GnRH analogue for the prevention of ovarian hyperstimulation syndrome: a pilot study
2008; Elsevier BV; Volume: 91; Issue: 4 Linguagem: Inglês
10.1016/j.fertnstert.2008.04.017
ISSN1556-5653
AutoresJuan Gilés, Alberto Requena, Juan A. García-Velasco, Alberto Pacheco, Jorge Pellicer, António Pellicer,
Tópico(s)Ovarian cancer diagnosis and treatment
ResumoContinuation of GnRH analogue after ovum retrieval produces a faster decline in vascular endothelial growth factor levels and ascitis in women at risk of ovarian hyperstimulation syndrome Continuation of GnRH analogue after ovum retrieval produces a faster decline in vascular endothelial growth factor levels and ascitis in women at risk of ovarian hyperstimulation syndrome Ovarian hyperstimulation syndrome (OHSS) is one of the most serious complications of assisted reproductive technologies. Patients with severe OHSS present a variety of manifestations, such as ascitis, pleural hemorrhage, hemoconcentration, and oliguria (1The Practice Committee of the American Society for Reproductive MedicineOvarian hyperstimulation syndrome.Fertil Steril. 2003; 80: 1309-1314Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar), and there have been cases of thromboembolism (2Levy T. Orvieto R. Homburg R. Peleg D. Dekel A. Ben-Rafael Z. Severe ovarian hyperstimulation syndrome despite low plasma oestrogen concentrations in a hypogonadotrophic, hypogonadal patient.Hum Reprod. 1996; 11: 1177-1179Crossref PubMed Scopus (33) Google Scholar), and even death (3Cluroe A.D. Synek B.J. A fatal case of ovarian hyperstimulation syndrome with cerebral infarction.Pathology. 1995; 27: 344-346Abstract Full Text PDF PubMed Scopus (79) Google Scholar). The main characteristic of these manifestations is an increase in capillary permeability because of the release of hCG mediators; however, this mechanism is not fully understood.Among the wide variety of vasoactive molecules, the one that plays a preponderant role is the vascular endothelial growth factor (VEGF), as many studies from our center describe. Pellicer et al. and others (4Pellicer A. Albert C. Mercader A. Bonilla-Musoles F. Remohi J. Simon C. The pathogenesis of ovarian hyperstimulation syndrome: in vivo studies investigating the role of interleukin-1beta, interleukin-6, and vascular endothelial growth factor.Fertil Steril. 1999; 71: 482-489Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 5Lee A. Christenson L.K. Stouffer R.L. Burry K.A. Patton P.E. Vascular endothelial growth factor levels in serum and follicular fluid of patients undergoing in vitro fertilization.Fertil Steril. 1997; 68: 305-311Abstract Full Text PDF PubMed Scopus (113) Google Scholar, 6Artini P.G. Fasciani A. Monti M. Luisi S. D'Ambrogio G. Genazzani A.R. Changes in vascular endothelial growth factor levels and the risk of ovarian hyperstimulation syndrome in women enrolled in an in vitro fertilization program.Fertil Steril. 1998; 70: 560-564Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 7Abramov Y. Barak V. Nisman B. Schenker J.G. Vascular endothelial growth factor plasma levels correlate to the clinical picture in severe ovarian hyperstimulation syndrome.Fertil Steril. 1997; 67: 261-265Abstract Full Text PDF PubMed Scopus (161) Google Scholar, 8Agrawal R. Tan S.L. Wild S. Sladkevicius P. Engmann L. Payne N. et al.Serum vascular endothelial growth factor concentrations in in vitro fertilization cycles predict the risk of ovarian hyperstimulation síndrome.Fertil Steril. 1999; 71: 287-293Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar) have shown that women at risk of OHSS present high serum VEGF levels. The production of VEGF by endothelial cells appears to increase by hCG, which in turn, increases capillary permeability (9Albert C. Garrido N. Mercader A. Rao C.V. Remohi J. Simon C. et al.The role of endothelial cells in the pathogenesis of ovarian hyperstimulation syndrome.Mol Hum Reprod. 2002; 8: 409-418Crossref PubMed Scopus (58) Google Scholar). A recent study has shown that the factors that most determine the future development of OHSS are the ability to secrete sVEGFR-1 and to reduce the availability of f-VEFG (10Pau E. Alonso-Muriel I. Gómez R. Novella E. Ruiz A. García-Velasco J.A. et al.Plasma levels of soluble vascular endothelial growth factor receptor-1 may determine the onset of early and late ovarian hyperstimulation syndrome.Hum Reprod. 