Cabergoline as a preventive measure against ovarian hyperstimulation syndrome in assistive reproductive programs

Size: px

Start display at page:

Download "Cabergoline as a preventive measure against ovarian hyperstimulation syndrome in assistive reproductive programs"

Marshall Ball
6 years ago
Views:

1 Cabergoline as a reventive measure against ovarian hyerstimulation syndrome in assistive reroductive rograms M.K.Ismayılova, PhD Central Clinic Hosital, Baku Abstract. Ovarian hyerstimulation syndrome is one of the comlication aearing not immeddiately but in early hases of regnancy, in the luteal hase. The aim of this study was to ivestigate the effectiveness of cabergoline in the revention of severe OHSS, assess its imact on the rocess of embryo imlantation. It was observed 192 women receving IVF treatment against infertility and studied the effectiveness of cagergoline in women with early and late forms of ovarian hyerstimulation syndrome. We determined that the women rescribed cabergoline had fewer reroductive losses against those of the control grou and our studies showed that use of cabergoline since the introduction of ovulation trigger decreases early and late tyes of severe OHSS. Introduction. One of the most dangerous comlications while alying assistive reroductive technologies (ART) during infertility treatment is ovarian hyerstimulation syndrome (OHSS). Taking into account that ART has become more widesread recently, the risk of OHSS has increased, as well. Generally, major symtoms of this comlication aear not immeddiately but in early hases of regnancy, in the luteal hase. OHSS is characterized by enlarged ovaries, raised oestradiol to a critical level in blood, redistribution of fluid to a art known as third sace which in turn may cause develoment of haemoconcentration, faulty erfusion, and thromboembolism [2,5]. Severe cases constitute 9-15% of all OHSS cases. The cases ending in death are rare. According to info by Wearld Health Organization (WHO), it is 1 in every 50,000 cases [4]. Most of the time what casues them are renal-heatic failure, cerebral infarction, thromboembolism, resiratory-distress-syndrome. Besides hazards it oses to women, OHSS also creates unfavorable condition for develoment of imlanted embryo [6]. The end-result is frequency of early reroductive losses, most notably in regnant women with mid and high clinical conditions [2]. There are numerous methods to treat and revent OHSS but no effective means have been roduced yet against OHSS that would not negatively affect frequency of regnancy, and as well as not cause increase in early reroductive losses. Recently, there have been news regarding use of selective doamine recetor agonists on D2 recetors (one of which is cabergoline) within treatment and revention of OHSS [7]. Preventive effect of cabergoline to the risk of develoment and rogression of OHSS is associated with the ability of its secific recetor tye 2 (VEGF R2) to block the interaction of vascular endothelial growth factor (VEGF) located on the endothelium, strongly formed by OHSS [1]. The result of the blockade of VEGF effects is reduction in vascular ermeability, which hels eliminate the trigger level in the athogenesis of clinical manifestations of OHSS [1]. It is known that VEGF and VEGF R2 exist in ovarial tissue, namely in granulosa cells and corus luteum and that VEGF is resonsible for the increased vascular ermeability. The mechanism of the mentioned rocess, binding of VEGF and recetor tye 2 (VEGF R2), lays a key role in the change in vascular ermeability. Gonadotroins used in IVF stimulation rotocols, increase the effect of VEGF R2, which reaches its maximum after the delivery of human chorionic gonadotroin (hcg). In this way, VEGF R2 will be directly correlated with the level of vascular ermeability [3]. It was also found that increased delivery of VEGF casuses reduced roduction of doamine. Doamine agonists have the ability to hoshorylate the recetor VEGF R2 and convert VEGF R2 57

