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Instituto Valenciano de Infertilidad (C.A., E.N.-M., R.G., M.F.-S., C.S., A.P.), University of Valencia; Departments of Obstetrics and Gynecology (A.P.) and Radiology (L.M.-B.), Hospital Universitario Doctor Peset, University of Valencia; and Department of Radiology (L.M.-B., R.S.), Hospital Quirón, 46015 Valencia, Spain
Address all correspondence and requests for reprints to: Prof. Antonio Pellicer, Instituto Valenciano de Infertilidad, Plaza de la Policía Local, 3, 46015 Valencia, Spain. E-mail: apellicer{at}ivi.es; antonio.pellicer{at}uv.es.
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Abstract |
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Objective: Our objective was to test whether Cb2 reduces VP and prevents OHSS in humans.
Design: We conducted a prospective, randomized, double-blind study on oocyte donors at risk of developing OHSS (>20 follicles, >12 mm developed, and >20 oocytes retrieved).
Interventions: Cb2 0.5 mg/d (n = 37) or a placebo (n = 32) was administered from the day of human chorionic gonadotropin (d 0) until d 8. Ascites (a pocket of peritoneal fluid > 9 cm2 in lithotomy position), hemoconcentration, and serum prolactin were recorded. Pharmacokinetic studies with magnetic resonance employing the transfer constant rate (Ktrans, measure of permeability) and the extravascular extracellular space (
e, marker of cellular leakage) were performed to measure VP objectively.
Results: Hematocrit (P < 0.01), hemoglobin (P = 0.003), and ascites (P = 0.005) were significantly lower on d 4 and 6 after treatment with Cb2 as compared with placebo. The incidence of moderate OHSS was 20.0 and 43.8%, respectively (P = 0.04). Magnetic resonance studies showed an increase in VP and extravascular leakage of fluid 5 d after human chorionic gonadotropin injection that was significantly prevented with Cb2 (Ktrans P = 0.04 and e P = 0.001, respectively).
Conclusions: Given that Cb2 is a well-established and safe medication, this study provides proof of concept for the use of dopamine agonists in the prevention of OHSS in women undergoing assisted reproduction.
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Introduction |
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The development of OHSS after controlled ovarian hyperstimulation with gonadotropins requires the administration of human chorionic gonadotropin (hCG) because the syndrome does not develop if hCG is withheld (5). Because hCG has no vasoactive activity, the angiogenic molecule vascular endothelial growth factor (VEGF) is the most important mediator of hCG-dependent ovarian angiogenesis. It is known that VEGF is expressed in human ovaries (6) and that VEGF mRNA levels increase after hCG administration in granulosa cells (7, 8), whereas elevated levels of secreted proteins are detected in serum, plasma, and peritoneal fluids in women at risk or with OHSS (9). VEGF stimulates new blood vessel development and vascular hyperpermeability by interacting with its VEGF receptor 2 (VEGFR-2) (10, 11, 12).
To demonstrate functionally the importance of the VEGF/VEGFR-2 pathway in OHSS, we showed in rodents that increased VP is due to overexpression of VEGF and VEGFR-2 in the ovaries (13, 14) and that this increase in VP is reversed by SU5416 (13), a compound that blocks the intracellular phosphorylation of VEGFR-2. Due to its side effects (thromboembolism and vomiting) (15, 16) and the possibility of its interference with early pregnancy development by altering implantation-related ovarian and uterine angiogenesis, this type of drug cannot be employed in the clinical treatment of OHSS.
In another series of experiments, we reversed gonadotropin-increased VP by employing the dopamine (Dp) agonist cabergoline (Cb2), a substance with high affinity for the Dp-receptor 2 (Dp-r2) (17), based on the finding that the gene coding for the enzyme tyrosine hydroxylase, which is critical for Dp production, was down-regulated 8-fold in OHSS conditions (18). Cb2 administered after the hCG injection blocked an increase in VP. We also demonstrated that the effects of Cb2 were derived from VEGFR-2 dephosphorylation, concluding that Cb2 may provide a new, specific, and nontoxic approach to the treatment of OHSS (19).