2006; 21: 1453-1460Crossref PubMed Scopus (55) Google Scholar). In addition, a decline in VEGF protein secretion (11Garcia-Velasco J.A. Zuniga A. Pacheco A. Gomez R. Simon C. Pellicer A. Coasting acts through downregulation of VEGF gene expression and protein secretion.Hum Reprod. 2004; 19: 1530-1538Crossref PubMed Scopus (49) Google Scholar, 12Tozer A.J. Iles R.K. Iammarrone E. Gillott C.M. Al-Shawaf T. Grudzinskas J.G. The effects of "coasting" on follicular fluid concentrations of vascular endothelial growth factor in women at risk of developing ovarian hyperstimulation syndrome.Hum Reprod. 2004; 19: 522-528Crossref PubMed Scopus (29) Google Scholar) and gene expression (11Garcia-Velasco J.A. Zuniga A. Pacheco A. Gomez R. Simon C. Pellicer A. Coasting acts through downregulation of VEGF gene expression and protein secretion.Hum Reprod. 2004; 19: 1530-1538Crossref PubMed Scopus (49) Google Scholar) take place after coasting in granulose cells. Our studies have shown that the blockage of VEGFR-2 with SU5416 (VEGFR-2 inhibitor) reverses the increase in vascular permeability caused by the hCG (13Gómez R. Simón C. Remohí 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). However, low doses of carbegoline block hyperpermeability not only in the rat OHSS model (14Gomez R. Gonzalez-Izquierdo M. Zimmermann R.C. Novella-Maestre E. Alonso-Muriel I. Sanchez-Criado J. 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), but also under similar conditions in humans (15Alvarez C. Martí-Bonmatí L. Novella-Maestre E. Sanz R. Gómez R. Fernández-Sánchez M. et al.Dopamine agonist cabergoline reduces hemoconcentration and ascites in hyperstimulated women undergoing assisted reproduction.J Clin Endocrinol Metab. 2007; 92: 2931-2937Crossref PubMed Scopus (160) Google Scholar).Serum and ascitis fluid levels of interleukin-1 (IL-1), IL-2, IL6, and IL-8 were also elevated, but accumulating evidence does not support a pivotal role in the pathogenesis of OHSS (16Pellicer A. Albert C. Mercader A. Bonilla-Musoles F. Remohí J. Simón C. The pathogenesis of ovarian hyperstimulation syndrome: in vivo studies investigating the role of interleukin-1beta, interleukin-6, and vascular endothelial growth factor.Fertil Steril. 1999; 71: 482-489Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 17Aboulghar M.A. Mansour R.T. Serour G.I. El Helw B.A. Shaarawy M. Elevated levels of interleukin-2, soluble interleukin-2 receptor alpha, interleukin-6, soluble interleukin-6 receptor and vascular endothelial growth factor in serum and ascitic fluid of patients with severe ovarian hyperstimulation syndrome.Eur J Obstet Gynecol Reprod Biol. 1999; 87: 81-85Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 18Rizk B. Aboulghar M. Smitz J. Ron-El R. The role of vascular endothelial growth factor and interleukins in the pathogenesis of severe ovarian hyperstimulation syndrome.Hum Reprod Update. 1997; 3: 255-266Crossref PubMed Scopus (175) Google Scholar).One of the strategies used to prevent OHSS has been to continue the administration of the GnRH agonist immediately after hCG administration. To date, and to our knowledge, there are no randomized studies in the literature available that compare the use of the GnRH agonist and antagonist immediately after hCG administration in women at risk of OHSS.The aim of the present study is to assess the usefulness of continuing with GnRH analogues in patients who are at a high risk of developing OHSS after ovulation induction with hCG to prevent its occurrence and to look into the mechanisms that trigger it.Materials and methodsBetween June 2004 and April 2005, a prospective randomized double-blind study was preformed with egg donors from our oocyte donation program who had undergone an ovarian stimulation and who were at risk of OHSS. An institutional review board approval was obtained. The protocols for ovarian stimulation have been described elsewhere (19Soares S.R. Troncoso C. Bosch E. Serra V. Simón C. Remohí J. et al.Age and uterine receptiveness: predicting the outcome of oocyte donation cycles.J Clin Endocrinol Metab. 