Document Type : Original Article
Authors
1 Infertility and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Infertility Center, Department of Obstetrics and Gynecology, Mazandaran University of Medical Sciences, Sari, Iran;Diabetes Research Center, Mazandaran University of Medical Sciences, Sari, Iran
3 4Department of Molecular and Cellular Sciences, Faculty of Advanced Sciences and Technology Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
Abstract
Keywords
Ovarian hyperstimulation syndrome (OHSS) could
be a life-threatening complication of assisted reproduction
treatment (ART) (
Raised serum estradiol levels to concentrations of
>2,500 pg/mL, and observations of large numbers of
small and intermediate-sized ovarian follicles, are signs
of high risk necessitating to proceed with great caution (
Several studies have indicated that quinagolide effectively
reduces the development of OHSS (
The present study was a parallel single-blind randomized clinical trial (IRCT2016053128187N1) with a 1:1 allocation ratio, recruiting 126 patients, who had undergone assisted reproductive procedure and were at risk of severe OHSS. The patients were randomly allocated to one of the study groups according to a random allocation sequence generated by a statistician using a computer software. The sequence was built through generating block size of 4.
The study was conducted in Infertility and Reproductive Health Research Center and Imam Hussein Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran, from March 2015 to February 2017. The project was approved by the Ethics Committee (IR.SBMU. RETECH.REC.1395.542) and institutional review board of Shahid Beheshti University of Medical Sciences, Tehran, Iran, and it was initiated after obtaining written informed consents from all participants. Randomization on the day of gonadotropin-releasing hormone (GnRH) agonist administration was based on a computer-generated random list which determined the random allocation of the subjects into the two groups.
Selection and randomization of the patients were
performed by a nurse, using a series of sequentially
numbered sealed envelopes; therefore, the sequence of
allocation was hidden. The study was single-blinded,
because the physicians were blind to the treatment
group, but the patients were aware of the management
option (
In this study, patients of 20-40 years old, who had 20 oocytes and serum estradiol levels of >3000 pg/ml on the day of GnRH agonist injection during ICSI cycles, were recruited. The inclusion criteria were being at high risk of developing OHSS and not having hepatic dysfunction, hypertension and a history of syncope. All participants underwent controlled ovarian hyperstimulation (COH) with gonadotropin/GnRH-antagonist protocol. Ovarian stimulation using recombinant-follicle-stimulating hormone (FSH, GONAL-f, Serono, Switzerland) was started on day 3 of cycle at a dose of 150 IU per day.
Transvaginal ultrasound was performed every 3 days to examine the follicular development. Also, serum estradiol levels were measured every 2-3 days using radioimmunoassay method. After 5 days of stimulation, when at least two follicles with diameters of 14 mm were observed, GnRH antagonist (Cetrotide, Merk, USA) or (Orgalutran, Organon, the Netherlands) was started with a daily dose of 0.25 mg until administration of GnRH agonist. Final oocyte maturation was triggered when at least two follicles with diameters of at least 17 mm were observed, using a single intramuscular injection of 0.2 mg GnRH agonist (Decapeptyl, Ferring GmbH, Germany). Oocytes were collected 36-38 hours later using transvaginal- guided follicle aspiration. All embryos were frozen after fertilization through ICSI. On day of GnRH agonist administration, patients were randomized using computer- generated random tables into two groups.
The first group comprised of 63 women, was treated with
0.5 mg cabergoline (Dostinex™, Pfizer, USA) every day
for 7 days and the second group comprised of 63 women,
was treated with quinagolide 75 mg (Norprolac™, Ferring,
Denmark) every day for 7 days. Diagnosis of OHSS
as well as determination of its severity was performed according
to Golan’s classification (
This was a randomized clinical trial study. To detect
20% difference in OHSS rates that is considered significant
(
A total of 130 women were recruited into the study.
Four women were omitted from the research due to
various reasons including declining to participate,
having hypertension, hepatic dysfunction, or history
of syncope, and discontinuing the treatment or loss to
follow-up (
Flowchart of the trial.
Clinical and hormonal characteristics of patients in two groups of patients entering the study
Variable | Quinagolide n=63 | Cabergoline n=63 | P value |
---|---|---|---|
Age (Y) | 31.63 ± 5.2 | 31.05 ± 4.4 | 0.503 |
Body mass index (BMI) | 26.4 ± 3.8 | 27.5 ± 3.2 | 0.174 |
Type of infertility | |||
Primary | 20 (31.7) | 21 (33.3) | 0.762 |
Secondary | 10 (15.8) | 11 (17.46) | 0.762 |
Cause of infertility | |||
Female factor | 3 (4.76) | 2 (3.17) | 0.644 |
Male factor | 11 (17.46) | 10 (15.87) | 0.644 |
Both (male+PCOS) | 4 (6.34) | 5 (7.93) | 0.644 |
Unexplained | 1 (1.58) | 2 (3.17) | 0.644 |
Data are presented as mean + SD or n (%). PCOS; Polycystic ovary syndrome.
