| Background: Most in vitro fertilization(IVF)/intracytoplasmic sperm injection(ICSI) programs use long gonadotrophin-releasing hormone agonist (GnRH-a) protocols for controlled ovarian hyperstimulation(COH) ,which GnRH-a is started in the luteal phase of previous menstrual cycle for pituitary down-regulation in order to increase the numbers of recruitment follicles and stimulate the growth of more synchronizing follicles to obtain multiple oocytes. Although GnRH agonist protocols induce hypophyseal desensitization, follicles present noticeable size heterogeneities in some IVF/ICSI cycles, even dominant follicles are observed in few patients. It is difficult to determine the day of human chorionic gonadotropin(HCG)administration when dominant follicles presented during ovarian stimulated, some Oocytes retrieved from those stimulated cycles with heterogeneous follicles are over mature or immature and number of oocytes recovered decreases, which resulting in adverse effect on outcome of IVF/ICSI.Objective: To investigate two different approaches and their clinical outcomes in the treatment of heterogeneity of follicles with dominant follicles during controlled ovarian hyperstimulation in the long protocol down regulated by GnRH-a.Methods: A retrospective analysis was performed in a total of 237 patients who undergo IVF/ICSI treatments using long GnRH agonist protocols for controlled ovarian hyperstimulation in Reproductive Medicine Center in Tongji Hospital with follicles presented noticeable size heterogeneities and difference of diameter reached 2mm between dominant follicle and subordinate follicles. They were divided into three groups according to different treatments: group A(DFR group, dominant follicle removed, n=97) ,in which the dominant follicle was removed by ultrasound-guided follicular aspiration on the day of the dominant follicle presented; group B(increasing GnRH-a dosage group, n=88) ,in which GnRH-a dosage was increased,patients received GnRH-a o.1mg/day(previous GnRH-a dosage was 0.05mg/day ); group C(control group , n=52),in which patients received none of above treatments. Outcomes such as number of retrieved oocytes and MⅡoocytes, number of embryos suitable for embryo transfer, pregnancy rate and live birth rate per ET cycle,and so on, were compared among three groups. The difference of diameter between dominant follicle and subdominant follicles, the stimulated days, the dosage of GnRH-a, the total Gonadotropin (Gn) ampoules were also compared among three groups. Proportional differences of the main outcome measures were analyzed withχ2-test, Analysis of variance(ANOVA) was used to sample mean comparison. Differences were considered to be significant if P-value<0.05.Results:1. Maternal baseline characteristics including Maternal age , duration of infertility, basal FSH level and LH level, BMI,and number of antral follicles on the day of stimulation started did not differ among the groups in a significant manner.2.The total dosage of GnRH-a in increasing GnRH-a dosage group was more than in DFR group and control group (13.94±1.71,11.82±2.50,11.27±2.38, respectively,P<0.05) during ovarian stimulation. The total stimulated days (9.81±2.07 VS 9.2±1.29, P<0.05)and the total Gn ampoules (32.61±13.03 VS 28.58±8.78,P<0.05) were more in DFR group than in increasing GnRH-a dosage group, the mean of daily dose of Gn were similar in the three groups. The follicular size discrepancy in DFR group was significant higher than in the other groups(3.67±1.43,3.01±0.71,2.96±0.75, respectively, P<0.05 ). There were no difference in the total number of follicles and the stimulated days on the day of dominant follicle presented among the three groups. After dominant follicle was aspirated, days of stimulation till HCG administration was more in DFR group than in the other groups(3.48±1.51,2.90±0.95,2.94±0.95, respectively, P<0.05).3. The mean number of oocytes retrieved (10.96±7.39 VS 8.60±3.97, P < 0.05)and metaphase II oocytes ( 9.80±6.94 VS 7.29±3.65, P < 0.05) were more in the DFR group than in the control group, fertilization rates (73.59%,79.22%,68.47%, respectively,P<0.05 )and mean number of embryos suitable for embryo transfer (4.88±4.06,4.84±0.39,3.35±2.48, respectively,P<0.05) were more in the DFR group and the increasing GnRH-a dosage group than in the control group with statistical significance, clinical pregnancy rate(32.14%,35.63%,27.08%, respectively), living birth rate(29.11%,31.77%,26.09%,respectively) and cumulative clinical pregnancy rate(42.31%,40.96%,32.61%,respectively) were higher in the DFR group and the increasing GnRH-a dosage group than in the control group, but the difference were not significant. Compared with the increasing GnRH-a dosage group,the difference of diameter between dominant follicle and subordinate follicles was greater(3.67±1.43 VS 3.01±0.71, P<0.05)and the rate of cancelling embryo transfer(10.31% VS 0.000%)was higher in the DFR group, but clinical outcomes were similar in both groups.Conclusion :In the treament of heterogeneity of follicles with dominant follicles, both aspiration of dominant follicle and increasing dosage of GnRH-a were effective to promote the coordination of follicular growth, obtain more embryos suitable for embryo transfer and improve clinical outcomes. When the difference of diameter between dominant follicle and subordinate follicles was 3.67mm or less, it was reasonable to increase dosage of GnRH-a, but the difference was more than 3.67mm, aspiration of dominant follicles was optimal approach.
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