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ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 2  |  Page : 492-496

Effects of cabergoline administration on uterine perfusion in women with polycystic ovarian syndrome


1 Department of Obstetrics and Gynecology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Obstetrics and Gynecology, El Tahrir General Hospital, El Tahrir, Al Behera, Egypt

Date of Submission30-Sep-2016
Date of Decision24-Oct-2019
Date of Acceptance04-Nov-2019
Date of Web Publication27-Jun-2020

Correspondence Address:
Hanaa H. AbdelMagied Gafar
El Tahrir General Hospital, Al Behera Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_299_19

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  Abstract 


Objective
The objective of this study was to assess the effects of cabergoline administration on uterine blood flow in women suffering from polycystic ovarian syndrome (PCOS).
Background
Many women with PCOs experience infrequent ovulation or lack of ovulation altogether and may face many challenges in becoming pregnant.
Patients and methods
A randomized controlled study was conducted on 108 patients with PCOS who attended the Shebin El-Kom Teaching Hospital outpatient clinic during the period spanning from May 2016 to March 2018. Doppler ultrasound was performed for both groups. Then weekly dose of cabergoline 0.5 mg was administrated for the case group for 12 weeks, while the control group did not receive any treatment. At the end of 12th week, another Doppler ultrasound was performed for all participants, and the results were recorded.
Results
There was no significant difference between the two groups with regard to age, BMI, luteinizing hormone and follicle-stimulating hormone levels. Before the intervention, the uterine pulsatility index and resistance index, and the ovarian stromal pulsatility index and resistance index, showed no significant difference between the case and control groups. Before treatment, 45 patients from the case group had oligomenorrhea, and, after treatment with cabergoline, 40 patients showed regular menstrual cycle. Side effects (vomiting and blurred vision) occurred in four patients from the case group; hence, they were excluded, and four patients (two got pregnant and two were on treatment) were also excluded during booking of the patients.
Conclusion
PCOS patients were shown to have more resistance in uterine blood flow and lower ovarian resistance than healthy people. Cabergoline administration proved to increase uterine blood perfusion, increase ovarian stromal resistance, and regulate the menstruation cycle.

Keywords: cabergoline, ovarian stromal, polycystic ovarian syndrome, pulsatility index, resistance index, uterine artery


How to cite this article:
El Kelany OA, El Khouly NI, Hamza HA, Gafar HH. Effects of cabergoline administration on uterine perfusion in women with polycystic ovarian syndrome. Menoufia Med J 2020;33:492-6

How to cite this URL:
El Kelany OA, El Khouly NI, Hamza HA, Gafar HH. Effects of cabergoline administration on uterine perfusion in women with polycystic ovarian syndrome. Menoufia Med J [serial online] 2020 [cited 2020 Aug 13];33:492-6. Available from: http://www.mmj.eg.net/text.asp?2020/33/2/492/287775




  Introduction Top


The major features of polycystic ovarian syndrome (PCOS), a common disorder affecting women of childbearing age, include oligomenorrhea or amenorrhea with clinical or laboratory signs of hyperandrogenemia. PCOS is probably an oligogenic or polygenic disorder. Its signs and symptoms start in puberty. PCOS is the most common cause of female infertility. Many women with polycystic ovary syndrome experience infrequent ovulation or lack of ovulation altogether and may face many challenges in becoming pregnant[1]. The diagnosis of PCOS is made on the basis of oligo-ovulation or anovulation manifested by oligomenorrhea or amenorrhea, biochemical evidence of blood androgen excess, and polycystic ovaries, as defined on ultrasonography[2]. Higher resistance in the uterine blood flow of PCOS patients may reduce endometrial receptivity and, eventually, increase chances of miscarriage, as well as having a very negative effect on the outcome of pregnancy. Some studies have revealed the effects of medications in reducing uterine blood flow resistance in PCOS patients. The effect of cabergoline on uterine blood flow of women suffering from PCOS shows that it can increase the uterine blood flow[3]. Doppler analysis of the utero-ovarian circulation is not part of the Rotterdam criteria for ultrasound diagnosis of PCOS, but understanding the changes in vascular patterns in PCOS may allow a better understanding of its pathophysiology. Most investigators agree that the blood flow and the vascular pattern of an organ are directly related to the morphology and function of the organ. There is evidence that Doppler characteristics in PCOS patients may differ from those of women without PCOS; however, reports have been conflicting. High resistance in the uterine artery and increased ovarian stromal blood flow in women with PCOS have been demonstrated by color Doppler blood flow imaging. The impaired uterine perfusion in women with PCOS may contribute to the reduced chance of conception due to endometrial dysfunction and due to the increased risk of spontaneous abortion[4]. The improved uterine hemodynamic status may contribute to the increased chances of pregnancy in those patients who ovulated normally after therapy[5]. Cabergoline, an ergot-derived dopamine agonist with a very long half-life, is an effective prolactin suppressor. Cabergoline oral administration contains a weekly dose of 0.5–3 mg, which could be increased, if needed, to twice a week. This medicine has slight dopamine agonistic side effects, headache being the most common one. Treatment, in the very beginning, should start with a partial dose (half a pill) at bedtime with a small amount of food. Low incidence of side effects and its weekly dose has made cabergoline a choice drug for treatment of related diseases[6].