The next step is to apply the concept to humans. It is important to find a noninvasive method to confirm changes in VP objectively, as we were able to demonstrate in rats (13, 14, 19). Pharmacokinetic modeling of images obtained after the rapid administration of low-molecular-weight gadolinium chelates employing dynamic contrast-enhanced magnetic resonance (MR) imaging, is widely used in the diagnosis and staging of pathological changes and shows great potential as a method for disease classification and monitoring responses to treatment (20).
Data regarding vascular volume and permeability can be obtained through pharmacokinetic modeling analysis of the tissue kinetics of MR contrast agents. When a contrast agent is injected iv, it rapidly occupies the vascular space and then diffuses into the interstitial space (21). Because this technique is noninvasive, the ovaries can be monitored longitudinally over a period of time to study the different vascular changes induced by a therapy.
The present study was designed to provide clinical confirmation of Cb2’s value as a new approach in the prevention of increased VP and hemoconcentration, both signs of OHSS in humans, and to explore its mechanism of action. To this end, a prospective, randomized, placebo-controlled study was designed in which Cb2 was employed in women at risk of OHSS after gonadotropin administration. Simultaneously, ovarian perfusion was assessed in these patients using MR pharmacokinetic modeling.
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Patients and Methods |
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This study included 82 oocyte donors between April 2004 and July 2006, it was approved by our institution’s ethical committee, and all participants signed a written consent form. The protocol for controlled ovarian hyperstimulation has previously been described (22), and coasting was considered an exclusion criterion. Only patients at risk of developing OHSS, defined by the development of 20–30 follicles larger than 12 mm in diameter and retrieval of more than 20 oocytes, were included. Once the decision to administer hCG was taken, patients were immediately allocated into two groups based on a computer randomization; the study group initially consisted of 41 patients, but six of these were discarded after randomization because fewer than 20 oocytes were retrieved. Thus, a remaining total of 35 patients received one 0.5-mg tablet of Cb2 daily for 8 d. The control group was also initially composed of 41 women. However, seven of these did not meet the criteria of number of oocytes retrieved, and two donors decided to withdraw themselves from the study. This left a remaining total of 32 women receiving a placebo tablet daily for 8 d. Women were monitored every 48 h from the day of hCG (d 0) until d 8.
On d 4 after hCG, provided that there was a certain degree of fluid in the pouch of Douglas after ovum pick-up, we employed transvaginal ultrasound (TVU) to measure two major perpendicular diameters of fluid pockets in 15 donors who showed no risk of OHSS. We observed 3.5 ± 2.8 cm2 of fluid in the pelvis after pick-up as a routine finding. Therefore, the existence of ascites was confirmed when a pocket of peritoneal fluid larger than 9 cm2 was observed when the patient was in lithotomy position (with the gynecological table always at 45° from the floor of the room), which is the result of the mean ± 2 SD of the value found in non-OHSS candidates. TVU scans were performed by the same researcher (C.A.), who was blind to the treatment to which the patient was submitted. A 6.5-MHz vaginal probe (Voluson 730 Pro V; General Electric, Madrid, Spain) was used for all TVU scans.
To evaluate the risk of hemoconcentration, we measured hemoglobin, hematocrit, and leukocyte count. Moreover, renal (creatinine) and liver [transaminases: aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] functions, and electrolytes (Na and K) were analyzed to ascertain the severity of the syndrome.
