Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of controlled ovarian stimulation in patients undergoing an assisted reproductive technique. The pathophysiology of OHSS is not fully understood; however, increased capillary permeability with a resultant third space fluid loss appears to be the main feature 1. Many substances involved in vascular permeability regulation have been investigated as potential causes of OHSS 2; however, vascular endothelial growth factor (VEGF) has emerged as the main substance implicated in its pathogenesis 3. VEGF exhibits both vasoactive properties and increased ovarian expression during the pathogenesis of OHSS, suggesting that it plays a major role in the development of this potentially life-threatening condition 3. Investigators have found a strong correlation between ovarian mRNA VEGF expression and an increase in VEGF receptor-2 (VEGFR-2) and OHSS development 4–6.
Cabergoline, an ergot derivative, is a potent dopamine receptor agonist on D2 receptors. It has been found to reverse VEGFR-2-induced vascular permeability 4–6, and has been found to reduce the incidence of moderate OHSS when compared with placebo in in-vitro fertilization (IVF) patients at risk of OHSS 7,8 without affecting implantation and pregnancy rates in IVF patients 9. Cabergoline, however, when administered chronically to patients with Parkinson’s disease, has been associated with valvular heart disease 10 and with valvular fibrotic changes when given at lower doses to patients with prolactinomas 11.
Quinagolide is a non-ergot-derived dopamine D2 receptor agonist that is used to treat patients with prolactinomas. Quinagolide has a much shorter half-life of about 17 h compared with cabergoline, which has a half-life of 60–69 h 12, thus avoiding any theoretical risks on organogenesis when used in IVF patients to prevent OHSS. Quinagolide also has no effect on the serotonin [5-hydroxytryptamine (5-HT)] receptor subtype 5-HT2b, the stimulation of which in the cardiac valve tissue may lead to fibroblast proliferation and subsequent valve damage 13,14. The potentially higher safety profile of quinagolide compared with cabergoline because of these two features makes quinagolide a potential candidate to be used in the prevention of OHSS.
The aim of the present study was to compare quinagolide with cabergoline in the prevention of OHSS in at-risk patients undergoing IVF treatments and to compare the pregnancy rate, the tolerability and the complication rate of the two drugs.
Patients and methods
The present study was carried out at a private assisted conception unit (Hayat Fertility and Women’s Health Center, Cairo, Egypt) on patients scheduled for IVF/intracytoplasmic sperm injection (ICSI) treatment from June 2011 to December 2012. The internal ethics committee of our unit approved the protocol of the study and all recruited patients signed informed consent forms before enrollment in the study. Patients were considered at risk of OHSS and offered enrollment in the study if they had more than 20 follicles more than 12 mm in size and serum E2 more than 3000 pg/ml on the day of human chorionic gonadotrophin (hCG) administration. Patients with more than 30 follicles or with serum E2 more than 6000 pg/ml were excluded from the study because they were considered at too high a risk of OHSS and were thus assigned either cycle cancellation or coasting as deemed appropriate. Recruited patients were randomized using computer-generated random tables into two groups: group I patients received quinagolide 75 µg (Norprolac; Novartis Pharma, Basel, Switzerland) and group II patients received cabergoline 0.5 mg (Dostinex; Pfizer Inc., Pfizer, New York, USA) for 8 days starting from the day of hCG injection.
The patients recruited had a long luteal agonist protocol using a GnRH agonist (Decapeptyl 0.1 mg; Ferring GmbH, Keil, Germany). After pituitary downregulation, all included patients were started on 150–225 IU of purified urinary human menopausal gonadotropin (Fostimon IBSA, Switzerland; Merional IBSA, Lagouna, Switzerland) with the dose adjusted according to the patient’s response. All patients included in the study received 5000 IU of hCG IM (Choriomon IBSA, Lagouna, Switzerland or Pregnyl; Organon, Chicago, USA) for triggering ovulation 36 h before oocyte retrieval when at least three follicles reached 18 mm in size and then had IVF or ICSI procedure (for severe semen abnormalities) followed by day-3 embryo transfer. All patients had a maximum of three embryos transferred per cycle. Natural progesterone (Prontogest, 200 mg; Marcyrl Pharmaceutical Industries, Cairo, Egypt) rectal suppository twice daily was used for luteal support starting on the day of oocyte retrieval.
All recruited patients were evaluated for symptoms and signs of OHSS using a structured form starting on the day of oocyte retrieval, on the day of embryo transfer and 6 and 10 days after oocyte retrieval to detect early (<10 days after hCG injection) and late (10 or more days after hCG injection) OHSS. The severity of OHSS was classified as mild, moderate, severe or critical requiring intensive care therapy on the basis of the classification suggested by Navot et al. 15. The patient’s vital signs and weight were recorded at every visit, and blood samples were obtained to detect hemoconcentration, hepatic or renal impairment and the coagulation profile in suspected severe cases. Transvaginal and transabdominal ultrasound was used to measure the ovarian volume and to estimate the volume of pelvic free fluid. Nausea and vomiting were not considered as symptoms of OHSS in this study as both cabergoline and quinagolide can commonly cause these symptoms and thus they could not be attributed to OHSS with certainty.
Pregnancy detection was by routine serum hCG measurement on day 14 after oocyte retrieval. Patients with a positive hCG had a transvaginal ultrasound 14 days later to detect the site of the pregnancy, as well as the number of gestational sac(s) and to document fetal cardiac activity. Follow-up transvaginal ultrasounds were performed as needed to determine viability.
Normality of data was tested for all continuous variables using the Shapiro–Wilk test. Normally distributed parameters are given as mean and SD, and non-normally distributed values are given as the median (range). Statistical comparisons between the two groups was made using the Mann–Whitney U-test for continuous data and the χ 2-test for parametric data. A P value of less than 0.05 was considered statistically significant. Statistical analysis was performed using the commercially available software [Excel 2010; Microsoft Corp., Redmond, Washington, USA; and Arcus QuickStat (Biomedical) version 1.0, Cambridge, UK].