The current study was designed to assess the effects of cabergoline administration on uterine blood flow in women suffering from PCOS.


  Patients and Methods Top


A randomized controlled study was conducted on 112 patients with PCOS who attended the Shebin El-Kom Teaching Hospital outpatient clinic during the period spanning from May 2016 to March 2018. Inclusion criteria were classically defined PCOS women. Exclusion criteria were pregnancy, hyperprolactinemia, and cabergoline side effects.

Ethical consideration

Approval of the study protocol by the Ethical Scientific Committee of Menoufia University was obtained, and informed consent was taken from all neonate's parents before their enrollment in the study.

Sample size

The sample size was determined depending on the number of female individuals in the childbearing period in Shebin El Kom and the prevalence of PCOS. The sample size was estimated by the following (and they are): sample size=n/(1+(n/population)). N=(t2×p (1−p))/m2. N=required sample size, t=confidence level at 95% (standard value of 1.96), P = estimated prevalence of PCO (9–10%). M=margin of error at 5% (standard value of 0.05). The number of female individuals in the childbearing period in Shebin El Kom City equals 110 000 female individuals. N=(1.962×0.08 (1–0.08))/0.052 = 113.08. Sample size = 113.08/(1+(113.08/110 000))=112. Hence, our sample size in the research is 112 female individuals.

All patients were subjected to the following: detailed history including name, age, marital status, obstetric code, menstrual history, past history, family history, duration of bleeding, history of drug intake, contraceptive methods, any systemic disease, and previous investigations and treatment. General and pelvic examinations were performed for all the participants. Clinical examination such as height, weight, and BMI was carried out. Ultrasonographic and color Doppler analyses were performed for all women by the same operator in the early follicular phase, between the second and sixth days of their spontaneous menstrual cycle, or withdrawal of bleeding. None had hypertension (systolic blood pressure >140 mmHg and/or diastolic blood pressure >90 mmHg).

Ultrasound examinations were performed with the Aplio-Toshiba Medical System (Rome, Italy) equipped with a 7.5 MHz vaginal transducer. The spatial peak temporal average intensity of ultrasound for B mode and Doppler examinations was more than 50 MW/cm2, which was within the safety limits recommended by the Bioeffects Committee of the American Institute of Ultrasound in Medicine according to Miller[7].

All the patients were studied between 8.00 am and 11.00 am to exclude the effects of circadian rhythmicity on the uterine blood flow. Furthermore, participants rested in a waiting room for at least 15 min before being scanned and completely voided their bladder in order to minimize external effects on blood flow.

The patient was rested on the bed. We introduced the vaginal probe through the vagina. Adjusted the probe in the midsagittal view to find the end cervical canal. We then tilted the transducer from side to side to identify the uterine arteries and put the color on the color box to identify the uterine artery. A pulsed wave Doppler was used with the sampling gate set at 2 mm to cover the whole vessel, and the angle of insonation was less than 30°. Three similar consecutive waveforms were obtained. The mean pulsatility index (PI) of right and left arteries was calculated.

In the second phase of the study, oral cabergoline (Cabergamoun; Amoun, Cairo, Egypt) was administered after dinner to the intervention group with a dose of 0.5 mg per week for 12 weeks. At the end of the 12th week after treatment, another Doppler ultrasound evaluation was performed on the uterine artery and ovarian stromal blood flow on the early follicular phase, and the results were recorded using a checklist.