2005; 90: 4399-4404Crossref PubMed Scopus (145) Google Scholar).Inclusion criteria demanded serum estradiol levels of >3,500 pg/mL (20Orvieto R. Prediction of ovarian hyperstimulation syndrome. Challenging the estradiol mythos.Hum Reprod. 2003; 18: 665-667Crossref PubMed Scopus (49) Google Scholar) together with retrieved oocytes of >15 (21Chenette P.E. Sauer M.V. Paulson R.J. Very high serum estradiol levels are not detrimental to clinical outcome of in vitro fertilization.Fertil Steril. 1990; 54: 858-863Abstract Full Text PDF PubMed Scopus (116) Google Scholar). Of the total 30 patients who met the inclusion criteria, 2 were excluded because of inadequate protocol compliance. Patients were randomly chosen by a table of random numbers. In this way, 10 women received triptorelin (Decapeptyl, 0.1 mg; Ipsen Pharma, Barcelona, Spain) for a period of 9 days (group A), starting on the day of oocyte retrieval. Another nine donors were treated with Cetrorelix (Cetrotide, 0.25 mg; Serono, Madrid, Spain) in the same way (group B), and nine other women (group C) only received supportive treatment, such as oral analgesics in case of pain and oral hydration, just as the other women from groups A and B did.All women were tested on days 3, 6, and 9 postoocyte retrieval. Transvaginal ultrasounds were performed, and the mean ovarian size diameter, the free fluid in the Pouch of Douglas (mm2), and clinical manifestations were noted to be analyzed by qualitative scales and were scored according to the severity of each one. Blood was taken for biochemical determinations of creatinine, urea, glutamate pyruvate transaminase, and serum VEGF. Thermo electron reagents (Melbourne, Australia) were used for biochemical tests, as well as a Chemistry Profile Analyzer (CPA; Coultronics, France). Finally, VEGF concentrations were determined by ELISA with human sVEGF-R1 reagents from BLK Diagnostics (CAT #BLK268; Barcelona, Spain) and a Mago ELISA reader.Statistical AnalysisSample size was calculated on the basis of detecting a 50% reduction (one-sided test) of the size of the free fluid packet in the Douglas pouch on day 3 after treatment (from 50 to 25 mm) from the control group with either of the study groups, with a confidence level of 95% (error α = 0.05) and a statistical power of 80% (error β = 20). For this purpose, eight patients per group were needed, although 10 patients per group were finally included to assume losses of 20%.A descriptive analysis of the clinical variables and the biochemical determinations of all women were conducted for this study. Quantitative variables were described by the means and standard deviations, whereas qualitative variables were described by their frequency distribution.The mean comparison between the study groups was evaluated using the nonparametrical Kruskal-Wallis test, and the chi-square test was used to evaluate the qualitative variables for the hypothesis contrast. The statistical analysis was performed by using the Statistical Package for Social Sciences (SPSS, Chicago, IL).ResultsNo significant differences were noted in age (28.2 ± 3.7, 24.5 ± 3.6, 24.7 ± 3.5), body mass index (23.2 ± 3.3, 21.1 ± 1.4, 22.2 ± 2.9), or in the stimulation parameters in terms of estradiol levels (pg/mL) on the third day of stimulation (115.1 ± 53.7, 140.5 ± 11.7, 105.1 ± 55.5), in estradiol levels on the day of hCG administration (3,277 ± 980, 3,044.1 ± 1,181, 2,554 ± 876), or in the oocytes obtained from all three groups (21 ± 4.8, 21.6 ± 2.9, 22.8 ± 2.1).The most common clinical manifestations were pain and abdominal distension, which eased after a few days. Hospitalization of patients or culdocentesis was not required in any case. When we analyzed the data in terms of groups, no significant differences were found among the three groups, although a higher incidence of vomiting was noted in patients who were administered Cetrolix (11.1%, n = 1, on days 3 and 6 postoocyte retrieval, and 0 in groups A and C), and of diarrhoea in the control group (22.22%, n = 2, on day 9 