the optimal protocol for poor ovarian responders ( por ) undergoing in vitro fertilization ( ivf ) has still been a challenge . poor response to ovarian stimulation occurs in 9%24% of women undergoing ivf which results in poor clinical pregnancy rates ( cpr ) and many of these cycles are cancelled without proceeding to egg collection ( 1 ) . for preventing cycle cancellation , several strategies have been suggested such as decreasing the dosage and timing of gonadotropin releasing hormone agonist ( gnrh - a ) ( 2 ) or the use of gnrh - a flare up regimens ( 3 ) . theoretically , these strategies should eliminate excessive ovarian suppression while capitalizing on the initial stimulatory effect of gnrh - a on pituitary gonadotropin release . the overall cpr when using flare protocols in por has ranged between 12% and 26.3% ( 4 , 5 ) . however , some reports on outcomes using a decreased dose of gnrh - a ( the so - called microdose flare protocol ) have revealed conflicting results in cycle cancellation rate ( ccr ) and cpr despite improved cycle outcomes ( 3 , 6 ) . in recent years , gnrh antagonists ( gnrh - ant ) the action of gnrh - ant does not result in early folliculogenesis inhibition , which is a critical point for patients with a limited cohort of follicles ( 4 , 7 ) because gnrh - ant can be administered during the late follicular phase . as a consequence , they promptly suppress pituitary gonadotropin secretion , which allows their use without the need for a desensitization period . after gnrh - ant was introduced into clinical practice , these two protocols became popular in terms of treatment of por but several studies compared flare - up and antagonist protocols have still reported conflicting results ( 810 ) . the aim of this study was to compare the effectiveness of gnrh - a microdose flare - up and multiple doses gnrh - ant protocols in patients with por undergoing intra - cytoplasmic sperm injection ( icsi ) and embryo transfer ( et ) cycles . a total of 285 patients diagnosed with por and treated in our ivf center ( zeynep kamil training and research hospital , assisted reproduction unit ) with either gnrh - a microdose flare - up or gnrh - ant protocols between january 2011 and january 2014 were enrolled in this observational retrospective study . all patients had fulfilled three criteria for poor response ; patients with less than 4 oocytes in all previous ivf cycles , who needed at least 375 iu of daily gonadotropin in the study cycle or having totally 4 antral follicle count ( afc ) on bilateral ovaries , patients with previous ovarian surgery , stage iii - iv endometriosis according to the revised american fertility society classification ( 1985 ) or with inflammatory , autoimmune , or chromosomal disorders . also , patients with endocrine or metabolic diseases who lacked medical records were all excluded . of 285 patients , 244 patients were included to the final analysis . for 135 patients ( 176 cycles ) , gnrh - a microdose flare - up protocol ( group 1 ) was administered and for 109 patients ( 138 cycles ) gnrh - ant protocol ( group 2 ) was used . patients in the flare - up protocol were started on 50 g sc of leuprolide acetate ( lucrin ; abbott , cedex , france ) twice daily on cycle day ( cd ) 2 followed by high dose gonadotropin stimulation on cd 3 . in the antagonist protocol , the gonadotropin was started on cd 3 and 0.25 mg cetrorelix ( cetrotide ; asta medica , frankfurt , germany ) was administered daily when two or more follicles reached 1314 mm in diameter . in both regimes , at least 375 iu of gonadotropins [ recombinant fsh ( gonal - f ; serono , istanbul , turkey ) and/or human menopausal gonadotropin ( menogon ; ferring , istanbul , turkey ) ] was administered to all patients by adjusting the doses according to the ovarian response . gnrh - a , gnrh - ant and gonadotropin administration continued until the day of hcg administration . hcg ( 6,500 iu i m , ovitrelle , merck serono , germany ) was administered when at least two leading follicles reached a mean diameter of 17 mm and serum estradiol ( e2 ) concentration was over 500 pg / ml . icsi was performed for all metaphase ii oocytes according to our clinical approach , and et for good - quality embryos was performed under ultrasound guidance on days 3 , 4 and 5 . after the transfer , luteal support was provided by administering 90 mg of vaginal progesterone gel ( crinone 8% gel , serono ) once daily . cpr was defined as the presence of gestational sac with accompanying fetal heart beat by ultrasound 4 weeks after et for each icsi cycle . implantation rate ( ir ) was defined as the ratio of gestational sac to the number of ets and fertilization rate ( fr ) was defined as the proportion of oocytes resulting in two pro - nuclei formation . statistical analyses were performed