We centered our attention on analyzing the incidence of moderate and severe OHSS, which were identified according to our modified (23) classification of Golan et al. (24). Moderate OHSS was confirmed when a patient presented ultrasonographic evidence of ascites, whereas diagnosis of severe OHSS required clinical evidence of ascites and/or hydrothorax and breathing difficulties or one of the following criteria: 1) increased blood viscosity, i.e. hemoglobin at least 15 g/dl, hematocrit at least 45%, or leukocyte count at least 20,000/mm3; 2) coagulation abnormality; 3) diminished renal perfusion and function (serum creatinine levels > 1.2 mg/dl); or 4) liver dysfunction, defined when transaminases (AST or ALT) were more than 40 U/ml (23, 24).
Additionally, serum prolactin (PRL) levels were measured and adverse drug reactions recorded. An end-of-study assessment was scheduled 7–10 d after the last dose of Cb2/placebo.
RT-PCR and TaqMan PCR assays
Because this was the first attempt at identifying the presence of Dp-r2 in human ovaries, we quantified Dp-r2 mRNA using a previously employed RT-PCR assay (13, 14, 20) and an assay involving TaqMan technology, which is a more sensitive and specific method than conventional RT-PCR (25).
In the first eight patients included in the study, follicular fluid aspirates without obvious blood contamination were collected, pooled, and centrifuged for 10 min at 2000 rpm. Supernatants were eliminated and the pellets directly homogenized in Trizol (Life Technologies, Inc./BRL, Gaithersburg, MD) according to the manufacturer’s instructions and cryopreserved at –80 C. Once the clinical trial was completed, three samples from placebo-treated women were further processed. Nucleic acids were extracted as previously described (13, 14, 20), and the total extracted RNA was purified using an RNA purification kit (RNeasy MiniElute Cleanup Kit 50; QIAGEN, Valencia, CA), including a DNase I treatment of the sample. RNA quantity and quality were determined by the Lab on a Chip technique (Agilent 2100 Bioanalyzer).
RT-PCR
Dp-r2 granulosa cell mRNA expression was quantified using the DNA thermocycler (LightCycler 2.0; Roche Diagnostics GmbH, Mannheim, Germany), specific primers, and universal PCR conditions, as previously described (13, 14, 20). The SYBR Green I double-stranded DNA binding dye (Roche) was chosen for these assays. Mitochondrial ribosomal protein L19 (MRPL19) was used as the internal expression control (26). The sequence of PCR primers for MRPL19 and Dp-r2 were as follows: MRPL19 primers, 5'-AGGCTCGCCTCTAGTGTCCT-3' and 5'-GGATGATCAGCCCATCTTTG-3', and Dp-r2 primers, 5'-CATCGC-TGTCATCGTCTTCG-3' and 5'-CTGCGAGGCTGACGATCA-3' (GenBank accession no. M29066). For quantitative PCR analysis, a relative standard curve was performed for each gene-specific primer pair, using as template serial dilutions of the cDNA obtained from the human umbilical vein endothelial cells (HUVEC) cell line (positive control) and sarcoma 180 tumor cells (S-180) (negative control) (27).
TaqMan RT-PCR
Duplicate TaqMan PCR assays for the Dp-r2 gene target were performed on cDNA samples in 96-well optical plates in an ABI Prism 7900 Sequence Detection system (PE Applied Biosystems, Foster City, CA). For the Dp-r2 gene, a predeveloped TaqMan PCR assay (Hs00241436_m1) was purchased from Applied BioSystems, in addition to the housekeeping 18S rRNA (Hs99999901_s1), which was used to normalize the target gene cycle threshold values. S-180 and HUVEC were used as controls (28) and to compare results (calibrator). For each 20-µl TaqMan reaction, 2.3 µl cDNA was mixed with 6.7 µl PCR-grade water, 10 µl TaqMan Universal PCR Master Mix (Applied Biosystems), and 1 µl 20x assay-on-demand containing the gene-specific primers and probe. PCR conditions were as follows: 10 min at 95 C for enzyme activation, followed by 40 two-step cycles (15 sec at 95 C and 1 min at 60 C). Final results, expressed as n-fold differences in Dp-r2 gene expression relative to the 18S rRNA gene and the calibrator, were determined as 2–
Ct (28).