postoocyte retrieval and 0 in the other groups).After analyzing the ultrasound scan variables, ascitis decreased more rapidly in those women receiving GnRH analogues, especially Cetrorelix, and became significant on day 3 postoocyte retrieval (group A 34.05 ± 7.7 mm2, group B 28.16 ± 13.36 mm2, group C 49.93 ± 20.34 mm2; P=.015). Nonetheless, there were no significant differences in the porcentual reduction of ascitis among groups over the observation period (days 3, 6, and 9).Cetrorelix also allowed a faster reduction in ovarian size after day 6, although this was not significant (Table 1).Table 1Ultrasound manifestations and serum VEGF determinations on days 3, 6, and 9 postoocyte retrieval.TriptorelineCetrorelixControlPDay 3 Free fluid packet (mm2)34.0 ± 7.728.1 ± 13.349.9 ± 20.3.015 Right ovary (mm)64.1 ± 9.961.4 ± 10.568.1 ± 5.4NS Left ovary (mm)62.8 ± 11.961.3 ± 10.561.5 ± 7.9NS VEGF (pg/mL)1.2 ± 8.31 ± 0.41.7 ± 0.4NSDay 6 Free fluid packet (mm2)33.8 ± 13.530.3 ± 20.241.1 ± 26.5NS Right ovary (mm)64.5 ± 9.750.3 ± 13.862.6 ± 10.2NS Left ovary (mm)62.7 ± 9.250.5 ± 8.957.6 ± 12.4NS VEGF (pg/mL)1.2 ± 6.31.3 ± 0.21.5 ± 0.4NSDay 9 Free fluid packet (mm2)20.4 ± 10.014.4 ± 19.928.2 ± 14.1NS Right ovary (mm)52.8 ± 5.650.3 ± 13.854.5 ± 19.0NS Left ovary (mm)50.3 ± 8.350 ± 8.945.6 ± 8.01NS VEGF (pg/mL)1.4 ± 0.20.8 ± 0.11.8 ± 0.8NS Open table in a new tab However, no significant correlation was observed between the ultrasound variables and clinical symptoms, except ovarian size on day 6 postoocyte retrieval, and vomiting, which appears to be coincidental.Serum VEGF concentrations were lower after using GnRH analogues, especially GnRH antagonists (1.4 ± 0.2 vs. 0.8 ± 1.8 ± 0.8 on day 9). Regarding hepatic (glutamate pyruvate transaminase) and renal (urea and creatinine) function markers, the results were normal and similar among the three groups.DiscussionSome investigators have suggested continuing the administration of GnRH agonists during the luteal phase after hCG administration, followed by an elective cryopreservation of all embryos (22Wada I. Matson P.L. Horne G. Buck P. Lieberman B.A. Is continuation of a gonadotrophin-releasing hormone agonist (GnRHa) necessary for women at risk of developing the ovarian hyperstimulation syndrome?.Hum Reprod. 1992; 7: 1090-1093Crossref PubMed Scopus (20) Google Scholar, 23Endo T. Honnma H. Hayashi T. Chida M. Yamazaki Kitajima Y. et al.Continuation of GnRH agonist administration for 1 week, after HCG injection, prevents ovarian hyperstimulation syndrome following elective cryopreservation of all pronucleate embryos.Hum Reprod. 2002; 17: 2548-2551Crossref PubMed Scopus (42) Google Scholar). Furthermore, the continuation of the GnRH agonist over 1 week in women whose embryos were transferred in the same cycle prevents severe OHSS from occurring (24Nikolettos N. Asimakopoulos B. Simopoulou M. al-Hasani S. GnRH agonist administration after embryo transfer, in long protocol stimulated cycles, prevents ovarian hyperstimulation syndrome. A report of five cases.In Vivo. 2003; 17: 655-658PubMed Google Scholar).With regard to the GnRH antagonist, many studies show a lower risk of developing OHSS when this kind of drug was used for ovarian stimulation (25Olivennes F. Cunha-Filho J.S. Fanchin R. Bouchard P. Frydman R. The use of GnRH antagonists in ovarian stimulation.Hum Reprod Update. 2002; 8: 279-290Crossref PubMed Scopus (117) Google Scholar, 26Borm G. Mannaerts B. The European Orgalutran Study GroupTreatment with the gonadotrophin- releasing hormone antagonist ganirelix in women undergoing ovarian stimulation with recombinant follicle stimulating hormone is effective, safe and convenient: results of a controlled, randomized, multicentre.Hum Reprod. 2000; 15: 1490-1498Crossref PubMed Scopus (341) Google Scholar, 27Coccia M.E. Comparetto C. Bracco G.L. Scarselli G. GnRH antagonists.Eur J Obstet Gynecol Reprod Biol. 2004; 115: S44-S56Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). However, to our knowledge, only two articles study the continuation of GnRH antagonist use to prevent OHSS. De Jong et al. (28de Jong D. Macklon N.S. Mannaerts B.M. Coelingh Bennink H.J. Fauser B.C. High dose gonadotrophin-releasing hormone antagonist (ganirelix) may prevent ovarian hyperstimulation syndrome caused by ovarian stimulation for in-vitro fertilization.Hum Reprod. 