Comparison of GnRH agonist with low-dose urinary hCG for induction of final oocyte maturation

The aim of this study is to compare clinical pregnancy rates in ICSI-ET cycles where GnRH agonist or hCG was used to induce final maturation of the oocytes. A total of 97 women who produced more than 14 follicles following ovulation induction with recombinant FSH and GnRH antagonist were selected for randomization. Human chorionic gonadotropin (hCG, 5.000 IU, IM) or GnRH agonist (triptorelin 0.2 mg, SC) was used for the induction of final maturation. Women in GnRH agonist group received higher dose of progesterone (100 mg vs. 50 mg) and estradiol (6 mg orally per day vs. none) compared to women in hCG group in the luteal phase starting on the day of oocyte pick-up. Age, duration of stimulation, dose of gonadotropins, peak estradiol levels were similar in both groups. The mean number of collected oocytes (14.7±2.1 vs. 13.8±4.3) and fertilization rates (70.7 ±18 vs.71.8 ±21) were not significantly different between women allocated to hCG group (n=53) and GnRH agonist group (n=44). Clinical pregnancy rates (37.7 vs. 36.3), miscarriage rates (15% vs. 18.7%) and ongoing pregnancy rates (32% vs. 29.5%) were similar between hCG group and GnRH agonist group, respectively. Two cases of moderate/severe OHSS occurred in the hCG group, and none in the GnRH agonist group. In conclusion, GnRH-agonist triggering together with high dose steroid supplementation in the luteal phase yields similar clinical pregnancy rate to that obtained with lower dose of hCG administration for final maturation. However, lower dose of hCG was associated with a higher incidence of moderate/severe OHSS. Introduction vulation induction using either Gonadotropin Releasing Hormone (GnRH) agonist or antagonist protocol has been used to achieve multifollicular development in IVF cycles. However, ovarian hyperstimulation syndrome (OHSS) is still the major complication of ovulation induction and may lead to ovarian torsion, hydrothorax, thromboembolism and liver dysfunction in its severe form. Although the incidence of severe OHSS is <2%, it may result in a life threatening condition. Thus, several strategies have been proposed to eliminate the risk of OHSS. GnRH antagonist protocol is commonly used with similar pregnancy rates and associated with a significant reduction in the incidence of severe OHSS when compared to GnRH agonist namely long-protocol. Besides, GnRH agonist can also be used for triggering in GnRH antagonist protocol for high risk patients. Administration of hCG to induce oocyte maturation results in prolonged luteotropic effect and subsequently increases the risk of OHSS in highrisk patients. GnRH agonist for inducing final oocyte maturation was used in many studies to reduce the risk of severe OHSS. Nevertheless, luteal phase hormone levels may be inadequate to sustain well developed endometrium O Comparison of GnRH agonist with low-dose urinary hCG for induction of final oocyte maturation Faiz A. Alwaeely Bas J Surg, March, 19, 2013 ٤٥ with GnRH agonist triggering due to rapid demise of the corpus luteum. A number of protocols have been proposed to overcome impaired luteal phase in women who had agonist triggerring such as lowdose hCG administration together with agonist, low-dose hCG administration on the day of oocyte pickup (OPU), the use of increased dose of estrogen and progesterone, administration of low-dose hCG in the mid-luteal phase. It was even recommended to cryopreserve all of the fertilized oocytes for a later transfer to circumvent suboptimal luteal phase. Thus, controversy still exists regarding the best method to obtain optimal pregnancy rates in IVF cycles with GnRH agonist triggering. The reduced risk of OHSS without affecting implantation rate with the administration of adjusted doses of estradiol and progesteron supplementation in GnRH agonist triggering cycles has been reported. Steroid doses were adjusted according to serum estradiol and progesterone levels in the same study. Shapiro et. al. used aggresively enhanced steroid doses in the luteal phase and obtained similar pregancy rate with the dual trigger. It is still not clear if using fixed increased doses of steroids in the luteal phase may restore an optimal endometrial environment. We therefore hypothesized that increasing the dose of progesterone and adding estradiol in the luteal phase may overcome the defective luteal endocrine/endometrial environment and restore implantation capacity after agonist triggering. In our prospective study, we compared the outcomes of ICSI-ET cycles where agonist was used for triggering combined with high dose steroidal supplementation with the low dose hCG for final maturation. Patients and methods A total of 97 patients undergoing ICSIET cycles from July 2011 to May 2012 were prospectively enrolled in this study. Inclusion criteria for women were age less than 40 years and with normal uterine cavity diagnosed with HSG or hysteroscopy and having more than 14 follicles >10 mm in diameter and estradiol level less than 4.000 pg/ml on the day of triggering final oocyte maturation. Baseline ultrasound assessment for antral follicle count and assessment of FSH level were performed prior to initiating ovulation induction. Ovarian response was monitored with serial transvaginal ultrasound and serum estradiol assessments. The starting dose of FSH (Puregon, Organon) was 150 IU per day and the dose of gonadotropins was adjusted according to response. A daily administration of cetrorelix (0.25 mg Cetrotide; Serono) was introduced in a fixed way on day 6 and continued until the day of hCG or GnRH agonist administration. All patients were triggered when at least three follicles reached to >17 mm with either hCG (5.000 IU, IM) or 0.2 mg of triptorelin SC (Decapeptyl). Randomization was performed by designed numerical chart. Coasting was carried out in women with estradiol level > 4.000 pg/ml and final oocyte maturation was administered when estradiol level dropped. Coasting was not continued for more than 3 days. Estradiol assessment was carried out by enzyme linked flourescent assay (VİDAS, Biomerıeux, France). Oocyte pick-up (OPU) was performed 34-36 hours later and oocytes were cultured in G-IVFPlus (VitrolifeSweden) medium supplemented with 10 % human serum albumin (HSA) (Vitrolife-Sweden) at 37° C under 6% CO2 for 2 hours. Cumulus – corona complex was removed by pipetting to hyaluronidase (Type VIII; Sigma, St.Louis, MO) after 2 hours, and the cells of the corona radiata were removed mechanically with the aid of a 150-μm pasteur pipette in G-MOPS-Plus (Vitrolife-Sweden) medium. ICSI procedure was performed in all cases as described in detail elsewhere. Fertilization was assessed 16-18 hours after ICSI, cleavage rate was checked 48Comparison of GnRH agonist with low-dose urinary hCG for induction of final oocyte maturation Faiz A. Alwaeely Bas J Surg, March, 19, 2013 ٤٦ 72 hours after OPU. Embryo transfer was performed on postOPU day 3 at the cleavage stage. In GnRH group, progesterone in oil 100 mg/day IM together with estradiol 6 mg (Estrofem tb, Novo Nordisk)) orally initiating on the day of OPU was used until the detection of fetal heart beat. In hCG group, progesterone in oil 50 mg/day IM (half of the dose used in GnRH agonist group) was administered starting on the day of OPU and continued until the presence of fetal heart beat. Estrogen supplementation was not used in the luteal phase in hCG group. Pregnancy was confirmed by assessing serum hCG level 12 days after the embryo transfer. Clinical pregnancy was defined by the presence of a gestational sac on a 7-week ultrasound. The diagnosis of OHSS was based on the criteria described previously Fertilization, implantation, clinical pregnancy, miscarriage and ongoing pregnancy rates as well as moderate/severe OHSS rates were compared among two groups by using the unpaired Student’s t test or X analysis as appropriate. A P value of <.05 was considered statistically significant. Values are expressed as mean ± SD.