MR studies
Dynamic contrast-enhanced MR was performed at three different stages of the study on six women in the study group and four controls selected at random: at baseline before gonadotropin administration was initiated, just before hCG injection, and on d 5 after hCG after oocyte pick-up.
Contrast-enhanced image sequence
MR images were obtained with a 1.5-T magnet (Philips Gyroscan Intera; Philips, Eindhoven, The Netherlands). The MR sequence was a dynamic contrast-enhanced spoiled T1-weighted fast gradient echo (repetition time = 71.3 msec, echo time = 1.13 msec, flip angle = 60°, and parallel imaging). Each dynamic set consisted of 20 slices of 6 mm thickness and 0.74 x 0.74 pixel size. The total number of dynamics was 50. The scan duration per dynamic was 4.4 sec, with a total scan duration of 5 min 35 sec.
Contrast media administration began after completion of the third dynamic. A dose of 0.2 ml/kg of the contrast agent (Gd-DTPA-BMA, Omniscan; GE Healthcare, Cork, Ireland) was injected iv at a rate of 4 ml/s, followed by a 40-ml saline flush.
Image analysis
Perfusion analysis was performed using our personally devised software. Ovaries were selected by means of a manually defined region of interest. For each region of interest, quantitative modeling parameters were calculated by applying a compartment model analysis to the tissue time-contrast medium concentration curve. Both ovaries were analyzed independently and then averaged. The arterial input function was defined at the internal iliac artery that was ipsilateral to the analyzed ovary. Signal intensity values were converted to concentration values using a third-order polynomial (20). To ensure that the initial concentration value was nullified, the first four values of the curves were averaged and subtracted from the whole series. Because we knew some pixels represented fluid within the cysts, those with fewer than 3 SD from baseline after contrast administration were excluded.
Concentration vs. time curves were then interpolated and introduced in the one-input, one-compartment model (21). The concentration of the contrast agent was expressed in terms of variation of the relaxation rate. The Levenburg-Marquardt least-squares method was selected for the resolution of the nonlinear equations system, based on the quality and amount of experimental points available (20).
Several pharmacodynamic parameters were available: transfer constant rate (Ktrans), rate constant (kep), and extravascular extracellular space (e) (21). Ktrans is the endothelial permeability surface area product and can be considered a measurement of permeability. The extravascular extracellular space (e) is the percentage of the unit volume of tissue occupied by the leakage space, formerly called leakage space. The e was calculated as the ratio Ktrans/ kep. We used Ktrans and e as the analyzed pharmacokinetic parameters because they do not depend on the shape of the tracer concentration vs. time data, as does kep, but on absolute values of the tracer concentration.
Values for each MR acquisition were calculated by averaging the results obtained in each ovary and were measured three times. The units of Ktrans (min–1) were converted to the more familiar blood flow units ml min–1 100 ml–1, whereas e does not have units. The parameter kep was used to calculate e and to exclude pixels with errors (Ktrans < kep). Figure 1
represents the ovarian perfusion studies.
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Statistical analyses were performed using the Statistical Package for Social Science version 12.0 (SPSS Inc., Chicago, IL), The study was designed to detect differences in the rate of moderate OHSS between treatment and placebo groups, assuming that the overall incidence would be 15–20% (1, 2). No attempt was made to analyze differences in severe OHSS due to its low incidence of 0.5–5.0% (1, 2). Our study required a sample size of 30 patients per group to exclude differences with Cb2 treatment that were higher than 50% via a one-sided test with an 
-risk of 5% and ß-risk of 15% (statistical power = 85%) Categorical data were expressed as number and percentage, and numerical data as mean ± SEM, except when specified. Student’s t test, 
2 test, and Fisher’s exact test were used when appropriate. Significance was defined as P < 0.05.
