Letrozole induced ovulation and pregnancies in anovulatory clomiphene citrate-resistant women

P-212 Tuesday, October 23, 2012 A NOVEL THERAPY WITH SITAGLIPTIN FOR METFORMININEFFECTIVE AGED ART REPEATERS: DRAMATICAL INCREASE IN PREGNANCY RATE BY DECREASING POSTPRANDIAL GLYCEMIC LEVELS AND ADVANCED GLYCATION M. Takeuchi,b A. Watanabe,a END-PRODUCTS. M. Jinno,a J. Hirohama,a R. Hiura,a N. Suciu.c aWomen’s Clinic Jinno, Choufu City, Tokyo, Japan; bDepartment ofAdvanced Medicine, Medical Research Institute, Kanazawa Medical University, Kahoku, Ishikawa, Japan; cDepartment of Obstetrics and Gynecology, Polizu Maternity Hospital, Bucharest, Romania. OBJECTIVE: Advanced glycation end-products (AGEs) are accumulated with ageing and diabetes and play a pivotal, pathogenic role. We showed adverse effects of AGEs on ART outcomes in study I and in study II we improved ART outcomes in very severe cases by decreasing postprandial glycemic levels and AGEs with sitagliptin. DESIGN: Retrospective analyses and case-control study. MATERIALS AND METHODS: Study I: Toxic AGE (TAGE), pentosidine (Pent), and carboxymethyl lysine (CML) in blood and follicular fluid (FF) were measured in 157 ART-patients. Study II: Sitagliptin was given in 44 severe ART repeaters (5.8
0.6) with 41.0
0.5 years of age. All subjects had failed with metformin. Examinations were done before and after sitagliptin. From ART data without sitagliptin, 44 women were extracted at random, except for being matched for age, past failed ARTs and day-3FSH (matched controls). RESULTS: Study I: TAGE, Pent and CML in FF and serum TAGE correlated negatively with follicular and embryonic developments. Only age, Pent in FF and serum TAGE correlated negatively with ongoing pregnancy. Women with higher serum TAGE showed decreased oocytes and lower pregnancy rate, even with younger age or lower day-3 FSH. Study II: Sitagliptin significantly enhanced follicular and embryonic growths. Rates of clinical and ongoing pregnancy were significantly improved with sitagliptin (20% and 14%), compared with matched controls (2.3% and 0%). Sitagliptin significantly decreased plasma glucose at 0, 30, 60 and 120 minutes in oGTT. Change ratio of serum TAGE by sitagliptin was correlated with increment of day-2 superior embryos (b¼-0.32). CONCLUSION: AGEs correlate highly with poor ART. Serum TAGE is a novel marker for diminished ovarian reserve independently of age and day-3 FSH. This is the first report to show that sitagliptin significantly improves follicular and embryonic developments and pregnancy rates in metformin-ineffective, aged ART-repeaters. Decreases in postprandial glycemic levels and TAGE may be involved in its mechanism.

P-213 Tuesday, October 23, 2012 GRANULOCYTE-COLONY STIMULATION FACTOR (G-CSF): AN OPTION TO IMPROVE IN VITRO FERTILIZATION (IVF) OUTCOMES IN POOR RESPONDERS. A. S. Cambiaghi R. B. F. Leao. Reproduction, IPGO, Sao Paulo, SP, Brazil. OBJECTIVE: To assess the effectiveness of granulocyte colony-stimulating factor for improving the ovary response in IVF cycles of poor responders women. DESIGN: It was a prospective, therapeutic, self-controlled clinical trial. MATERIALS AND METHODS: Between July and December 2011 we selected 10 women that would be submitted to an IVF cycle. The inclusion criteria were: 2 previous failures in cycles with less than 3 oocytes and early follicular phase serum levels of FSH within normal limits. All of them were submitted to the same protocol for ovarian stimulation used in their last cycle, with the association of 0,25 ml Filgrastim 300 mcg/ml subcutaneous every other day from the day of the beginning of ovary stimulation and repeated for 4 times. The study variables were: number of oocytes, mature oocytes and third day embryos, expressed as mean; and pregnancy rate, expressed as percentage. These variables were compared to the last cycle of the same women. T student test was performed to compare means. Pregnancy rate was compared using Fisher’s exact test. RESULTS: Before G-CSF, it were found means of 1,1 oocytes, 0,9 mature oocytes, 0,6 embryos, without any pregnancy. After G-CSF treatment, it was observed 2,4 oocytes, 1,7 mature oocytes, 1,1 embryos and pregnancy rate of 20%. We observed an increasing in number of retrieved oocytes, mature oocytes and embryos in the group that used G-CSF in comparison to those seen in the preceding cycles. All the results haven’t had statistical significance probably due to a small number of cases.

