not at risk for OHSS had higher follicular fluid (FF) concentrations of VEGF than younger women (2Friedman C.I. Danforth D.R. Herbosa-Encarnacion C. Arbogast L. Alak B.M. Seifer D.B. Follicular fluid vascular endothelial growth factor concentrations are elevated in women of advanced reproductive age undergoing ovulation induction.Fertil Steril. 1997; 68: 607-612Abstract Full Text PDF PubMed Scopus (101) Google Scholar). We do not see any conflict between such a finding and the actual role of VEGF in the etiology of OHSS. Increased vascular permeability (VP) leading to OHSS is the consequence of global VEGF activity that is, by its turn, related to a high number of follicles and active granulosa (GC)/luteal cells, rather than to VEGF concentration in individual follicles of women with a low ovarian response.Also, we believe that in the past 20 years crucial knowledge was gained on the importance of VEGF to the occurrence of OHSS. A close temporal relationship between hCG exposure, the increase in VEGF expression, and increased VP in such cases was established (3Soares S.R. Gómez R. Simón C. García-Velasco J.A. Pellicer A. Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome.Hum Reprod Update. 2008; 14: 321-333Crossref PubMed Scopus (160) Google Scholar). In addition, in vitro and in vivo studies in humans and animals demonstrated that molecules targeting specifically the VEGF-VEGF receptor (VEGFR) pathway (such as VEGF antibodies and inhibitors of VEGF receptor phosphorilation) significantly inhibit VP induced by hCG after ovarian stimulation (4McClure N. Healy D.L. Rogers P.A. Sullivan J. Beaton L. Haning Jr., R.V. et al.Vascular endothelial cell growth factor as permeability agent in ovarian hyperstimulation syndrome.Lancet. 1994; 344: 235-236Abstract PubMed Scopus (342) Google Scholar, 5Gómez R. Simon C. Remohi J. Pellicer A. Vascular endothelial growth factor receptor-2 activation induces vascular permeability in hyperstimulated rats, and this effect is prevented by receptor blockade.Endocrinology. 2002; 143: 4339-4348Crossref PubMed Scopus (142) Google Scholar, 6Levin E.R. Rosen G.F. Cassidenti D.L. Yee B. Meldrum D. Wisot A. et al.Role of vascular endothelial cell growth factor in ovarian hyperstimulation syndrome.J Clin Invest. 1998; 102: 1978-1985Crossref PubMed Scopus (146) Google Scholar).Another issue raised by Dr. Orvieto refers to the use of dopamine agonists (namely, cabergoline) to lower the risk of OHSS. First, it is indisputable that the efficacy of cabergoline in preventing the occurrence of the syndrome is not 100%. Still, concerning its impact on the incidence of severe forms, it shall not be forgotten that no published study was large enough to detect significant differences in events with such a low incidence. Regarding the need to compare cabergoline use with other strategies to prevent OHSS, we see this subject in quite a different way. Whenever preventive strategies being evaluated are not mutually exclusive and none of them is 100% efficient, it makes more sense considering their association in the management of ovarian stimulation. For example, coasting and the use of cabergoline may be considered together. If any comparison is to be made, this might be, for instance, between coasting and cabergoline versus coasting alone.Finally, with regard to the mechanisms through which cabergoline may have an impact on OHSS pathophysiology, available evidence is strong enough to identify the VEGF-VEGFR pathway inhibition as relevant for the effect seen. In rodents, it was shown that dopamine/dopamine agonists binding to their receptor determines, depending on the dose used, either the reduced availability of VEGFR due to its internalization or a reduction in the phosphorilation of some of its specific intracellular domains (7Basu S. Nagy J.A. Pal S. Vasile E. Eckelhoefer I.A. Bliss V.S. et al.The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor.Nat Med. 2001; 7: 569-574Crossref PubMed Scopus (316) Google Scholar, 8Gómez R. González-Izquierdo M. Zimmermann R.C. Novella-Maestre E. Alonso-Muriel I. Sanchez-Criado J. et al.Low-dose dopamine agonist administration blocks vascular endothelial growth factor (VEGF)-mediated vascular hyperpermeability without altering VEGF receptor 2-dependent luteal angiogenesis in a rat ovarian hyperstimulation model.Endocrinology. 2006; 147: 5400-5411Crossref PubMed Scopus (136) Google Scholar). The phosphorilation of said tyrosine sites in the transmembrane and carboxy-terminal regions are known to onset subsequent VEGFR downstream signaling (9Parast C.V. Mroczkowski B. Pinko C. Misialek S. Khambatta G. Appelt K. Characterization and kinetic mechanism of catalytic domain of human vascular endothelial growth factor receptor-2 tyrosine kinase (VEGFR-2 TK), a key enzyme in angiogenesis.Biochemistry. 1998; 37: 16788-16801Crossref PubMed Scopus (76) Google Scholar). That said, we agree that it is possible that, due to multiple molecular interactions, cabergoline may interfere with the establishment of OHSS through more than one mechanism. We thank Dr. Orvieto for the interest in our recent publication on the etiology of ovarian hyperstimulation syndrome (OHSS) and the use of dopamine agonists (1Soares S.R. Etiology of OHSS and use of dopamine agonists.Fertil Steril. 