Statistical analysis

Data were coded and entered using the statistical package SPSS, version 20. IBM SPSS statistics for Windows, version 20.0, IBM Corp., Armonk, New York, USA). Data were summarized using mean and SD for quantitative variables. Comparisons between two groups were carried out using unpaired t test and χ2 test. A comparison between the observations before and after treatment was carried out using the paired t test[8]. P values less than 0.05 were considered statistically significant.


  Results Top


There was no significant difference between two groups with regard to age, BMI, luteinizing hormone, follicle-stimulating hormone levels and menstruation period [Table 1]. Before intervention, the uterine PI was 3.62 ± 0.6 in the case group and 3.75 ± 0.57 in the control group, but there was no significant difference between the two groups (P = 0.647); the uterine resistance index (RI) was 0.88 ± 0.05 in the case group and 0.87 ± 0.04 in the control group, which also did not show a significant difference between the two groups (P = 0.751); the ovarian stromal PI in the case group was 0.94 ± 0.1 and 0.95 ± 0.11 in the control group, and it did not show a significant difference between the two groups (P = 0.898)); the ovarian stromal RI in the case group was 0.57 ± 0.03 and 0.58 ± 0.04 in the control group, and it did not show a significant difference between the two groups (P = 0.774) [Table 2].
Table 1: Comparison of demographic data and hormonal pattern for both groups

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Table 2: Comparison between cases and controls with regard to uterine and ovarian stromal pulsatility index and resistance index before administration of cabergoline for cases

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After the intervention, the uterine PI was 2.97 ± 0.52 in the case group; this shows significant difference in uterine PI for cases before and after the administration of cabergoline (P < 0.001). In the control group, the uterine PI was 3.74 ± 0.53; this shows no significant difference (P = 0.981). The uterine RI was 0.83 ± 0.04 in the case group; this shows a significant difference in uterine RI for cases before and after the administration of cabergoline (P = 0.001). In the control group, who did not receive any treatment, the uterine RI was 0.855 ± 0.037; this shows no significant difference (P = 0.983). The ovarian stromal RI in the case group was 0.76 ± 0.05, and this shows significant difference in ovarian stromal RI for cases before and after the administration of cabergoline (P < 0.001), while, in the control group, it was 0.575 ± 0.038. which did not show a significant difference (P = 0.886). The ovarian stromal PI in the case group was 1.98 ± 0.22, and this shows significant difference in ovarian stromal PI for cases before and after the administration of cabergoline (P < 0.001), while, in the control group, it was 97 ± 0.09, which did not show a significant difference (P = 0.938). Before treatment, 45 patients from the case group had oligomenorrhea, and, after treatment, 40 patients showed regular menstrual cycle after treatment with cabergoline. Side effects (vomiting and blurring of vision) occurred in four patients from the case group; hence, they were excluded, and four patients (two got pregnant and two were on treatment) were also excluded during booking of the patients ([Table 3] and [Figure 1]).
Table 3: Comparison between cases and controls with regard to uterine and ovarian stromal pulsatility index and resistance index in the studied groups before and after administration of cabergoline

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Figure 1: Algorithm of the pathway of study participants.

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  Discussion Top


Doppler ultrasound was performed for both case and control groups between the second and sixth day of menstruation, and the values of uterine PI and RI and ovarian stromal PI and RI were recorded, which showed an increase in the uterine PI and RI and decrease in the ovarian stromal PI and RI in PCOS patients. This was in agreement with the Battaglia et al.[9] study of the role of color Doppler imaging in the diagnosis of polycystic ovary syndrome and with the Fisher and Swain[10] study of the effect of some sex hormones on blood pressure and vascular connective tissue. Ovarian stromal PI has been studied in patients with PCOS and has been found to be lower than that in controls[4]. The low PI values indicate that ovarian stromal vessels are probably dilated and engorged and more abundant in the ovaries of women with PCOS[11]. This is not in agreement with the Fetouh and Mohamed[12] study on ovarian Doppler in polycystic syndrome in relation to body weight that showed that there were statistically insignificant differences between (cases) PCOS patients and (control) normal menstruating female individuals with regard to uterine PI and RI; however, this was in agreement as regards there being a statistically significant decrease in the ovarian PI and RI in cases in comparison with controls.