1998; 13: 573-575Crossref PubMed Scopus (50) Google Scholar) administered 2 mg/day of ganirelix to a patient who was at high risk of OHSS and who had not yet been administered the hCG injection, and observed a rapid decrease in both serum estradiol levels and ovarian size. More recently, Lainas et al. (29Lainas T.G. Sfontouris I.A. Zorzovilis I.Z. Petsas G.K. Lainas G.T. Kolibianakis E.M. Management of severe early ovarian hyperstimulation syndrome by re-initiation of GnRH antagonist.Reprod Biomed Online. 2007; 15: 408-412Abstract Full Text PDF PubMed Scopus (47) Google Scholar) reinitiated the daily administration of 0.25 mg of Ganirelix for 1 week in three patients with severe early OHSS on day 3 postoocyte retrieval, and simultaneously performed embryo cryopreservation. None of the patients required hospitalization, and a marked decrease in ovarian size, volume, ascitis, white blood cell count, and hematocrit was observed.The possible mechanism of action of the GnRH analogues could be because of the decrease in VEGF production in the ovary (23Endo T. Honnma H. Hayashi T. Chida M. Yamazaki Kitajima Y. et al.Continuation of GnRH agonist administration for 1 week, after HCG injection, prevents ovarian hyperstimulation syndrome following elective cryopreservation of all pronucleate embryos.Hum Reprod. 2002; 17: 2548-2551Crossref PubMed Scopus (42) Google Scholar), as observed in rats (30Kitajima Y. Endo T. Henmi H. et al.Gonadotropin-releasing hormone agonist suppress the expression of vascular endothelial growth factor and its receptors messenger ribonucleic acid in newly formed corpora lutea of superovulated rats.Biol Reprod. 1998; 58: 107Google Scholar), which was caused by the luteolytic effect of these drugs (31Goto T. Endo T. Henmi H. Kitajima Y. Kiya T. Nishikawa A. et al.Gonadotropin-releasing hormone agonist has the ability to induce increased matrix metalloproteinase (MMP)-2 and membrane type 1-MMP expression in corpora lutea, and structural luteolysis in rats.J Endocrinol. 1999; 161: 393-402Crossref PubMed Scopus (39) Google Scholar, 32Fridén B.E. Nilsson L. Gonadotrophin-releasing hormone-antagonist luteolysis during the preceding mid-luteal phase is a feasible protocol in ovarian hyperstimulation before in vitro fertilization.Acta Obstet Gynecol Scand. 2005; 84: 812-816Crossref PubMed Scopus (24) Google Scholar). This luteolytic effect might be related to the reduction of the ovarian volume in the analogue group, mainly in the antagonist group.A recent work by Kitajima et al. (33Kitajima Y. Endo T. Manase K. Nishikawa A. Shibuya M. Kudo R. Gonadotropin-releasing hormone agonist administration reduced vascular endothelial growth factor (VEGF), VEGF receptors, and vascular permeability of the ovaries of hyperstimulated rats.Fertil Steril. 2004; 81: 842-849Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar) shows that the continuation of the GnRH agonist for the days following HCG injection reduces the expression of VEGF, VEGFR-1, VEGFR-2, and also reduces the vascular permeability in hyperstimulated rat ovaries. Comparably, the GnRH antagonist led to a decrease in VEFG concentrations in human granulosa lutein cell cultures (32Fridén B.E. Nilsson L. Gonadotrophin-releasing hormone-antagonist luteolysis during the preceding mid-luteal phase is a feasible protocol in ovarian hyperstimulation before in vitro fertilization.Acta Obstet Gynecol Scand. 2005; 84: 812-816Crossref PubMed Scopus (24) Google Scholar), and to the expression of the VEGF and VEGF receptors in ovaries of hyperstimulated rats (34Taylor P.D. Hillier S.G. Fraser H.M. Effects of GnRH antagonist treatment on follicular development and angiogenesis in the primate ovary.J Endocrinol. 