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ASRM Abstracts

CONCLUSION: In poor responders, G-CSF adjuvant therapy seems to improve the number of retrieved oocytes, mature oocytes, embryos and pregnancy rate. Nevertheless, larger studies are needed to confirm the effectiveness of this approach for poor responders.

P-214 Tuesday, October 23, 2012 LATE START OF GONADOTROPIN-RELEASING HORMONE ANTAGONIST DOES NOT COMPROMISE IVF-ET OUTCOMES IN MULTIPLE-DOSE FLEXIBLE PROTOCOL. J. H. Kim,a J. R. Lee,a,b B. C. Jee,a,b C. S. Suh,a,b S. H. Kim.b aDepartment of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Korea; bDepartment of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea. OBJECTIVE: GnRH antagonist (GnRHant) is generally started when a leading follicle reaches a diameter of 14 mm in multiple-dose flexible protocol. There have been few studies on clinical outcomes when GnRHant started lately (leading follicle diameter>14 mm). The objective of this study was to evaluate clinical outcomes of GnRHant late start protocol. DESIGN: Retrospective study. MATERIALS AND METHODS: A number of 209 cycles from 155 women who underwent controlled ovarian hyperstimulation (COH) with GnRHant multiple-dose flexible protocol. The cycles divided into three groups according to the timing of GnRHant (Cetrotide 0.25mg) start based on leading follicle diameter. GnRHant was initiated when leading follicle diameter%14 mm (group 1), 15, 16 mm (group 2), R17 mm (group 3). Duration of GnRHant use and COH outcomes such as number of oocytes retrieved, fertilization, clinical pregnancy and live birth rate were compared among the groups.

Comparison of IVF outcomes among the groups.

Group 1 (n¼34)

Group 2 (n¼84)

Group 3 (n¼91)

2.6
1.0a 2.2
0.9b Duration of 2.7
0.8a GnRH antagonist use (d) No. of oocytes 7.8
7.3 7.5
6.5 8.5
6.8 retrieved No. of mature 3.9
4.2 4.3
4.9 4.7
4.1 oocytes Fertilization 49.1 (130/265) 59.2 (371/627) 50.5 (391/775) rate (%) No. of embryos 2.3
1.0 2.2
0.7 2.4
0.8 transferred Pregnancy rate 26.7 (8/30) 25.3 (19/75) 33.8 (25/74) per ET (%) Live birth 26.7 (8/30) 18.7 (14/75) 24.3 (18/74) rate (%)

P 0.001

0.582 0.669 0.001 0.335 0.499 0.584

RESULTS: There was no significant difference in the clinical characteristics such as age, body mass index, basal FSH, and distribution of infertility causes among the groups. Numbers of retrieved total and mature oocytes were not different among the groups. Clinical pregnancy and live birth rates were not different among the groups. Duration of GnRHant use was significantly reduced in the group 3 compared with others. CONCLUSION: Late start of GnRH antagonist does not compromise the clinical pregnancy and live birth rate with reducing the GnRH antagonist use.

