To the Editor:
I read with interest the recently published discussion on the etiology and prevention of OHSS (1). While the review comprehensively covered its aims, there are some issues that should be highlighted.
OHSS, being a major complication of controlled ovarian hyperstimulation (COH), is characterized by marked ovarian enlargement and acute third space fluid sequestration that almost always develops after hCG administration or in early pregnancy. OHSS is similar to vascular leak syndrome (VLS), which may be attributable to the massive increase in systemic inflammatory cytokines, including vascular endothelial growth factor (VEGF), observed also during the course of severe OHSS (2).
As was already mentioned (1), many factors and mediators have been proposed as the intermediate, released by gonadotropin-hyperstimulated ovaries at ovulation, which causes the increase in capillary permeability. However, no significant evidence exists to prove any absolute or ultimate role of these ovarian regulators in the pathophysiology of OHSS (2).
In this review, the reader might get the wrong impression that VEGF is the ultimate culprit of OHSS (1). Indeed, while there is no doubt that VEGF is the most investigated cytokine in OHSS (1), it is still unclear whether this cytokine has a causative role, or is just an epiphenomenon. Of mention is the study by Friedman et al that supports the notion that the increase in ovarian VEGF is an epiphenomenon rather than the cause of OHSS (3). In this study, they observed that follicular fluid from women of advanced reproductive age (not at risk to develop OHSS) showed increased VEGF concentrations compared with younger women, an increase that could be consistent with a hypoxic environment within follicles of older women.
Cabergoline for preventing OHSS
The observed ability of cabergoline to inhibit VEGF production by cultured granulosa cells has prompted studies on the role of cabergoline in the prevention of OHSS. Tang et al have recently conducted a systematic review on the effectiveness and safety of cabergoline in preventing OHSS in high-risk women undergoing ART treatment (4). Oral cabergoline, when given as an intervention and compared with a matched placebo, was demonstrated to significantly decrease the incidence of moderate but not severe OHSS. They therefore concluded that further research should consider the comparison between cabergoline and established treatments (such as intravenous albumin and coasting to further evaluate the role of cabergoline in OHSS prevention (4).
To our opinion, the possible explanation to this incomplete beneficial effect of cabergoline, is not solely due to its effect on VEGF, but more importantly, by its proven anti-inflammatory properties. Cabergoline was shown to regulate the immune/inflammatory process and to reduce inflammatory markers (5). Since OHSS represents a state of systemic inflammatory response, with a close interaction between cytokines, growth factors, and OHSS (2, 6), the potential therapeutic role of anti-inflammatory agents, such as cabergoline, is plausible. Indeed, both steroids and intravenous immunoglobulin (IVIG) were previously claimed to prevent and improve OHSS (7). In our previous experimental study, we could demonstrate a significantly lower ascites response and a tendency toward a decreased change in body weight following IVIG, despite comparable serum E2 levels and after adjusting for serum oncotic properties (7).
Professor Raoul Orvieto, M.D.
Infertility and IVF Unit, Barzilai Medical Center, Ashkelon, and
Faculty of Health Science, Ben Gurion University of the Negev, Beer Sheva, Israel
1. Soares SR. Etiology of OHSS and use of dopamine agonists. Fertil Steril 2012;97:517–22.
2. Orvieto R, Ben-Rafael Z. Ovarian hyperstimulation syndrome: A new insight into an old enigma. J Soc Gynecol Invest 1998;5:110-3.
3. Friedman CI, Danforth DR, Herbosa-Encarnacion C, Arbogast L, Alak BM, Seifer DB. Follicular fluid vascular endothelial growth factor concentrations are elevated in women of advanced reproductive age undergoing ovulation induction. Fertil Steril 1997;68:607-12.
4. Tang H, Hunter T, Hu Y, Zhai SD, Sheng X, Hart RJ. Cabergoline for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev. 2012 Feb 15;2:CD008605.
5. Jara LJ, Medina G, Saavedra MA, Vera-Lastra O, Navarro C. Prolactin and autoimmunity. Clin Rev Allergy Immunol. 2011;40:50-9.
6. Orvieto R. Controlled ovarian hyperstimulation—an inflammatory state. J Soc Gynecol Invest 2004;11:424–426.
7. Orvieto R, Achiron A, Margalit R, Ben-Rafael Z. The role of intravenous immunoglobulin in the prevention of severe ovarian hyperstimulation syndrome. J Assist Reprod Genet 1998;15:46-9.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2012.03.018
The author responds:
We thank Professor Orvieto for the interest in our recent publication on the etiology of OHSS and the use of dopamine agonists (1). In his letter, Professor Orvieto expresses his belief in the absence of significant evidence to ascribe to 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 concentrations of VEGF than younger women (2). 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/luteal cells, rather than to VEGF concentration in individual follicles of women with a low ovarian response.
Also, we believe that in the last 20 years crucial knowledge was gained on the importance of VEGF to the occurrence of OHSS. A close temporal relationship between hCG exposure, the rise in VEGF expression and increased VP in such cases was established (3). Moreover, 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 (4-6).
Another issue raised by Professor Orvieto refers to the use of dopamine agonists (namely, cabergoline) to lower the risk of OHSS. First of all, it is indisputable that the efficacy of cabergoline (Cb2) 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 Cb2 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 (7, 8). The phosphorilation of said tyrosine sites in the transmembrane and C-terminal regions are known to onset subsequent VEGFR downstream signaling (9). 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.
Sérgio Reis Soares, M.D.
Instituto Valenciano de Infertilidade, IVI-Lisboa, Lisbon, Portugal
1. Soares SR. Etiology of OHSS and use of dopamine agonists. Fertil Steril 2012; 97:517–22.
2. Friedman CI, Danforth DR, Herbosa-Encarnacion C, Arbogast L, Alak BM, Seifer DB. Follicular fluid vascular endothelial growth factor concentrations are elevated in women of advanced reproductive age undergoing ovulation induction. Fertil Steril 1997;68:607-12.
3. Soares SR, Gómez R, Simón C, García-Velasco JA, Pellicer A. Targeting the vascular endothelial growth factor system to prevent ovarian hyperstimulation syndrome. Hum Reprod Update 2008 Jul-Aug;14:321-33.
4. McClure N, Healy DL, Rogers PA, Sullivan J, Beaton L, Haning RV Jr. et al. Vascular endothelial cell growth factor as permeability agent in ovarian hyperstimulation syndrome. Lancet 1994;344:235-6.
5. Gómez 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;143:4339-48.
6. Levin ER, Rosen GF, Cassidenti DL, Yee B, Meldrum D, Wisot A et al. Role of vascular endothelial cell growth factor in ovarian hyperstimulation syndrome. J Clin Invest 1998;102:1978-85.
7. Basu S, Nagy JA, Pal S, Vasile E, Eckelhoefer IA, Bliss VS, et al. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nat Med 2001;7:569-74.
8. Gómez R, González-Izquierdo M, Zimmermann RC, 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;147:5400-11.
9. Parast CV, 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;37:16788-801.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2012.03.021