using the spss software version 15.0 for windows ( spss , chicago ) . data were expressed as the meansd or percentages . the student t - test , mann whitney u test , and -test were used to compare the groups . the mean age of the patients , mean duration of infertility , body mass index , the number of previous ivf cycles , basal afc , serum basal fsh and e2 level were similar between groups ( table 1 ) . demographic and baseline characteristics of the groups gnrh - a : gonadotropin releasing hormone analog , gnrh - ant : gonadotropin releasing hormone antagonist , bmi : body mass index , ivf : in vitro fertilization , fsh : follicle stimulating hormone , e2 : estradiol the comparison of cycle parameters and clinical outcomes including total gonadotropin doses used , duration of stimulation , mean number of follicles , mean number of oocytes retrieved , mean number of embryos transferred and fr , ccr and cpr are given in table 2 . the mean total gonadotropin doses were 3814891 iu in group 1 and 3539877 iu in group 2 ( p=0.02 ) . no statistical significance between the protocol types with respect to the duration of stimulation , mean number of follicles , peak e2 level was found . the number of metaphase - ii oocytes ( 3.62.4 vs. 2.81.9 , p=0.005 ) and ir ( 27.8% vs. 18.8% , p=0.04 ) in group 1 and group 2 , respectively were significantly different . comparison of the cycle characteristics and outcomes between groups values are given as meansd , unless otherwise indicated ; gnrha : gonadotropin releasing hormone analog , gnrhant : gonadotropin releasing hormone antagonist , hcg : human chronionic gonadotropine , e2 : estradiol the fr in group 1 and group 2 was 73% vs. 68% , respectively ( p=0.5 ) and cpr was 19.8% vs. 14.4% , respectively ( p=0.13 ) . despite the improvements in the success of ivf in all age groups , the treatment of por remains a significant problem in assisted reproductive techniques . the best stimulation protocol for por should have an acceptable rate of cycle cancellation , yield the maximum number of mature , good - quality oocytes , at a reasonable cost with optimal side effects and duration of therapy and have reasonable pregnancy and delivery rates . according to the results of a recent survey ( 11 ) in which 272 ivf units from 45 countries responded , the preferred protocol for por was the gnrh - ant protocol ( 52% ) , the short gnrh - a flare - up ( 20% ) and the microdose protocols ( 15% ) . in this retrospective study , an attempt was made to compare the most common protocols , microdose flare - up and antagonist , used in the treatment for por . a microdose flare - up regimen has been developed to minimize the ovarian suppression of the gnrh - a long protocols while taking the advantage of the initial up - regulatory effect of leuprolide on follicular recruitment which was used successfully in por . toth et al . ( 12 ) reported that using flare protocols in patients with basal fsh level > 15 iu / l significantly increased cpr over long agonist protocols . leonodris et al . ( 6 ) retrospectively analyzed 170 patients in either gnrh - a long or flare protocol , and found no statistically significant differences in regard to cpr but found a higher cancellation rate in microdose flare group . ( 3 ) reviewed different regimens used in por and concluded that a microdose flare - up protocol was more beneficial to the cycle outcomes than other regimens . the addition of gnrh - ant to the ovarian stimulation in por brought new hope to the clinicians . the studies about the gnrh - ant in the treatment of por resulted in reducing the amount of gonadotropins used , the length of the stimulation , the number of cancelled cycles , and the overall cost normally associated with the long protocol and in increasing the number of oocytes retrieved with satisfactory pregnancy rates ( 10 , 1317 ) . gnrh - ant characteristics will always be reasonable for por since a high gonadotropin requirement is commonly associated with high cancellation rates and low numbers of oocytes retrieved . prior randomized controlled trials ( rcts ) compared microdose flare - up to the gnrh - ant protocols in por and they offered varied results . the reason of these may be due to the lack of a uniform definition of poor responders . this makes it difficult to compare treatment outcomes and develop and assess protocols for prevention and management . ( 8) showed that using flare - up protocols when compared with using antagonist yielded significantly higher mature oocytes , higher ir in flare protocols with similar cpr . ( 9 ) found higher peak e2 level in flare protocols , apart from the fact that no statistically significant differences were noted in cycle outcomes or cpr . a meta - analysis in 2006 ( 18 ) reported higher number of retrieved oocytes in the gnrh - a protocols