2004; 183: 1-17Crossref PubMed Scopus (57) Google Scholar).The aim of the present study was to compare the efficacy of the administration of the GnRH agonist with the GnRH antagonist after oocyte retrieval in an IVF cycle to prevent early OHSS. As seen in our results, it seems evident that the use of GnRH analogues (especially antagonists) leads to a faster recovery from ascitis and to a reduction of ovarian size. This may be related to the decrease of VEGF observed when these drugs are used, which once again indicates that VEGF may be the main mediator responsible for the development of OHSS.However, no significant differences were found with regard to the incidence or intensity of the clinical manifestation or to a faster reduction in ovarian size as might be expected, and this is probably because of the small sample size.Therefore, the use of GnRH analogues seems to lower the risk of developing OHSS given their luteolytic effect, and apparently causes a decline in VEGF production, although the action mechanism of these drugs in the ovary is not accurately known. If we assume that these drugs act in the ovarian gonadotropic cells as they do in the hypophisis, the antagonists would produce a faster and more potent steroidogenesis suppression, and would block the luteinization, actions which have already been observed after administering agonists (35Harwood J.P. Clayton R.N. Catt K.J. 1980. Ovarian gonadotropin-releasing hormone receptors. I. Properties and inhibition of luteal cell function.Endocrinology. 1980; 107: 407-413Crossref PubMed Scopus (92) Google Scholar, 36Harwood J.P. Clayton R.N. Chen T.T. Knox G. Catt K.J. Ovarian gonadotropin-releasing hormone receptors. II. Regulation and effects on ovarian development.Endocrinology. 1980; 107: 414-421Crossref PubMed Scopus (59) Google Scholar). This justifies the good results obtained in our work in terms of reducing the ascitis, ovarian size, and serum VEGF levels.In conclusion, even though the pathogenesis of OHSS is not currently well understood, VEGF seems to be the most important vasoactive mediator of hCG action. Administration after ovum retrieval, especially of antagonists, induces a faster decline in VEGF levels, which might be related to a faster reduction of ascitis and ovarian size in women at risk of early OHSS, as our study points out. However, more studies are needed to clarify the action mechanism of the GnRH analogues and the efficacy of these drugs as a good option toward the prevention of OHSS. Ovarian hyperstimulation syndrome (OHSS) is one of the most serious complications of assisted reproductive technologies. Patients with severe OHSS present a variety of manifestations, such as ascitis, pleural hemorrhage, hemoconcentration, and oliguria (1The Practice Committee of the American Society for Reproductive MedicineOvarian hyperstimulation syndrome.Fertil Steril. 2003; 80: 1309-1314Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar), and there have been cases of thromboembolism (2Levy T. Orvieto R. Homburg R. Peleg D. Dekel A. Ben-Rafael Z. Severe ovarian hyperstimulation syndrome despite low plasma oestrogen concentrations in a hypogonadotrophic, hypogonadal patient.Hum Reprod. 1996; 11: 1177-1179Crossref PubMed Scopus (33) Google Scholar), and even death (3Cluroe A.D. Synek B.J. A fatal case of ovarian hyperstimulation syndrome with cerebral infarction.Pathology. 1995; 27: 344-346Abstract Full Text PDF PubMed Scopus (79) Google Scholar). The main characteristic of these manifestations is an increase in capillary permeability because of the release of hCG mediators; however, this mechanism is not fully understood. Among the wide variety of vasoactive molecules, the one that plays a preponderant role is the vascular endothelial growth factor (VEGF), as many studies from our center describe. Pellicer et al. and others (4Pellicer A. Albert C. Mercader A. Bonilla-Musoles F. Remohi J. Simon C. The pathogenesis of ovarian hyperstimulation syndrome: in vivo studies investigating the role of interleukin-1beta, interleukin-6, and vascular endothelial growth factor.Fertil Steril. 1999; 71: 482-489Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 5Lee A. Christenson L.K. Stouffer R.L. Burry K.A. Patton P.E. Vascular endothelial growth factor levels in serum and follicular fluid of patients undergoing in vitro fertilization.Fertil Steril. 