Hum. Reprod. Advance Access originally published online on February 17, 2006
Human Reproduction 2006 21(6):1453-1460; doi:10.1093/humrep/del005
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Plasma levels of soluble vascular endothelial growth factor receptor-1 may determine the onset of early and late ovarian hyperstimulation syndrome
1 Instituto Valenciano de Infertilidad Foundation and 2 Instituto Valenciano de Infertilidad, University of Valencia, Valencia, Spain
3 To whom correspondence should be addressed at: Instituto Valenciano de Infertilidad, Plaza Policía Local, 3, 46015, Valencia, Spain. E-mail: apellicer{at}ivi.es
* Both the authors contributed equally to patients’ recruitment, follow-up and biochemical measurements.
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Abstract |
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BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is a life-threatening condition associated with ovarian stimulation. Its pathophysiology is unknown and its treatment continues to be empirical. Early (E)- and late (L)-OHSS occur in women at risk, though not in all cases. Vascular endothelial growth factor (VEGF) is related to increased vascular permeability in OHSS. We analysed the dynamics of the VEGF system in E- and L-OHSS. METHODS: A prospective cohort of women undergoing IVF–ICSI treatment were divided into groups. E-OHSS: Nonpregnant patients classified as women not at risk (group 1) (n = 11) and patients at risk who did not (group 2) (n = 18) and did (group 3) (n = 8) develop severe OHSS. Blood was drawn on the day of ovum retrieval (day 0) and 3, 6, 10 and 14 days later. L-OHSS: Single pregnancies classified as women who did not (group 4) (n = 8) and did develop (group 5) (n = 4) OHSS. Single pregnancies after oocyte donation (OD) (n = 4) were compared with groups 4 and 5 (IVF–ICSI). Blood was obtained weekly (weeks 4–12). Total VEGF (VEFG-A), free (f)-VEGF and soluble VEGF receptor 1 (sVEGFR-1) in plasma and in serum
2-macroglobulin (M) were also measured. RESULTS: Group 3 showed significantly (P < 0.05) higher VEFG-A and f-VEGF than group 1 on day 6 because of lower sVEGFR-1 secretion. Similarly, group 5 had significantly (P < 0.05) more VEFG-A and f-VEGF and less sVEGFR-1 than group 4. Oocyte donation was associated with decreased sVEGFR-1 secretion, and 2M was not relevant in OHSS development. CONCLUSION: In E- and L-OHSS, the ability to secrete sVEGFR-1 and bind VEGF seems to be the determinant factor in OHSS. f-VEGF acts locally in the ovary.
Key words:
ovarian hyperstimulation syndrome/vascular endothelial growth factor/soluble VEGF receptor 1/free VEGF/2-macroglobulin
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Introduction |
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Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of ovulation induction which can seriously affect the health of patients, with 0.1–2% developing severe forms of the condition (Navot et al., 1992
). Incidences of OHSS have increased on a worldwide level due to the expansion of assisted reproduction techniques (ART). The aetiology of OHSS is still unclear, but it is accepted that HCG—either exogenous or endogenous (e.g. pregnancy-derived)—is the triggering factor.
There are two clear patterns in the onset of OHSS (Lyons et al., 1994). Early OHSS (E-OHSS) generally appears 3–7 days after HCG administration. In fact, when HCG is withheld (Navot et al., 1996) or replaced by an endogenous surge of LH induced with GnRH analogues (Orvieto, 2005), the incidence of E-OHSS is dramatically reduced or eliminated.
The late onset of OHSS (L-OHSS) refers to the appearance of OHSS 12–17 days after HCG administration, late on in the luteal phase, and induced by HCG produced by the implanted embryo. L-OHSS halts rapidly if the pregnancy is terminated, which confirms the pregnancy as the origin of the problem. L-OHSS causes more severe complications than E-OHSS (Navot et al., 1996; Papanikolaou et al., 2005).