when the meta - analysis was applied to the four trials that had used gnrh - ant vs. flare - up protocols . also , it was reported that there was no difference between gnrh - ant and gnrh - a ( long and flare - up protocols ) with respect to ccr and pr . similarly , in our study , significantly higher numbers of oocytes retrieved and higher implantation rates in microdose flareup were found compared to gnrh - ant protocol with similar fr and cpr . these results may show that the number of oocytes is not always predictive of pregnancy rates . in a recent rct , ibrahim et al . ( 10 ) examined the use of microdose triptorelin ( 3035 g s.c . once a day ) starting on the first day of the cycle compared with using cetrorelix when the leading follicle was > 14 mm . although the fr , ir and ongoing pregnancy rate were higher and cancellation rate was lower in antagonist protocol , they did not achieve statistical significance . it was noted that when using gnrh - ant protocol , significantly less gonadotropin was required . in a cochrane review ( 19 ) , it was reported that the gnrh - ant produced higher number of oocytes and used lower dose of gonadotropins compared with gnrh - a long protocol and gnrh - a flare up protocol had an increased frequency of ivf cancellation compared with the gnrh - a long protocol . it was concluded that the evidence was not sufficient to support any ivf protocol in routine practice . 20 ) reported that gnrh - ang protocols resulted in significantly lower duration of stimulation compared to gnrh - a protocols in por ; however , ccr and cpr were similar between the groups . in our study , the total gonadotropin doses were significantly lower in the gnrh - ant protocol without any difference in the length of stimulation . our study included 244 patients ( 314 cycles ) who received either the gnrh - a flare or the gnrh - ant protocol . to our knowledge , it had the largest sample size among the previous researches published in the literature . one of the limitations of our study was that the choice of the protocol , whether to use gnrh - a flare or the antagonist protocol , was based on the individual preference of the clinicians carrying out the treatment . although the patients can not be randomized in a retrospective analysis such as this and the administered gonadotropins were different , the similarity in the baseline characteristics of the groups can make it possible to compare the outcomes . the results of our study appear to confirm the conclusion of some already published reviews indicating higher number of oocyte retrieved , higher implantation rate in gnrh - a cycles compared with gnrh - ant cycles ( 8 , 18 ) with similar cpr ( 9 , 18 , 21 ) . nevertheless , additional rct with better planning and larger sample size are still needed to further confirm these results . the gnrh - a microdose flare - up protocol has favorable outcomes with respect to the number of oocytes retrieved and ir ; nevertheless , the cpr was found to be similar in comparison to gnrh - ant protocol in por . gnrh - ant protocol appears to be promising with significantly lower gonadotropin requirement and lower treatment cost in por .
background : microdose flare - up gnrh agonist and gnrh antagonist have become more popular in the management of poor ovarian responders ( por ) in recent years ; however , the optimal protocol for por patients undergoing in vitro fertilization has still been a challenge.methods:in this observational study design , two hundred forty four poor ovarian responders were retrospectively evaluated for their response to gnrh agonist protocol ( group-1 , n=135 ) or gnrh antagonist protocol ( group-2 , n=109 ) . 
 clinical pregnancy rate was the primary end point and was compared between the groups . 
 student t - test , mann whitney u test and 2-test were used to compare the groups . 
 the p<0.05 was considered to show a statistically significant result.results:the mean total gonadotropin doses were 3814891 iu in group 1 and 3539877 iu in group 2 ( p=0.02 ) . 
 the number of metaphase - ii oocytes ( 3.62.4 vs. 2.81.9 , p=0.005 ) and implantation rates ( 27.8% vs. 18.8% , p=0.04 ) in group 1 and group 2 , respectively were significantly different . 
 the fertilization rate in group 1 and group 2 was 73% vs. 68% , respectively ( p=0.5 ) and clinical pregnancy rate was 19.8% vs. 14.4% , respectively ( p=0.13).conclusion : the gnrh agonist microdose flare - up protocol has favorable outcomes with respect to the number of oocytes retrieved and implantation rate ; nevertheless , the clinical pregnancy rate was found to be similar in comparison to gnrh antagonist protocol in poor ovarian responders . 
 gnrh antagonist protocol appears to be promising with significantly lower gonadotropin requirement and lower treatment cost in poor ovarian responders .