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Results |
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RT-PCR revealed expression of Dp-2r in granulosa-luteal cells of two of the women (Fig. 2A). Quantification of Dp-r2 mRNA expression by RT-PCR (Fig. 2B) and TaqMan (Fig. 2C) revealed marked differences among the patients. The samples G2 (4.1 ± 0.7) and G3 (3.2 ± 0.1) showed that Dp-r2 was four and three times overexpressed with respect to HUVEC (1.0 ± 0.3), respectively, employing TaqMan (Fig. 2C).
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A total of 63 women received 2.0 ± 0.04 embryos resulting from oocytes displayed by donors in the Cb2 group, and 50 recipients received 1.9 ± 0.05 embryos in the placebo group [not significant (NS)]. Implantation rates were, respectively, 33.1 and 35.0% (NS), resulting in clinical pregnancy rates of 46.0 and 50.0% (NS) and ongoing-term pregnancy rates of 34.9 and 42.0% (NS), respectively.
Figure 3 shows significantly lower (P < 0.0001) serum PRL levels in the study group than among controls on d 2, 4, 6, and 8. No differences were detected between Cb2 and placebo patients with respect to age (24.6 ± 0.7 vs. 24.0 ± 0.8 yr), serum estradiol on the day of hCG administration (3287 ± 193 vs. 3078 ± 165 pg/ml), number of oocytes retrieved (28.3 ± 1.2 vs. 26.6 ± 1.1), or body mass index (22.1 ± 0.4 vs. 22.2 ± 0.5). Similarly, side effects were comparable in the two groups (eight Cb2 and four placebo).
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). These patients were considered to have severe OHSS. Nine subjects presented ultrasonographic evidence of ascites, but two of the four women diagnosed with severe OHSS had no ascites. Thus, the total number of patients in this group having moderate OHSS was seven (20%), whereas four (11.4%) were considered to have severe OHSS (Table 1).
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Figure 4, A and B, shows changes in hematocrit and hemoglobin. Patients treated with Cb2 displayed a significant decrease in both hematocrit (P < 0.01) and hemoglobin (P = 0.003) after 4 and 6 d of treatment. The amount of ascitic fluid accumulated is shown in Fig. 4C. On d 4 and 6, the presence of ascites was found to have decreased significantly in the Cb2 group (P = 0.01) but not in the placebo.
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Figure 5 shows that there was no difference in the Ktrans and e values for either treatment or placebo group at the time of baseline study (P = 0.6 and 0.9, respectively). Similarly, on the day of hCG administration, no significant difference in Ktrans and e values was found (P = 0.08 and 0.9, respectively). However, the pharmacokinetic parameters obtained after treatment showed the Ktrans value significantly (P = 0.04) higher in the placebo group (Fig. 5A) and the e value significantly (P = 0.001) increased among the placebo-treated patients (Fig. 5B).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The action of Cb2 on the ovaries seems to be mediated through activation of Dp-r2, because endogenous PRL secretion, a marker of Dp-r2 activity, was consistently reduced by the administration of said agonist. The presence of Dp-r2 in human granulosa-luteal cells was confirmed by two different molecular methods. To our knowledge, this is the first report that describes Dp-r2 in human ovarian cells. Moreover, quantification of Dp-r2 mRNA expression showed variations among patients that may explain, at least in part, any variations in responses to Dp agonists in subsequent clinical trials.
Previous inconclusive reports in the literature have suggested that this approach may be effective. Ferraretti et al. (29) described an improvement in urinary output and overall symptoms in seven critically ill patients after iv Dp infusion. Tsunoda et al. (30) administered docarpamine, an oral Dp prodrug, in 27 hospitalized patients and reported a subsequent gradual improvement in urinary output and ascites. Similarly, Manno et al. (31) began administering Cb2 at a dose of 1 mg/48 h, on the evening after pick-up, to 20 patients at risk of hyperstimulation and to 10 severely hyperstimulated pregnant women after 24–48 h Dp infusion. They reported an absence of OHSS and a prompt improvement in hospitalized patients (31). However, it must be said that a lack of appropriate controls characterized all these studies, and moreover, the mechanism underlying a potential beneficial effect of Dp agonists was not explored.