The mechanism by which HCG increases vascular permeability inducing ascites and other complications of OHSS is not fully understood, but it is known that the vascular endothelial growth factor (VEGF) system, composed of ligands and receptors, plays a pivotal role in the pathophysiology of OHSS. In humans, five different VEGF mRNAs have been detected, encoding the isoforms VEGF121, VEGF145, VEGF165, VEGF189 and VEGF206 (Neufeld et al., 1999). The receptors for VEGF belong to the tyrosine kinase receptor family (De Vries et al., 1992). Two specific endothelial cell membrane receptors for VEGF have been identified—VEGFR-1 (Flt-1) and VEGFR-2 (Flk1/KDR) (Waltenberger et al., 1994; Shalaby et al., 1995). VEGFR-1 is also produced as a soluble receptor (sVEGFR-1) through the alternative splicing of the precursor mRNA (Kendall et al., 1996), acting as a modulator of VEGF bioactivity (Horning et al., 1999). In fact, the soluble molecules compete with the full length VEGFR-1 to bind with VEGF and inhibit vascular permeability (Kendall and Thomas, 1993; Roeckle et al., 1998).
The isoforms VEGF121 and VEGF165 are normal products of the ovary (Olson et al., 1994; Gómez et al., 2002). The receptors are present mainly in the endothelium but also in the ovarian follicles (Gómez et al., 2003). The soluble form has been quantified in human follicular fluid as a possible product of the ovarian capillary endothelia (Neulen et al., 2001). Other tissues are also an important source of the VEGF system. Of particular interest in the context of OHSS are blood cells (leucocytes, granulocytes, etc.) and the placenta. The contribution of blood cells to total VEGF (VEGF-A) should be evaluated by measuring molecules in the plasma rather than in the serum. The placenta is an important source of the VEGF system (Clark et al., 1998; Geva et al., 2002; Sugino et al., 2002), and its role in the development and disappearance of L-OHSS may be relevant.
There are intrinsic characteristics of patients developing OHSS, such as polycystic ovaries, young age, low BMI and history of allergies, all of which are well documented (Golan et al., 1989; Navot et al., 1992, 1996). However, it is still somewhat of a mystery why some patients develop E- and/or L-OHSS, whereas others presenting the same risk factors do not develop the syndrome. In this sense, it has been proposed that 2-macroglobulin (2M), a major serum protein associated with tissue remodelling during ovulation and corpus luteum maintenance (Gaddy-Kurten et al., 1989), may be an inhibitor of VEGF because 2M binds to VEGF (Soker et al., 1993). Thus, higher 2M levels in some patients may protect against OHSS (McElhinney et al., 2002). It is also possible that the natural VEGF inhibitor, sVEGFR-1, performs a similar, albeit complementary, function.
This study was designed to analyse the substances of the VEGF system that are relevant in the pathogenesis of E- and L-OHSS, i.e. VEFG-A, free (f)-VEGF, sVEGFR-1 and 2M in women at high risk of developing OHSS during the luteal phase and first trimester of pregnancy. The objectives of the study were (i) to compare the dynamics of these molecules in women who did/did not develop E- and L-OHSS to throw light on the pathogenesis of OHSS and (ii) to gain knowledge about the tissue(s) implicated in the secretion of these molecules during pregnancy, and specifically in L-OHSS, the most serious of the clinical situations studied. To this end, patients undergoing ART were monitored by regularly drawing blood to measure the secretion of these proteins.
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Materials and methods |
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This is a prospective cohort study of patients undergoing ART between February 2002 and October 2004. The study was approved by our Institutional Review Board, and patients included signed a written consent. The protocols for ovarian stimulation and general IVF, ICSI and oocyte donation (OD) procedures have been described elsewhere (Gil-Salom et al., 1996
; Pellicer et al., 1996; Bosch et al., 2003; Soares et al., 2005). Patients were classified after oocyte retrieval according to whether or not they were at risk of developing OHSS (Golan et al., 1989; Navot et al., 1996). The presence of multiple (>15 per ovary) small antral follicles in basal conditions (before ovarian stimulation) and the retrieval of 
20 oocytes were considered to be identifiers of a risk factor, provided that in our centre all the visible follicles are aspirated at retrieval. Serum estradiol (E2) levels were highly dependent of the use of GnRH antagonists (Bosch et al., 2003). Other risk factors, such as age, BMI and history of allergies, were evaluated (Golan et al., 1989; Navot et al., 1992, 1996) but not used as criteria for classifying the patients.