1997; 68: 305-311Abstract Full Text PDF PubMed Scopus (113) Google Scholar, 6Artini P.G. Fasciani A. Monti M. Luisi S. D'Ambrogio G. Genazzani A.R. Changes in vascular endothelial growth factor levels and the risk of ovarian hyperstimulation syndrome in women enrolled in an in vitro fertilization program.Fertil Steril. 1998; 70: 560-564Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 7Abramov Y. Barak V. Nisman B. Schenker J.G. Vascular endothelial growth factor plasma levels correlate to the clinical picture in severe ovarian hyperstimulation syndrome.Fertil Steril. 1997; 67: 261-265Abstract Full Text PDF PubMed Scopus (161) Google Scholar, 8Agrawal R. Tan S.L. Wild S. Sladkevicius P. Engmann L. Payne N. et al.Serum vascular endothelial growth factor concentrations in in vitro fertilization cycles predict the risk of ovarian hyperstimulation síndrome.Fertil Steril. 1999; 71: 287-293Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar) have shown that women at risk of OHSS present high serum VEGF levels. The production of VEGF by endothelial cells appears to increase by hCG, which in turn, increases capillary permeability (9Albert C. Garrido N. Mercader A. Rao C.V. Remohi J. Simon C. et al.The role of endothelial cells in the pathogenesis of ovarian hyperstimulation syndrome.Mol Hum Reprod. 2002; 8: 409-418Crossref PubMed Scopus (58) Google Scholar). A recent study has shown that the factors that most determine the future development of OHSS are the ability to secrete sVEGFR-1 and to reduce the availability of f-VEFG (10Pau E. Alonso-Muriel I. Gómez R. Novella E. Ruiz A. García-Velasco J.A. et al.Plasma levels of soluble vascular endothelial growth factor receptor-1 may determine the onset of early and late ovarian hyperstimulation syndrome.Hum Reprod. 2006; 21: 1453-1460Crossref PubMed Scopus (55) Google Scholar). In addition, a decline in VEGF protein secretion (11Garcia-Velasco J.A. Zuniga A. Pacheco A. Gomez R. Simon C. Pellicer A. Coasting acts through downregulation of VEGF gene expression and protein secretion.Hum Reprod. 2004; 19: 1530-1538Crossref PubMed Scopus (49) Google Scholar, 12Tozer A.J. Iles R.K. Iammarrone E. Gillott C.M. Al-Shawaf T. Grudzinskas J.G. The effects of "coasting" on follicular fluid concentrations of vascular endothelial growth factor in women at risk of developing ovarian hyperstimulation syndrome.Hum Reprod. 2004; 19: 522-528Crossref PubMed Scopus (29) Google Scholar) and gene expression (11Garcia-Velasco J.A. Zuniga A. Pacheco A. Gomez R. Simon C. Pellicer A. Coasting acts through downregulation of VEGF gene expression and protein secretion.Hum Reprod. 2004; 19: 1530-1538Crossref PubMed Scopus (49) Google Scholar) take place after coasting in granulose cells. Our studies have shown that the blockage of VEGFR-2 with SU5416 (VEGFR-2 inhibitor) reverses the increase in vascular permeability caused by the hCG (13Gómez R. Simón C. Remohí 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). However, low doses of carbegoline block hyperpermeability not only in the rat OHSS model (14Gomez R. Gonzalez-Izquierdo M. Zimmermann R.C. Novella-Maestre E. Alonso-Muriel I. Sanchez-Criado J. 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), but also under similar conditions in humans (15Alvarez C. Martí-Bonmatí L. Novella-Maestre E. Sanz R. Gómez R. Fernández-Sánchez M. et al.Dopamine agonist cabergoline reduces hemoconcentration and ascites in hyperstimulated women undergoing assisted reproduction.J Clin Endocrinol Metab. 2007; 92: 2931-2937Crossref PubMed Scopus (160) Google Scholar). Serum and ascitis fluid levels of interleukin-1 (IL-1), IL-2, IL6, and IL-8 were also elevated, but accumulating evidence does not support a pivotal role in the pathogenesis of OHSS (16Pellicer A. Albert C. Mercader A. Bonilla-Musoles F. Remohí J. Simón C. The pathogenesis of ovarian hyperstimulation syndrome: in vivo studies investigating the role of interleukin-1beta, interleukin-6, and vascular endothelial growth factor.Fertil Steril. 1999; 71: 482-489Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 17Aboulghar M.A. Mansour R.T. Serour G.I. El Helw B.A. Shaarawy M. Elevated levels of inter
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