P-215 Tuesday, October 23, 2012 LETROZOLE INDUCED OVULATION AND PREGNANCIES IN ANOVULATORY CLOMIPHENE CITRATE-RESISTANT WOMEN. F. S. Chuong, A. Nardandrea, C. Silva, S. Plosker. Department of Obstetrics and Gynecology, University of South Florida, Tampa, FL.

Vol. 98, No. 3, Supplement, September 2012

OBJECTIVE: To determine the efficacy of the aromatase inhibitor letrozole (LET) 7.5 mg/d for 5 days at achieving ovulation and pregnancy in anovulatory women previously resistant to ovulation (RO) with clomiphene citrate (CC) 200 mg/d for 5 days. DESIGN: Case Time Control. MATERIALS AND METHODS: We identified anovulatory women treated from 1/2007-10/2011 with the following inclusion criteria: 1) RO at initial CC doses of 50-100 mg/d, requiring incremental increases to CC 200 mg/d; 2) continued RO at CC 200 mg/d; 3) treatment with LET 7.5 mg/d after manifesting RO with CC 200 mg/d. CC and LET were administered for 5 days. Ovulation was defined by luteal phase progesterone R3 ng/ml or administration of hCG in the presence of at least 1 dominant follicle R16 mm in the late follicular phase. Using the subjects as their own controls, ovulation and pregnancy rates between CC and LET were compared with an exact binomial test. RESULTS: 23 women were identified. Median age was 30 years (range, 20-39). Outcomes of all CC cycles from 50 mg-200 mg and LET 7.5 mg are illustrated in Table 1.

Ovulation and Pregnancy in 23 CC resistant patients using LET

At least one ovulation Ovulation/cycle Pregnancy/cycle Ongoing pregnancy/cycle Ongoing pregnancy/patient Patients achieving at least one pregnancy

CC(%)

LET(%)

P

13/23 (57) 15/86 (17) 1/86 (1) 1/86 (1) 1/23 (4) 1/23 (4)

18/23 (78) 50/60 (83) 10/60 (17) 3/60 (5) 3/23 (13) 9/23 (39)

0.058 <0.001 <0.001 0.045 0.125 <0.001

CONCLUSION: LET achieved ovulation in 83% of treatment cycles in patients resistant to CC 200 mg, resulting in a pregnancy rate of 17% per cycle and 39% per patient. LET can be considered prior to gonadotropin treatment in CC resistant patients. Given the low ongoing pregnancy rates with LET in this preliminary study, further studies evaluating the efficacy of LET in patients resistant to ovulation at high doses of CC are indicated.

P-216 Tuesday, October 23, 2012 OUTCOMES OF PROTRACTED IVF CYCLES IN POOR RESPONDERS UNDERGOING CLOMIPHENE CITRATE PROTOCOLS. E. Mok-Lin, A. Aelion Brauer, O. Davis, Z. Rosenwaks. The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical College, New York, NY. OBJECTIVE: Clomiphene citrate (CC) is used as an adjunct to gonadotropins in poor responders, many of whom have a protracted cycle. The objective is to compare outcomes in women who were given hCG by cycle day (CD) 13 to those whose stimulation continued to CD14-16 and beyond. DESIGN: Retrospective study. MATERIALS AND METHODS: Patients who underwent CC/antagonist IVF cycles between 1/1/2007-4/1/2012 were identified. Daily CC 100mg was given on CD2-6 and FSH/hMG was started on CD5. hCG was administered when there were at least 2 follicles R18mm and retrieval was performed 35 hours later. Main outcome measures included pregnancy and live birth rates. Statistical analyses included Kruskal-Wallis and c2 tests. P<0.05 was deemed statistically significant. RESULTS: 600 IVF cycles met criteria; hCG was given by CD13 (range 713) in 446 cycles and by CD14-16 in 130 cycles. 24 cycles were continued until at least CD17 (range 17-28). Patients in the CD R17 group used significantly more units of gonadotropins and had fewer oocytes retrieved. The