A total of 112 patients undergoing IVF/ICSI cycles were included in the present study with 56 patients randomized to each treatment group. There was no difference between the two groups regarding their age, BMI, the duration or the cause of infertility as shown in Table 1. The two groups also showed no difference in the days of stimulation needed to achieve mature follicles, the level of serum E2 on the day of hCG injection, fertilization and the clinical pregnancy rate (Table 1).
The total number of patients who developed OHSS in our study was similar in the two groups, with nine (16.1%) patients in the quinagolide group compared with 11 (19.6%) in the cabergoline group (P=0.81). However, the majority of these patients developed only mild OHSS comprising 5/9 (55.6%) in the quinagolide group and 7/11 (63.6%) in the cabergoline group. There was no statistical difference between the two groups regarding the incidence of early OHSS (P=0.77) or late OHSS (P=1.0). Severe/critical grades of OHSS occurred in only 2/56 (3.6%) of the cases in the quinagolide group and 1/56 (1.8%) cases in the cabergoline group, whereas the incidence of moderate OHSS was 3.6 and 5.4% in the quinagolide and the cabergoline groups, respectively.
The side effects attributed to the two drugs, cabergoline and quinagolide, used by patients of the two groups are compared in Table 2. Quinagolide was responsible for significantly more nausea (P=0.03) and vomiting (P=0.009) than cabergoline, but there was no statistically significant difference between the two groups regarding the other side effects. None of the patients in either group dropped out of the study or declared that they had discontinued their allocated medication including the patients who reported severe side-effect.
The main outcome measure in the present study was the difference in the incidence of OHSS between the patients of the two study groups as shown in Table 3. Only two cases in the quinagolide group required hospitalization (one severe and one1 critical OHSS), and similarly, only the one severe case of OHSS in the cabergoline required hospital treatment. All hospitalized cases were subsequently discharged after improvement of their condition.
In this prospective randomized study, 112 patients undergoing IVF/ICSI treatment considered to be at risk of OHSS were randomized to receive either 0.5 mg cabergoline or 75 µg quinagolide daily for 8 days starting on the day of hCG injection in an attempt to prevent the development of this potentially life-threatening condition. To our knowledge, this is the first randomized trial to compare these two drugs for the prevention of OHSS.
The dose of cabergoline used in our study was based on a previously published study by Alvarez et al. 7, who found that 0.5 mg cabergoline daily for 8 days could help reduce the incidence and severity of OHSS, whereas the dose of quinagolide chosen was based on the available drug formulation in the Egyptian market, which is as a 75 µg tablet only. The price of a single tablet of 75 µg quinagolide is 3.9 Egyptian Pounds (L.E.), which is significantly cheaper than cabergoline, which costs 37.5 L.E./0.5 mg tablet.
A recently published systematic review on randomized trials comparing cabergoline with placebo or no treatment in the prevention of OHSS found considerable variation in the dose of cabergoline used (0.25–0.5 mg) and the duration and frequency of administration. However, reviewers found that all the examined evidence suggests that prophylactic treatment with cabergoline reduced the incidence of OHSS with an absolute risk reduction of 12% 16 without any harmful effect on implantation and pregnancy rates.
In our study, quinagolide was responsible for a significantly higher rate of nausea (P=0.003) and vomiting (0.009) than cabergoline; however, these symptoms were controlled by antiemetics and did not cause the patients to discontinue treatment. Our results are in agreement with the study by Busso et al. 12, who noted that upper gastrointestinal symptoms, especially nausea and vomiting, were more frequently encountered in the quinagolide group than in the placebo group, especially when given in high doses.
Busso et al. 12 conducted a randomized double-blind placebo-controlled trial to evaluate the role of quinagolide at different doses in the prevention of early OHSS. They found, similar to our study, that quinagolide when given in the three dose titrations used (50, 100, 200 µg/day) was effective in reducing the incidence of moderate and severe OHSS between 4–12% and 0–1%, respectively, according to the dose given compared with placebo with no detrimental effects on pregnancy rates.
Shaltout et al. 17 performed a randomized controlled trial comparing cabergoline at a dose of 0.25 mg daily with placebo in the prevention of OHSS in at-risk patients undergoing IVF treatment. They found that cabergoline treatment significantly reduced the incidence of both moderate and severe OHSS compared with placebo. Their results regarding the incidence of moderate (4%) and severe (1%) OHSS in the group taking cabergoline were similar to the result of the cabergoline group in the present study.
There was no difference between the two study groups in the present study regarding the clinical pregnancy rate (41.1% in the quinagolide group and 39.3% in the cabergoline group, P=0.75, both of which are generally acceptable and similar to the overall pregnancy rate in our unit). Thus our results seem to be in agreement with previously published data about the absence of a negative impact on pregnancy rate by either cabergoline 16 or quinagolide 12.
The present study can be criticized for not including a placebo group. However, we found that there was a substantial body of literature 7–9,16,18, a systematic review 16 and a Cochrane Systematic review 18 that support the role of prophylactic cabergoline in the prevention of OHSS; thus, we used the cabergoline group as the reference by which to compare the efficacy of quinagolide.
In conclusion, the present study shows that quinagolide seems to be just as effective as cabergoline in the prevention of OHSS with the advantage of being substantially cheaper in the Egyptian market, not carrying a risk of cardiac valve fibrosis and having a shorter half-life, thus avoiding any potential risk on organogenesis. Further large multicenter randomized studies are needed to collaborate our findings.
Conflicts of interest
There are no conflicts of interest.
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