Early OHSS
To study E-OHSS, only nonpregnant patients were considered. These included unsuccessful embryo replacements, oocyte donors and cancelled transfers because of the high numbers of oocytes obtained as a strategy to avoid OHSS. Three groups were established: group 1 (n = 11) consisted of women who were considered not to be at risk of OHSS according to the number of oocytes retrieved and appearance of the ovaries in basal conditions, who in fact did not develop any degree of OHSS (Golan et al., 1989; Navot et al., 1992); group 2 (n = 18) was composed of women at risk who did not develop severe OHSS but the moderate form excluding ascites (Golan et al., 1989; Navot et al., 1992). The presence of ascites was recorded when a cul-de-sac pocket of fluid measuring at least 9 cm2 was visualized by ultrasound; group 3 (n = 8) included women at risk who developed severe OHSS (Golan et al., 1989; Navot et al., 1992), which was ascertained by the presence of ascites and at least two of the following criteria: hydrothorax, haematocrit >45%, white blood cell count >15 000, oliguria, creatinemia >1.6 mg/dl, creatinine clearance <50 ml/min or hepatic dysfunction. All of the patients in group 3 required culdocentesis to reduce ascites, which is a clear indicator of the severity of OHSS, but none reached the critical stage described by Navot et al. (1992).
The recruitment of patients in the study was as follows: women were selected at oocyte retrieval according to the number of oocytes obtained. If >20 oocytes were obtained and if women had a documented multicystic appearance of the ovaries in basal conditions, they were candidates for groups 2 and 3. For each patient candidate to groups 2 and 3, the immediately previous and/or consecutive case meeting the criteria required for group 1 was selected. Forty-nine women were initially recruited for group 1, but only 11 with the five time-points collected were finally analysed after appropriate power analysis.
A clinical evaluation, including measurement of basic blood parameters and pelvic ultrasound to evaluate ovarian size and the presence of fluid in the abdominal cavity, was performed on the day of ovum retrieval (day 0) and 3, 6 10 and 14 days later. Blood was also drawn to obtain serum and/or plasma. Blood samples collected during the study were immediately centrifuged. Aliquots of plasma and serum were stored at –20°C until they were analysed. In addition, other symptoms, such as breathing difficulties, abdominal distension and discomfort, nausea, diarrhoea and vomiting, were also recorded.
Late OHSS
To study L-OHSS, a second population of patients was considered, none of whom were included in the E-OHSS study. The recruitment prerequisite was a positive serum 
-HCG 14 days after day-3 embryo replacement and the diagnosis of a single clinical pregnancy by week 6. Patients at risk of developing L-OHSS (multicystic ovaries in basal conditions and 20 oocytes obtained) were classified into two groups: those who did not develop severe OHSS (group 4, n = 8) and those who did develop (group 5, n = 4). Initially, 10 women fulfilled the criteria to be included in group 4, but one abandoned the study and another patient miscarried. Similarly, group 5 was initially composed of nine women; three had twin pregnancies and one miscarried, all being excluded from the study. The criteria for including women in group 5 were the same as that for E-OHSS: presence of ascites in the third space which required culdocentesis. The subjects were monitored weekly to evaluate the clinical status of OHSS, and blood was drawn to measure biochemical parameters and the molecules under study.
An additional control group (n = 4) was formed from women with absent ovaries, who were diagnosed with a single clinical pregnancy following oocyte donation (OD). The study was initially composed of seven patients, but two of them carried twins and one abandoned the study. The protocol for exogenous steroid administration and overall OD procedure has been described previously (Soares et al., 2005). These patients underwent a similar follow-up protocol as those in groups 4 and 5.
Immunoassays
Plasma levels of VEGF-A (free and bound VEGF) were measured through a competitive enzyme immunoassay (ChemiKineTM human VEGF EIA KIT, Chemicon, Temecula, CA, USAa). The intra- and inter-assay coefficients of variation (CVs) were 8.9 and 11.1%, respectively. Sensitivity for this test was 0.195 ng/ml. Plasma levels of the soluble form of VEGFR-1 and f-VEGF were measured using the sandwich enzyme immunoassay technique (Bender MedSytems, Vienna, Austria). Intra- and inter-assay CVs were 8 and 10.7% for sVEGFR-1 and 5.9 and 17.7% for f-VEGF, respectively. Sensitivities for f-VEGF and sVEGFR-1 were 11 pg/ml and 0.06 ng/ml, respectively.