FERTILITY & STERILITYÒ

CD%13 N Age Previous cycles Total gonadotropins (IU) Oocytes % Mature % 2PN Embryos transferred Embryo grade Implantation (%) Clinical pregnancy (%) Live birth (%)

CD14-16

CDR17

P-value

446 130 24 38.0
4.3 38.1
4.4 37.9
4.7 NS 4.0
2.8 4.3
2.7 2.9
1.3 NS 2328
1113 3659
1617 5797
2881 <0.001 8.7
5.8 9.6
5.0 5.5
5.3 76.3
23.3 75.7
23.7 78.2
29.2 66.7
30.1 69.3
24.9 73.3
31.4 2.8
1.2 3.0
1.3 2.5
1.3 2.0
0.5 2.1
0.6 2.0
0.2 11.1
22.4 15.8
26.1 18.5
32.0 17.3 21.9 21.4 10.0 15.2 21.4

0.005 NS NS NS NS NS NS NS

cancellation rate was significantly higher in this group compared to patients whose cycle ended by CD16 (42% vs. 22%, P¼0.02). Embryo quality and pregnancy rates per retrieval were similar. There were no pregnancies after CD18. CONCLUSION: CC/antagonist IVF cycles continued to CD17 and beyond have a higher rate of cancellation, but patients in this group who proceeded to retrieval had similar pregnancy rates to those with shorter cycles. However, no pregnancies were noted after CD18.

P-217 Tuesday, October 23, 2012 TREATMENT OUTCOMES IN WOMEN RECEIVING IVF/ICSI IN REAL-WORLD SETTING – FSH ALONE VS. LH-CONTAINING GONADOTROPIN REGIMENS. E. Bosch,a S. Crespi,b N. Garrido,a M. Meseguer,a H. Hu.b aIVI Valencia, Valencia, Spain; bMerck & Co., Inc., Whitehouse Station, NJ. OBJECTIVE: To assess the impact of luteinizing hormone (LH) activity on IVF/ICSI outcomes. DESIGN: Retrospective analysis of 11,660 IVF/ICSI cycles performed between 2005 and 2010 in a university-affiliated private fertility clinic. MATERIALS AND METHODS: Univariate and multivariate analyses were conducted to evaluate the effect of LH-containing gonadotropin regimens (FSH + LH, FSH + hMG, or hMG alone) on ongoing pregnancy (OP) and live birth (LB). The following variables were evaluated in multivariate logistic models for OP and LB: age, BMI, # of previous cycles, oral contraceptive pretreatment, basal antral follicle count, stimulation duration, # of oocytes aspirated, total follicle stimulating hormone (FSH) used, initial FSH dose, gonadotropin (FSH alone vs FSH + LH activity), female etiology, and # of embryos transferred. Separate models were built for GnRH antagonist cycles, long GnRH agonist cycles, and all cycles. RESULTS: Univariate analyses show that most of the clinical and demographic factors were statistically significant predictors of OP and LB. OP rates varied by gonadotropin regimen: FSH alone (19.7%), FSH + LH (17.7%), FSH + hMG (18.3%), and hMG alone (14.5%), although the patient profiles vary in clinical and demographic variables. Similar OP rates were seen in antagonist and agonist cycles. After adjusting for potential confounding factors, the OP and LB rates were statistically lower with LH-activity (OR¼0.69 P¼0.044; OR¼0.62, P¼0.017) in GnRH antagonist cycles. In long GnRH agonist cycles, the effect of LH-activity was not statistically significant. For all cycles combined, the ORs for OP and LB were lower with LH-containing regimens than FSH alone (OR¼0.73, P¼0.009; OR¼0.70, P¼0.005). CONCLUSION: In a real-world setting, LH-containing gonadotropin regimens were not associated with better clinical outcomes compared to FSH alone in agonist cycles and were associated with lower pregnancy and live birth rates in antagonist cycles. Supported by: This study was supported by Merck & Co., Inc.

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