2 into a form that is not caable of binding with growth factor, a revention against increase in vascular ermeability and the develoment of OHSS [3, 7] It noteworthy to state that cabergoline is quite safe in the treatment of atients with rolactinomas and this makes its introduction easier into clinical ractice for the revention of OHSS. However there are certain questions that remain oen: what are the criteria for the rescrition of cabergoline, in what dosages it should be administered, in what eriod of controlled ovarian simulation it should be administered, how safe it is in the rocess of imlantation of transferred embryos, how it affects regnancy rate, and whether there is connection between use of cabergoline and reroductive losses. [4, 8] Considering aforementioned oints, we have set our goal in this aer: to study the effectiveness of cabergoline in the revention of severe OHSS, assess its imact on the rocess of embryo imlantation, regnancy rate and the incidence of early reroductive losses in Azerbaijani oulation. Materials and methods: between years 2009 and women receving IVF treatment against infertility were examined at Central Clinic Hosital, Baku. Target grou who received cabergoline were 98 eole while the control grou were 94. In the rearatory hase to IVF, all atients went through standard examinations-which included ultrasonograhy, hormonal rofile on 2-3 days of the menstrual cycle (FSH, LH, TSH, free T4, T3, rolactin, estradiol, testosterone, rogesterone, hysterosalingograhy (HSG ). There has also been examining of the infection status, and evaluation karyotying. Women with olycystic ovary syndrome (PCOS) were required to undergo glucose load test (100 mg), to determine glycohemoglobin and insulin levels. Controlled ovarian hyerstimulation was erformed by standard antagonist rotocols, used drugs - Fostimon, Puregon, Bravel, Merional, and Menogon. For ovulation regnyl, choriomon, and Dekaetil agonists. Statistical rocessing: Obtained results were rocessed using variations statistics method through the comuter software EiInfo 7. While analyzing relative risk level confidence interval of 95% was calculated. While comaring differences, statistical signifance for values of <0.05 was calculated. Results. All atient grous studied were from 20 to 38 years old, the average age was 29. All atients came to the clinic comlaining of infertility, and it was the rimary reason for all of them. As shown in figure 1, menstrual dysfunction was observed in 89 atients, and the tye oligomenorrhea in 47 (53%), amenorrhea in 22 (25%), hyerolymenorrhea- 20 (22%). We did not observe dysfunctional uterine bleeding in our atients. Anovulation was diagnosed in 49 atients. 58

Figure 1. Clinical characteristics of the study grous (%) Structure of gynecological and somatic diseases was examined. Of gynecological diseases cervicitis and vaginitis were dominant.

3 Figure 1. Clinical characteristics of the study grous (%) Structure of gynecological and somatic diseases was examined. Of gynecological diseases cervicitis and vaginitis were dominant. With regard to somatic diseases the leading diseases were of the gastrointestinal tract. When any abnormalities rior to the IVF rogram are identified there is a comulsory treatment of infections, sexually transmitted diseases and TORCH anel infections, as well as correction of hormonal and metabolic disorders following more research and exert advice. During hyerrolactinemia bromocritine drugs or doamine recetor agonists (Dostinex) are rescribed after conducting magnetic resonance imaging (MRI) of the ituitary, and consultation with neurosurgeon and endocrinologist. During hyerfunction of the adrenal cortex glucocorticoids drugs were administered. Thyroid dysfunction was eliminated with aroriate medication after ultrasonograhy of the thyroid gland and consultation with an endocrinologist. After a series of tests and examinations on atients with PCOS who were overweight, had hirsutism, hyerinsulinemia and imaired glucose tolerance, we were able to correct metabolic and endocrine disorders through food diet and drugs that lower body weight, hyerinsulinemia and hyerandrogenism. Patients received medication of 1000 mg dose "Metformin" or "Siafor" er day during 2-3 cycles. The criteria for the adequacy of the treatment is the reduction in body weight, normalized glucose tolerance test, normalization of glycohemoglobin level and hormonal arameters in blood. We have also examined the main causes of infertility in our study grous. Table 1. Etiological reasons of infertility in target and control grous. Etiological factors Control grou n=94 Target grou n=98 PCOS Tubal factor Anovulatory cycle Idiohathic infertility It should be noted that all the women were reorted to be with normal uterus, a normal karyotye by ultrasonograhy. On the Hysterosalingograhy (HSG) test 12 women were reorted to have one or two-sided hydrosalinx, to whom during the rearatory hase laaroscoic tubectomy and / or tubal ligation were carried out