The outcomes of ovarian stimulation in quinagolide and cabergoline-treated groups
Variable | Quinagolide n=63 | Cabergoline n=63 | Effect (95% CI) | P value |
---|---|---|---|---|
E2 on day of GnRH agonist (pg/ml) | 3293.74 ± 3836.9 | 3615.79 ± 1473.5 | 0.11 (-0.24-0.46) | 0.304 |
HB (g/dl) | 12.10 ± 1.42 | 12.61 ± 1.17 | -0.39 (-0.74-0.04) | 0.034 |
HCT | 36.85 ± 4.38 | 38.37 ± 3.77 | -0.37 (-0.72-0.02) | 0.045 |
Number of oocytes retrieval | 29.02 ± 11.45 | 28.76 ± 6.46 | 0.03 (-0.32-0.38) | 0.443 |
Number of GV | 4.02 ± 2.93 | 3.60 ± 2.38 | 0.16 (-0.19-0.51) | 0.834 |
Number of MI | 2.81 ± 1.92 | 3.49 ± 2.15 | -0.33 (-0.68-0.02) | 0.786 |
Number of MII | 22.58 ± 9.57 | 22.05 ± 7.88 | 0.06 (-0.29-0.41) | 0.386 |
Number of embryo | 6.22 ± 15.00 | 5.59 ± 17.23 | -0.38 (-0.73-0.02) | 0.037 |
Number of high quality of embryos | 18.3 ± 5.1 | 14 ± 8.6 | 0.61 (0.25-0.96) | 0.001 |
OHSS | 14 (22.2) | 30 (47.6) | 0.46 (0.27-0.79) | 0.001 |
Mild | 6 (9.5) | 9 (14.28) | 0.66 (0.25-1.76) | 0.432 |
Moderate | 6 (9.5) | 11 (17.46) | 0.54 (0.22-1.38) | 0.545 |
Severe | 2 (3.1) | 10 (15.8) | 0.2 (0.04-0.87) | 0.001 |
GI symptoms | 38 (59.4) | 40 (63.5) | 0.95 (0.72-1.25) | 0.857 |
Ascites | 14 (21.9) | 39 (61.9) | 0.36 (0.22-0.59) | 0.0001 |
Paracentesis | 7 (10.9) | 17 (27.0) | 0.41 (0.18-0.92) | 0.021 |
Admission | 2 (3.1) | 14 (22.2) | 0.14 (0.03-0.60) | 0.001 |
Data are presented as mean + SD or n (%). E2; Estradiol, GnRH; Gonadotropin releasing hormone, HB; Hemoglobin, HCT; Hematocrit, GV; Germinal vesicle, MI; Metaphase I, MII; Metaphase II, OHSS; Ovarian hyper stimulation syndrome, GI; Gastrointestinal, and CI; Confidence interval.l.
The incidence of severe OHSS was considerably lower in
the Quinagolide group (3.1% in quinagolide-treated group
vs. 15.8% in the cabergoline-treated group, P<0.001). Ascites
were less frequent after treatment with quinagolide as
compared to cabergoline (21.9 vs. 61.9%, P=0.0001). Also,
ascites paracentesis was significantly lower in quinagolide
group compared to cabergoline group (10.9 and 27%, respectively,
P=0.021). Hematocrit and hemoglobin were
significantly lower after treatment with quinagolide as
compared to cabergoline (P=0.045 and 0.034, respectively)
and admission rate was significantly lower in quinagolide
group compared to cabergoline (3.1 vs. 22.2%, P=0.001,
OHSS is a life-threatening complication induced by
ART which is more frequently observed when a strong
ovarian response occurs (
This prospective randomized study showed that risk of
OHSS is more markedly reduced following administration
of quinagolide at a dose of 75 mg compared to cabergoline
at a dose of 0.5 mg among high risk patients. In our study,
the incidence of severe OHSS in quinagolide-treated group
was significantly lower compared to that of cabergoline-
treated group. Kamel et al. (
Patients received drugs for 8 days starting from the day
of human chorionic gonadotropin injection. The number
of patients who developed OHSS was similar in the two
groups, which was not consistent with our findings. Busso
et al. (
According to our results, the number of patients with ultrasound
evidence of ascites within the 6 days after GnRH
agonist administration, was significantly reduced in quinagolide
compared to cabergoline-treated group. Similarly,
Baumgarten et al. (
In our study, admission rate was significantly reduced
in quinagolide-treated group as compared to cabergoline-
treated group. Kamel et al. (
We found no significant statistical differences between
the two groups in terms of the number of oocytes, metaphase
I and metaphase II oocytes, and germinal vesicles.
Although the number of embryos in cabergoline-treated
group was significantly higher compared to quinagolide-
treated group, the number of good quality embryos in quinagolide-
treated group was significantly higher than that of
the cabergoline-treated group. Kiliç et al. (
In our study, there was no statistically significant differences
were observed between the two groups in terms of
gastrointestinal symptoms. Busso et al. (
Quinagolide seems to be more effective than cabergoline in preventing OHSS among high-risk patients undergoing ICSI. Further studies should be performed to compare quinagolide and cabergoline to achieve a firm conclusion.