Furthermore, Papaleo et al. (32) administered Cb2 to a group of women with polycystic ovarian disease and hyperprolactinemia during ovarian stimulation. They observed a reduced incidence of OHSS. In addition, pituitary adenomas have been associated with plurihormonal production, including FSH, thereby inducing spontaneous OHSS, which has been successfully treated with Cb2 (33).
The dose of 0.5 mg/d (total dose of 4 mg) of Cb2 applied in this study was based on past experience with our rodent studies and on the average dose used to treat prolactinomas according to the literature (34). Published reports have used up to 7 mg/wk (35), and the potential adverse and teratogenic effects of Cb2 administration in early pregnancy have been ruled out in humans. Therefore, we firmly believe that our findings pave the way for future prospective, randomized, placebo-controlled studies in which implantation of a human embryo is the ultimate goal. Moreover, we did not observe a significant increase in side effects in Cb2-treated women as opposed to placebo subjects.
In the present study, quantitative dynamic contrast-enhanced MR imaging was used for the first time, as a noninvasive method, to test the effects of gonadotropin stimulation. An increase in the Ktrans in patients receiving a placebo was observed, whereas those receiving Cb2 displayed slightly lower values before administration of hCG and significantly lower values after administration. Ktrans determines the amount of tracer that enters the extravascular extracellular space (21) and, therefore, is related to permeability. Because the capillary wall was less permeable under Cb2 treatment, the volume occupied by the extravascular extracellular space as a fraction of the total tissue volume (e) decreased. Whereas both Cb2- and placebo-treated women showed no changes in ovarian vascular permeability or leakage of fluid into the extravascular space after GnRH-a administration, or even after ovarian stimulation with FSH and/or human menopausal gonadotropin, hCG induced significant increases in both pharmacokinetic markers in patients receiving the placebo. This goes a long way to explain why withholding hCG prevents OHSS in at-risk women after a high and uncontrolled response to gonadotropins.
We measured hematocrit, hemoglobin, and leukocyte concentrations as biological markers of hemoconcentration, which is considered to be the best indicator of the severity of OHSS (36). Similarly, hepatic and renal functions were evaluated because both have been reported to become altered in severe cases of OHSS (37). Although none of these markers was dangerously elevated in our patients, largely because we took care to avoid excessive hyperstimulation of our donors, some did exceed the cutoff values established and fell into the category of severe OHSS. Surprisingly, patients from both groups with hemoconcentration and/or liver disorders did not have ascites. As a result, Table 1
shows no difference between groups in the incidence of severe OHSS. Moreover, as stated above, the study was not planned to measure differences in severe OHSS because of its low incidence (1, 2).
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Acknowledgments |
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Footnotes |
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Disclosure Statement: The authors have nothing to declare.
First Published Online April 24, 2007
Abbreviations: ALT, Alanine aminotransferase; AST, aspartate aminotransferase; Cb2, cabergoline; Dp, dopamine; Dp-r2, dopamine receptor 2; e, extravascular extracellular space; hCG, human chorionic gonadotropin; HUVEC, human umbilical vein endothelial cells; kep, rate constant; Ktrans, transfer constant rate; MR, magnetic resonance; MRPL19, mitochondrial ribosomal protein L19; NS, not significant; OHSS, ovarian hyperstimulation syndrome; PRL, prolactin; S-180, sarcoma 180 tumor cells; TVU, transvaginal ultrasound; VEGF, vascular endothelial growth factor; VEGFR-2, VEGF receptor 2; VP, vascular permeability.
Received February 27, 2007.
Accepted April 16, 2007.
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