4 All the husbands of studied atients had normal semen and normal karyotye. All the atients in target and control grous underwent controlled suerovulation simulation due to antagonist rotocol. 50atients in the control grou of 94, and 54 atients in the target grou of 98 - suerovulation was carried out with the use of drugs containing human menoausal gonadotroin HMG (menogon, Merional, Menour) on their 2nd-3rd day of menstruation, for other atients stimulation was started with the use of FSH -containing drugs (Puregon, Fostimon, Gonal-F, Bravel). When the follicles reached diameter of mm by about 6-8 days of the menstrual cycle, ie, the day of the treatment FSH antagonists were combined with HMG - containing drugs. As antagonists used daily injections Tsetrotida 0.25 mg or 0.25 mg Orgalutran. We used hcg and / or agonists (Decaetyl) as ovulation triggers. The criterion for selection was the number of stimulated follicles and estradiol levels in the blood. If the number of stimulated follicles was less than 20, and estradiol levels were less than 5000 mol, the atient was administered mg hcg. This, we named a. If the number of stimulated follicles were more than 20, and estradiol levels were less than 5000 mol, two injections of Decaetyl and 5000 IU hcg were designated for this we called b. If the number of stimulated follicles were more than 20, and estradiol levels were less than 5000 mol, only two injections of Decaetyl were designated for this we called v. For these last two grous, on the day of the aointment of the trigger ovulation atients have begun taking Cabergoline 0.25 mg / day or 0.5 mg / day orally for 8 days. Dose of cabergoline was selected deending on the body-mass-index (BMI) of the atient. When BMI was less than 25, 0.25mg/day Dostinex was administered while 0.50 mg/day Dostinex was administered for those over BMI of 25. After embryo transfer all atients were administered rogesterone (Crynon gel 8% or Utrogestan 200 mg) and continued to receive till regnancy was confirmed or denied. If regnancy was confirmed rogesterone was administered till the 14th week of regnancy. After the introduction of the ovulation trigger, tracking the signs of OHSS we monitored the overall status of atients till the confirmation / denial of clinical regnancy by ultrasound,. All cases of OHSS occurring during the first days after the uncture of oocytes were regarded as early OHSS. Cases of all syndromes occurring 9 days after the uncture of oocytes were regarded as late OHSS. Note that at the time of the study, we only considered the cases of moderate and severe OHSS degree classification. The effectiveness of IVF in the comared grous was assessed by the rate of regnancy in the stimulated cycle (table 2). Patients with confirmed clinical regnancy were further tracked in the I trimester, recording the incidence of early reroductive losses (miscarriages and develoing regnancy). Table 2. Prohylactic effect of cabergoline in target and control grous.. Analyzed indicators Control grou n=94 Target grou n=98 а=30 b=30 60 v=34 а=30 b=30 v=38 Use of cabergoline no no no no yes yes Early OHSS (absolute numbers and %) 0 (%) 4 (13,3% ) 10 (26,6% ) 12 (35,2% ) 2 (6,6%) 3 (10,0%) 3 (7,8%) 0 (%) Late OHSS (absolute numbers and 2 (10,0% (26,2% (16,6% 5 (15,5% %) (6,6%) ) ) ) (16,6%) )