Serum 2M levels were determined by nephelometry using the DadeBehring BN II, standardized to the International Reference Preparation for Plasma Proteins, lot CRM 470, certified by the Bureau of Reference of the European Community (BCR). The intra- and inter-assay CVs were 5.1 and 5.6%, respectively.
Statistical analysis
Data were expressed as the mean ± SEM. Sample size was calculated to detect a mean difference in sVEGFR-1 concentration between patients exposed and not exposed to OHSS of 65 ng/ml, with a statistic power of 80% and significance defined as P = 0.05. Statistical calculations were performed using the Statistical Package for Social Sciences, version 11.0 (SPSS, Chicago, IL, USA). In E-OHSS, analysis of variance (ANOVA) was initially applied, whereas post hoc Tukey analysis was used to identify differences among the groups at each time-point. In L-OHSS, Student’s t-test was employed to find significant differences between groups. Chi-square test was employed in both studies when appropriate.
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Early OHSS
Table I summarizes the clinical characteristics of the patients included in the study. Women in group 3 were significantly (P = 0.017) younger than those in group 1. The total dose of gonadotrophins necessary to reach an optimal response was significantly (P < 0.001) higher in group 1 than in groups 2 and 3, whereas the levels of serum E2 reached on the day of HCG administration were significantly (P < 0.007) lower in group 1 than in group 2, showing a heightened sensitivity to gonadotrophins among the women in groups 2 and 3. As a consequence, the number of oocytes retrieved was also significantly higher (P < 0.001) in groups 2 and 3.
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Figure 1 shows plasma levels of VEGF-A, f-VEGF and sVEGRFR-1 during the entire luteal phase in the three groups studied. VEGF-A (Figure 1A) levels were significantly (P < 0.05) higher in group 3 than in groups 2 and 1 on day 6. Similarly, women in group 3 who developed OHSS showed significantly higher f-VEGF levels (Figure 1B) than those in group 2 (P < 0.05) on day 6. Moreover, f-VEGF levels were significantly (P < 0.05) higher at each time-point measured, when group 3 was compared with group 1. Plasma levels of sVEGFR-1 were significantly (P < 0.05) lower in group 3 than in group 2 on day 6 (Figure 1C). A clear improvement in symptomatology was observed 9–11 days after retrieval (mean 9.8 ± 0.8 days).
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3, bP < 0.05 group 1
Late OHSS
The data comparing the clinical characteristics of the women included in groups 4 and 5 are summarized in Table II. Women in group 5 who developed severe OHSS were significantly (P = 0.048) younger than those in group 4.
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Figure 2 shows a comparison of VEGF-A, f-VEGF and sVEGFR-1. Women who developed OHSS secreted significantly (P < 0.05) higher amounts of VEGF-A at 6, 9 and 12 weeks of pregnancy. Similarly, plasma f-VEGF was significantly higher in these patients during weeks 5 and 9. Panel C shows that sVEGFR-1 was lower in group 5 than in group 4 at week 9 (P < 0.05). An improvement of symptoms was observed 22–36 days after oocyte retrieval (mean 29.4 ± 5.2 days).
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All the patients in groups 4 and 5 were analysed once more as a single group named IVF–ICSI, because all these women became pregnant with their own oocytes following controlled ovarian stimulation. The secretion of the molecules under study was compared with that seen in four single pregnancies, achieved after OD in women with no ovaries. These patients were 39.5 ± 5.5 years old, with a BMI of 21.1 ± 3.6 kg/m2 and received 1.5 ± 0.5 embryos in the treatment cycle. Figure 3 shows a similar pattern of VEGF-A (Figure 3A) secretion in the IVF–ICSI and OD groups, but f-VEGF was slightly higher in the latter, reaching significance (P < 0.05) during week 7 (Figure 3B). When sVEGFR-1 was analysed, both groups showed an increase after week 7, but this enhancement was significantly (P < 0.05) higher in IVF–ICSI pregnancies (Figure 3C).
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2-Macroglobulin
Serum levels of 2M were analysed in E- and L-OHSS. Figure 4A shows the 2M levels reached in the luteal phase. No difference was found among groups 1, 2 and 3. In the L-OHSS study, serum levels of 2M were elevated in group 5, with statistical significance (P < 0.05) reached during week 9 (Figure 4B). This protein was always higher in IVF–ICSI than in OD pregnancies (Figure 4C).