The case group under treatment with cabergoline showed an increase in the uterine blood flow, with PI being 2.97 ± 0.52, while, before treatment, the PI was 3.62 ± 0.6. The uterine artery RI was 0.88 ± 0.05 before treatment, and, after treatment, it was 0.83 ± 0.04. The ovarian stromal RI before treatment was 0.57 ± 0.04, and, after treatment, it was 0.76 ± 0.05. The ovarian stromal PI before treatment was 0.94 ± 0.1, and, after treatment, it was 1.98 ± 0.22. No significant difference was observed in the control group, which did not receive any treatment. Our results agree with the results of Ajossa et al.[13] who carried out their study to assess the effect of chronic administration of cabergoline on uterine perfusion in women with polycystic ovary syndrome. This study was carried out on 30 patients, who were divided into 20 patients diagnosed with PCOS as cases and 10 patients with normal menstrual cycle as controls, with average PI of the uterine artery being 3.29 ± 0.5 and 2.01 ± 0.2, respectively. Thereafter the 20 PCOS patients were divided into two groups: 10 patients treated with cabergoline and another 10 patients treated with placebo; the average PI of the uterine artery was 3.14 ± 0.6 and 3.28 ± 0.5, respectively. During the second part of the study, patients with PCOS who were treated with cabergoline showed a statistically significant decrease in uterine perfusion resistance with a mean PI value of 2.39 ± 0.5. During cabergoline treatment, the PI was similar to that of normal controls. No difference was found in patients with PCOS who were treated with placebo (3.33 ± 0.6 during treatment). Our results agree with the results of Robabeh et al.[14] who carried out a study to assess the effect of cabergoline administration on uterine perfusion in women with polycystic ovary syndrome, This study was carried out on 40 patients who were diagnosed with PCOS with an average PI of the uterine artery being 2.51 ± 0.52, which was less than the PI average of our study (3.62 ± 0.6). In the later stage of the study, the average of the uterine artery PI for the PCOS patients after administration of cabergoline decreased significantly to 1.98 ± 0.52, while, in our study, the average of PI for the cases was decreased to 2.97 ± 0.52, with P value less than 0.001. The uterine RI was 0.85 ± 0.07, which reduced to 0.77 ± 0.1 after administration of cabergoline, which was statistically significant, and, in our study, the uterine RI was 0.88 ± 0.5, which reduced to 0.83 ± 0.4 after the administration of cabergoline, which was also statistically significant.

The different findings in the present study compared with those of other studies may be due to the fact that Doppler measurements depend on personal variations or due to the relatively small number of patients included in the previous studies. Cabergoline could be used as an alternative treatment in these patients, knowing that this drug is well tolerated and has no side effects. This medicine could be prescribed to young patients who are suffering from PCOS and are determined to get pregnant. Cabergoline can facilitate pregnancy in PCOS patients. Cabergoline has no side effects such as ovarian hyperstimulation syndrome or multiple pregnancies, which could be seen in other ovarian stimulation methods; therefore, usage of cabergoline could be considered as safe for pregnancies.

The main strength of our study is the randomized design; we were able to recruit our calculated sample size for achieving adequate power to detect a clinically significant difference in our result. In addition, the study was conducted at the same clinic with a single sonographer to avoid any interassessor variation in Doppler ultrasound evaluation. The study including all patients with no significant difference between the case and control groups with regard to BMI (<30 kg/m2) could limit the applicability of our results in obese patients. One of the limitations of our study was that the endometrial blood flow was not included in the data collected. Only the uterine and ovarian Doppler were measured; therefore, assessment of subendometrial blood flow in future studies will be a good strategy to evaluate the real effect of Cabergoline in enhancing receptivity through increasing the blood supply to the endometrium. The end result of how many patients of the case group became pregnant cannot be estimated, as other related male, tubal, and uterine factors should be included.


  Conclusion Top


Polycystic ovarian patients were shown to have more resistance in the uterine blood flow and engorgement in the blood flow to ovaries. The study shows that the administration of cabergoline proved to increase the uterine blood perfusion, decrease the ovarian engorgement, and improve menstrual irregularities in women with PCOS, which may be some of the possible mechanisms by which cabergoline improves the reproductive outcome in the PCOS patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Ajossa S, Paoletti AM, Guerriero S, Floris S, Mannias M, Melis GB. Effect of chronic administration of cabergoline on uterine perfusion in women with polycystic ovary syndrome. Fertil Steril 1999; 71 :314–318.  Back to cited text no. 13
    
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    Tables

  [Table 1], [Table 2], [Table 3]



 

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