2012; 97: 517-522Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). In his letter, Dr. Orvieto expresses his belief in the absence of significant evidence to ascribe to vascular endothelial growth factor (VEGF) a key role in the genesis of the syndrome. To support this view, a 1997 study is quoted in which women of advanced reproductive age and not at risk for OHSS had higher follicular fluid (FF) concentrations of VEGF than younger women (2Friedman C.I. Danforth D.R. Herbosa-Encarnacion C. Arbogast L. Alak B.M. Seifer D.B. Follicular fluid vascular endothelial growth factor concentrations are elevated in women of advanced reproductive age undergoing ovulation induction.Fertil Steril. 1997; 68: 607-612Abstract Full Text PDF PubMed Scopus (101) Google Scholar). We do not see any conflict between such a finding and the actual role of VEGF in the etiology of OHSS. Increased vascular permeability (VP) leading to OHSS is the consequence of global VEGF activity that is, by its turn, related to a high number of follicles and active granulosa (GC)/luteal cells, rather than to VEGF concentration in individual follicles of women with a low ovarian response. Also, we believe that in the past 20 years crucial knowledge was gained on the importance of VEGF to the occurrence of OHSS. A close temporal relationship between hCG exposure, the increase in VEGF expression, and increased VP in such cases was established (3Soares S.R. Gómez R. Simón C. García-Velasco J.A. Pellicer A. Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome.Hum Reprod Update. 2008; 14: 321-333Crossref PubMed Scopus (160) Google Scholar). In addition, in vitro and in vivo studies in humans and animals demonstrated that molecules targeting specifically the VEGF-VEGF receptor (VEGFR) pathway (such as VEGF antibodies and inhibitors of VEGF receptor phosphorilation) significantly inhibit VP induced by hCG after ovarian stimulation (4McClure N. Healy D.L. Rogers P.A. Sullivan J. Beaton L. Haning Jr., R.V. et al.Vascular endothelial cell growth factor as permeability agent in ovarian hyperstimulation syndrome.Lancet. 1994; 344: 235-236Abstract PubMed Scopus (342) Google Scholar, 5Gómez R. Simon C. Remohi J. Pellicer A. Vascular endothelial growth factor receptor-2 activation induces vascular permeability in hyperstimulated rats, and this effect is prevented by receptor blockade.Endocrinology. 2002; 143: 4339-4348Crossref PubMed Scopus (142) Google Scholar, 6Levin E.R. Rosen G.F. Cassidenti D.L. Yee B. Meldrum D. Wisot A. et al.Role of vascular endothelial cell growth factor in ovarian hyperstimulation syndrome.J Clin Invest. 1998; 102: 1978-1985Crossref PubMed Scopus (146) Google Scholar). Another issue raised by Dr. Orvieto refers to the use of dopamine agonists (namely, cabergoline) to lower the risk of OHSS. First, it is indisputable that the efficacy of cabergoline in preventing the occurrence of the syndrome is not 100%. Still, concerning its impact on the incidence of severe forms, it shall not be forgotten that no published study was large enough to detect significant differences in events with such a low incidence. Regarding the need to compare cabergoline use with other strategies to prevent OHSS, we see this subject in quite a different way. Whenever preventive strategies being evaluated are not mutually exclusive and none of them is 100% efficient, it makes more sense considering their association in the management of ovarian stimulation. For example, coasting and the use of cabergoline may be considered together. If any comparison is to be made, this might be, for instance, between coasting and cabergoline versus coasting alone. Finally, with regard to the mechanisms through which cabergoline may have an impact on OHSS pathophysiology, available evidence is strong enough to identify the VEGF-VEGFR pathway inhibition as relevant for the effect seen. In rodents, it was shown that dopamine/dopamine agonists binding to their receptor determines, depending on the dose used, either the reduced availability of VEGFR due to its internalization or a reduction in the phosphorilation of some of its specific intracellular domains (7Basu S. Nagy J.A. Pal S. Vasile E. Eckelhoefer I.A. Bliss V.S. et al.The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor.Nat Med. 2001; 7: 569-574Crossref PubMed Scopus (316) Google Scholar, 8Gómez R. González-Izquierdo M. Zimmermann R.C. Novella-Maestre E. Alonso-Muriel I. Sanchez-Criado J. et al.Low-dose dopamine agonist administration blocks vascular endothelial growth factor (VEGF)-mediated vascular hyperpermeability without altering VEGF receptor 2-dependent luteal angiogenesis in a rat ovarian hyperstimulation model.Endocrinology. 2006; 147: 5400-5411Crossref PubMed Scopus (136) Google Scholar). The phosphorilation of said tyrosine sites in the transmembrane and carboxy-terminal regions are known to onset subsequent VEGFR downstream signaling (9Parast C.V. Mroczkowski B. Pinko C. Misialek S. Khambatta G. Appelt K. Characterization and kinetic mechanism of catalytic domain of human vascular endothelial growth factor receptor-2 tyrosine kinase (VEGFR-2 TK), a key enzyme in angiogenesis.Biochemistry. 1998; 37: 16788-16801Crossref PubMed Scopus (76) Google Scholar). That said, we agree that it is possible that, due to multiple molecular interactions, cabergoline may interfere with the establishment of OHSS through more than one mechanism. Etiology of ovarian hyperstimulation syndromeFertility and SterilityVol. 97Issue 6PreviewI read with interest the recently published discussion on the etiology and prevention of ovarian hyperstimulation syndrome (OHSS) (1). Although the review comprehensively covered its aims, there are some issues that should be highlighted. Full-Text PDF