5 As seen from the table, early and late OHSS cases aear less in target grou who used cabergoline than the control grou. B grou (early OHSS) RR =0.3 (95% CI 0.09:0.9), <0.05 B grou (late OHSS) RR=0.3 (95% CI 0.13: 0.9) <0.05 V grou (early OHSS) RR=0.2 (95% CI 0.06:0.7) <0.05 V grou (late OHSS) RR=0.4 (95% CI 0.17:0.9) <0.05 We must also emhasize that cabergoline is relatively more effective means to revent early OHSS than late OHSS. As shown on the table 3, target grou has much more regnancy rate than control grou. B grou RR=0.6 (95% CI 0.4:0.9), <0.05; V grou RR=0.4 (95% CI 0.2:0.7), <0.05. Table 3. Pregnancy rate in IVF atients comared grous based on factor use or non-use of cabergoline.. Analyzed indicators Control grou n=94 Target grou n=98 a=30 b=30 v=34 a=30 b=30 v=38 Use of Cabergoline no no no no Yes yes Pregnancy rate (absolute numbers and %) (33,3%) (6%) (35%) (33%) (50%) (71%) It should also be noted that use of cabergoline not only decreases the frequency of OHSS cases but also revents further develoment of comlications of OHSS. According to our results among women with OHSS, those treated with cabergoline had fewer cases with severe manifestations of OHSS than those atients develoing OHSS- who did not use the drug. Our studies have also shown that the use of cabergoline does not imair the ability to get embryo imlantation and does not increase the relative risk of reroductive losses in the first trimester of regnancy. As seen from the table 4, target grou that were administered cabergoline had fewer reroductive losses against those of the control grou: RR=0.5 (95% CI 0.2:0.9) <0.05. Table 4. Reroductive losses in the administration of cabergoline in studied grous. Analyzed indicators Pregnancy loss (absolute numbers and %) Pregnant women who were NOT treated with cabergoline n = (25,5%) Pregnant women who were treated with cabergoline n = (13,2%) Thus, our studies showed that use of cabergoline since the introduction of ovulation trigger decreases early and late tyes of severe OHSS, as well as not affect imlantation caability of embryo nor increase incidence of early reroductive losses. 61

6 References 1. Alvarez C. Alonso-Muriel J. Garcia G, Creso J., Bellver Y., Simon C., Pellicer A. Imlantation is aarently Unaffected by the doamine agonist Cabergoline when administered to revent ovarian hyerstimulation syndrome in women undergoing assisted reroduction treatment: a ilot study. Hum. Rerod. 2007; 22; Rizk B. Ovarian hyerstimulation syndrome-eidemiology, athohysiology, revention and management, 1 st ed. New York, Cambridge University Press, 2006, Gomez R., Simon C., Remolin J., Pellicer A. Vascular endothelial growth factor recetor - 2 activation induces vascular ermeability in hyerstimulated rats and this effect is revented by recetor blockade. Endocrinology 2002; 143; Carizza C., Abdelmassih V., Addelmassih S., Ravizzini R, Salqueiro L, Salgueiro PT. Jine LT, et al. Cabergoline reduces the early onset of ovarian hyerstimulation syndrome: a rosective randomized study. Rerod. Biomed online, 2008; 17; Mathur R., Kailagani C, Jenkins J. Review of the evidence base of strategies to revent ovarian hyerstimulation syndrome. Hum. Fertil (Camb) 2007; 10; Madill JJ, Mullen NB, Harrison BP. Ovarian hyerstimulation syndrome: a otentially fatal comlication of early regnancy. J. Emerg. Med. 2008; 35; Краснопольская К.В., Ашхаруа Т.А. Применение селективных стимуляторов дофаминовых Д2 рецепторов для профилактики синдрома гиперстимуляции яичников. Проблемы репродукции т.17 3 с Kalamokas T., Creatsos G., Kalamokas E., Cabergoline as treatment of ovarian hyerstimulation syndrome; a review. Gynekol. Endocrinol Feb.; 29 (2);

Laboratoires Genevirer Menotrophin IU 1.8.2

Laboratoires Genevirer Menotrophin IU 1.8.2 Important missing information VI.2 VI.2.1 Elements for a Public Summary Overview of disease epidemiology Infertility is when a woman cannot get pregnant (conceive) despite having regular unprotected sexual