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Discussion |
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The aim of the present study was to explore the pathophysiology of E- and L-OHSS provoked by the use of gonadotrophins, which represents >99% of cases. It is true that OHSS may develop when there are abnormal HCG levels in a molar pregnancy, or due to hypothyroidism with elevated serum TSH bound to the FSH receptor, or because of a mutation in the FSH receptor that binds HCG (Vasseur et al., 2003
; Montanelli et al., 2004). It is also true that L-OHSS has been described in nonpregnant women (Papanikolaou et al., 2005), but most of these cases have been a consequence of HCG administration in patients undergoing ART, particularly when they become pregnant. We have addressed the intrinsic dynamics of the VEGF system (and 2M) secretion in women who develop OHSS, with the aim of understanding why, though equally at risk, only some develop OHSS. As others have pointed out (Molskness et al., 2004), the investigation of angiogenic factors in women undergoing ovarian stimulation is complex. We have only partially addressed the plethora of angiogenic molecules that may be involved in angiogenesis during the luteal phase and early pregnancy, but our findings are of considerable interest. A group of women at risk of developing E-OHSS shared recognized characteristics such as young age and a special sensitivity to gonadotrophins, evident in the low amounts of FSH/HMG required to provoke a positive response (serum E2 and number of oocytes). However, what differed between those who developed OHSS and those who did not was the presence of excessive total and f-VEGF. This was basically due to the fact that the ovaries of women (both at risk and not at risk) who did not develop OHSS secreted higher amounts of the natural antagonist sVEGFR-1 (Figure 1C). In this way, most of the VEGF secreted by hyperstimulated ovaries was bound to sVEGFR-1 during the luteal phase in groups 1 and 2, whereas women in group 3 were unable to secrete sufficient amounts of the natural antagonist and therefore developed E-OHSS. It is true that the statistical analysis of the data only showed differences at particular time-points, but the figures show clear trends that would probably reach statistical significance with more cases included in the study. Moreover, clinical improvement was observed when the levels of sVEGFR-1 showed an approximation among groups (around day 10) (Figure 1C). It is also worth underlining that patients in group 3 displayed even lower sVEGFR-1 levels than the controls, who were not at risk. This would seem to be the intrinsic characteristic of patients who develop E-OHSS. Future studies should address the mechanisms involved in this response.
There has been controversy in the literature as to whether VEGF-A and f-VEGF may be employed as markers of OHSS in women undergoing controlled ovarian hyperstimulation (COH). Although some authors have argued in favour of such (Artini et al., 1998; Agrawal et al., 1999), others have not found a correlation between VEGF-A and OHSS (Ludwig et al., 1999; Pellicer et al., 1999). However, most of these publications measured serum VEGF rather than plasma VEGF, thereby adding the contribution of other nonreproductive cells such as granulocytes or platelets. The present study identifies a clear pattern of VEGF dynamics in OHSS: higher total and f-VEGF and lower sVEGFR-1 on day 6 after oocyte retrieval. These data confirm our previous conclusions (Pellicer et al., 1999), as there was no difference among the groups in VEGF-A or f-VEGF shortly after oocyte retrieval. However, the data were not clinically relevant because by the time the differences became evident, it was too late to employ plasma measurements of VEGF as a marker of OHSS. Our data contradict those of the only other report in the literature in which f-VEGF levels were measured (Ludwig et al., 1999), as we did not find elevated f-VEGF shortly after HCG administration.
In this study, we also addressed the phenomena involved in L-OHSS. To this end, we monitored different patients in an attempt to throw light on the mechanisms of E- and L-OHSS. Some of the patients in the L-OHSS group may also have experienced E-OHSS, but we only included those who did not attend the clinic because of discomfort. Thus, although it may be true that some of the patients in groups 4 and 5 already had OHSS when included in the study, we can verify that it was at most moderate. Only single pregnancies were recorded since the placenta has been shown to be an important organ in the expression and secretion of the different components of the VEGF system (Clark et al., 1998; Geva et al., 2002; Sugino et al., 2002).
