Mechanism of severe ovarian hyperstimulation syndrome

Abstract

To the Editor: We read the work of Ata et al. (1Ata B, Yakin K, Alatas C, Urman B. Dual renin-angiotensin blockade and total embryo cryopreservation is not a risk-free strategy in patients at high risk for ovarian hyperstimulation syndrome. Fertil Steril. Published online November 13, 2007 [Epub ahead of print].Google Scholar) recently published online in Fertility & Sterility on the dual blockage of the renin-angiotensin system and embryo cryopreservation to prevent ovarian hyperstimulation syndrome (OHSS) in high-risk patients. We are really concerned about the possibility of the implementation of such a preventive approach for several reasons. The first is that renin-angiotensin system activation and the previously described correlation between renin activity and OHSS severity probably could be the effect and not the cause of this complication. In fact, every clinical condition characterized by hypovolemia leads to a secondary reactive hyperaldosteronism by renin-angiotensin cascade activation. Severe OHSS is a model of hypovolemia produced by third-space fluid shift and subsequent hematocrit increase: it is not surprising but, on the contrary, completely normal that renin activity increases in such patients. The second is that the great majority of such patients are pregnant, and both angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists are not first-choice drugs during pregnancy because of a possible teratogenic effect in humans that cannot be excluded completely at present. The third is that many of such patients show hypotension and pre-renal failure with increased creatinine levels because of hypoperfusion, both of which may worsen after renin-angiotensin system inhibition. Moreover the frequency of 20% of severe OHSS observed in the study of Ata et al. (1Ata B, Yakin K, Alatas C, Urman B. Dual renin-angiotensin blockade and total embryo cryopreservation is not a risk-free strategy in patients at high risk for ovarian hyperstimulation syndrome. Fertil Steril. Published online November 13, 2007 [Epub ahead of print].Google Scholar) seems to suggest that this approach is not very effective, and even if no deleterious effect has been observed during such study this could have been related to the small number of patients receiving treatment. On the contrary with cabergoline administration we have experienced only 2% severe OHSS in our high-risk subgroup of patients (8/369). We do not fully agree with the assertion by Ata et al. that “no single mechanism is universally accepted to cause the syndrome” (1Ata B, Yakin K, Alatas C, Urman B. Dual renin-angiotensin blockade and total embryo cryopreservation is not a risk-free strategy in patients at high risk for ovarian hyperstimulation syndrome. Fertil Steril. Published online November 13, 2007 [Epub ahead of print].Google Scholar). In recent years several contributions starting from the work of McClure et al. (2McClure N. Healy D.L. Rogers P.A. Sullivan J. Beaton L. Haning Jr., R.V. et al.Vascular endothelial growth factor as capillary permeability agent in ovarian hyper stimulation syndrome.Lancet. 1994; 344: 235-236Abstract PubMed Scopus (342) Google Scholar) in 1994 have directed our attention to the prominent role of vascular endothelial growth factor (VEGF) in the pathologic increase of vascular permeability as the main responsible agent of this complication. They observed that monoclonal antibody for such a cytokine is able to reduce ascites by approximately 70% in gonadotropin-stimulated animals. Moreover hCG has been demonstrated as a potent VEGF inducer (3Wang T.H. Horng S.G. Chang C.L. Human chorionic gonadotropin–induced ovarian hyperstimulation syndrome is associated with up regulation of vascular endothelial growth factor.J Clin Endocrinol Metab. 2002; 87: 3300-3308Crossref PubMed Scopus (134) Google Scholar), and recently the molecular mechanism of action of VEGF also has been clarified as endothelial cell adherent junction remodeling due to β-arrestin–dependent internalization of the surface adhesion molecule VE-cadherin (4Gavard J. Gutkind J.S. VEGF controls endothelial-cell permeability by promoting the β-arrestin–dependent endocytosis of VE-cadherin.Nat Cell Biol. 2006; 8: 1223-1239Crossref PubMed Scopus (757) Google Scholar). Therefore, we think that for the future some of the most promising ways to prevent OHSS perhaps could be hCG dose tapering to reduce VEGF production or effect, cabergoline-mediated VEGF antagonism by dopamine D2 receptor stimulation as recently proposed (5Aboulghar M.A. Preventing ovarian hyperstimulation syndrome.J Clin Endocrinol Metab. 2007; 92: 2882-2884Crossref PubMed Scopus (4) Google Scholar), or a combination of these two new approaches. Reply of the Authors: Mechanism of severe ovarian hyperstimulation syndromeFertility and SterilityVol. 89Issue 6PreviewAlthough we agree with Manno and Tomei in general, there are issues that require further explanation. Full-Text PDF