Our study shows that women who developed L-OHSS presented higher total and f-VEGF levels than those who were also at risk, but who did not develop OHSS (Figures 2A and B). This was due to the higher amounts of sVEGFR-1 secreted in nonaffected patients. The fact that the difference in sVEGFR-1 secretion was observed after week 9 (Figure 2C) points to the placenta’s fundamental role in determining who will and who will not develop L-OHSS. Again, we would like to stress that significant differences were found only on week 9, but the trend of the slope suggests that more individuals included in the study would show significant differences at all time-points after week 9.
There was no clear correlation between improvement in symptoms and biochemical parameters in L-OHSS. The subjective nature of these symptoms especially in pregnant patients, plus the fact that culdocentesis may have an effect on them, make comparisons impossible in the present study.
Although we studied E- and L-OHSS in different populations, conclusions can be drawn from the comparison of the figures obtained in our study. First, it is clear that plasma levels of VEGF-A increase in pregnancy, probably due to the contribution of the placenta. These data confirm other studies measuring VEGF in serum (Molskness et al., 2004). Second, as others reported (Molskness et al., 2004), the amount of f-VEGF slowly decreased up to week 8, basically because the levels of the natural inhibitor sVEGFR-1 also increased once a patient became pregnant. Thus, these studies confirm the placenta as a source of VEGF (Geva et al., 2002; Sugino et al., 2002) and sVEGFR-1 (Clark et al., 1998).
The introduction of a control group of ovariectomized women undergoing successful OD has provided several interesting observations. First, it would seem that increased capillary permeability and ascites is a phenomenon restricted to the ovaries. In fact, we have shown in rodents that VEGF and VEGF-R2 expression is located in the ovaries (Gómez et al., 2002, 2003). In the present study, patients who became pregnant after OD did not hyperstimulate, despite higher f-VEGF levels. This has also been suggested by other authors who have measured the different products of the ovary (Blumenfeld et al., 1997; Itskovitz-Eldor et al., 1997). Second, the placenta of OD pregnancies was defective in terms of sVEGFR-1 secretion when compared with pregnancies achieved after IVF–ICSI, which is the main reason why f-VEGF was higher in OD during the first trimester of pregnancy. Whether the pattern of sVEGFR-1 secretion in OD was due to the fact that the ovaries were absent, or to a different expression of VEGF in these pregnancies, needs to be investigated further, given that preeclampsia is more frequent in these pregnancies (Soares et al., 2005) and that the expression of the entire system has been shown to be different in preeclamptic pregnancies, mRNA VEGF expression being three times that in normal pregnancies (Geva et al., 2002; Chung et al., 2004).
In this study, we also intended to analyse the serum pattern of 2M secretion. Its ability to bind and inactivate VEGF is well known (Soker et al., 1993; Bhattacharjee et al., 2000). McElhinney et al. (2002) have recently shown that high 2M levels protect against OHSS, suggesting that the difference in the secretion of this major serum protein determines who develops OHSS. Our work, however, shows that the secretion of 2M by the corpus luteum is not as relevant to the development of E-OHSS as has been suggested (McElhinney et al., 2002). In E-OHSS, serum 2M levels were similar in the three groups and sometimes higher in group 3 (Figure 4A). Similarly, during the L-OHSS study, serum 2M was actually higher in women who developed the syndrome, thereby negating the relevance of this protein as a natural VEGF inactivator in the pathophysiology of L-OHSS (Figure 4B). On the other hand, the study provided further evidence of 2M as a characteristic product of the corpus luteum (Gaddy-Kurten et al., 1989), as serum levels did not change before or during pregnancy, and especially when the pattern of 2M secretion was compared in pregnancies with and without functional ovaries showing much higher levels in IVF–ICSI pregnancies (Figure 4C).
In summary, our studies have shown that the factor that most determines the future development of the syndrome of E- and L-OHSS is the ability to secrete sVEGFR-1 and to reduce the availability of f-VEGF. Other VEGF-sequesters, such as 2M, are not relevant to the pathophysiology of OHSS. The entire phenomenon is restricted to the ovaries, because women who become pregnant following OD do not develop OHSS, despite their high levels of f-VEGF.
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This work was supported by FIS PI021324 of the Spanish Government. The authors are grateful to Dr Ernesto Bosch for his assistance in the statistical evaluation of the data.
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Submitted on September 27, 2005; resubmitted on November 22, 2005; accepted on November 28, 2005.
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