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Letrozole can be used in combination with GnRH agonists in poor responders without negating its beneficial effects
TABLE
Variable Age (yrs) Cycle cancellation (%) FSH/hMG (IUs) E2 day of HCG (pg/ mL) FollicleR14mm Oocytes (#) 2PNs (#) ICSI (%) Grade 1-2 embryos Embryos transferred Implantation Rate (%) Clinical PR (%) Ongoing PR (%)
Conventional IVF (Cycles¼87)
Letrozole IVF (Cycles¼66)
P value
37.5 2.7 56.3 (49/87)
37.9 2.8 18.2 (12/66)
0.38 <0.01
3915 1183 858 634
4811 1461 830 543
<0.01 0.76
3.5 3.0 7.2 3.2 4.0 2.4 42.5 (37/87) 2.1 1.4 2.7 1.1 4.9 (5/102) 5.6 (5/87) 4.6 (4/87)
5.7 2.7 8.2 4.8 3.8 2.8 53.1 (35/66) 2.0 1.9 2.2 1.4 14.0 (17/121) 16.7 (11/66) 15.2 (10/66)
<0.01 0.26 0.72 0.20 0.40 0.06 0.02 0.03 0.03
CONCLUSIONS: We have previously reported in poor responders that the addition of letrozole to IVF cycles decreases cancellation rates and improves ongoing pregnancy rates (PR) (Kapoor; F&S 2007). The current report represents an expanded data set and now shows significance for improved implantation and clinical pregnancy rates. The fact that there is a statistically significant improvement in implantation rates further validates the use of letrozole in poor responders. A prospective randomized study is indicated to further define the potential beneficial effect of letrozole in ovarian stimulation protocols. Supported by: None.
Monday, November 10, 2008 4:45 pm
(BP) which favored the cycles of LZ þ G (3 BP) and CC þ G (2 BP), ongoing clinical pregnancy rates were too low for valid comparisons and were 1 with CC, 2 with G and 1 with LZþG. CONCLUSIONS: In poor responders, the addition of CC or LZ to gonadotropin treatment significantly enhanced the oocyte and embryo yield. The data suggest that the addition of LZ may be somewhat more efficacious than CC, although this is preliminary. The overall pregnancy rates in this group of women, nevertheless, is poor. Supported by: None.
Monday, November 10, 2008 5:00 pm O-93 LETROZOLE CAN BE USED IN COMBINATION WITH GnRH AGONISTS IN POOR RESPONDERS WITHOUT NEGATING ITS BENEFICIAL EFFECTS. M. Kapoor, A. J. Polotsky, C. Benadiva, M. P. Leondires, S. S. Richilin, J. M. Hurwitz. OB/GYN, Danbury Hospital, Danbury, CT; OB/GYN, Albert Einstein College of Medicine, Bronx, NY; OB/GYN, University of Connecticut, Farmington, CT; Reproductive Medicine Associates of Connecticut, Norwalk, CT. OBJECTIVE: To compare agonist and antagonist protocols and the role of letrozole in IVF for poor responders. DESIGN: Retrospective cohort study. MATERIALS AND METHODS: 55 patients defined as poor responders based on previous COH/IVF performance (at least 1 previous cycle with %4 mature follicles or estradiol (E2) %500 pg/mL) were treated with letrozole 5mg/day on cycle days (CD) 2-6 in addition to either an antagonist FSH/ hMG protocol (Let-Ant) or a microdose flare FSH/hMG protocol (Let-MDF). MDF was started on CD3 and gonadotropin injections were started on CD4. Ovarian stimulation and oocyte retrieval were performed according to established protocols. RESULTS: Mean SD, unless indicated.
O-92
TABLE
DOES THE ADDITION OF CLOMIPHENE CITRATE OR LETRAZOLE TO GONADOTROPIN TREATMENT ENHANCE THE OOCYTE YIELD IN POOR RESPONDERS UNDERGOING ANTAGONIST IVF CYCLES? V. P. Jovanovic, M. M. Guarnaccia, D. H. Kort, M. V. Sauer, R. A. Lobo. REI/OB-GYN, Columbia University Medical Center, New York, NY; REI/OB-GYN, Center for Womens Reproductive Care, New York, NY. OBJECTIVE: To determine whether the addition of clomiphene citrate (CC) or letrazole (LZ) enhance the oocyte and embryo yield of poor responders undergoing antagonist IVF cycles; and whether one regimen may be superior to the other. DESIGN: Retrospective analysis of matched IVF antagonist cycles in women who had received more than one of the treatment regimens. MATERIALS AND METHODS: Between 2006-2008 we identified 423 cycles of poor responding women who underwent gonadotropin treatment (450-600 IU/day) alone or in combination with either CC or LZ; as well as women who have undergone gonadotropin treatment combined with both CC and LZ in sequential cycles. The sequential treatments were carried out within a 3-4 month time frame. The women studied were 41.1 2.2 years old, with FSH values of 9.5 4.5 mIU/ml and where characterized by prior poor responses, having % 3 mature follicles during prior gonadotropin therapy. CC 100 mg/day or letrazole 5 mg/day were given for the first 5 days of gonadotropin therapy starting on cycle day 2. A standard IVF antagonist protocol was followed otherwise. Responses of oocyte yield, maximum E2, embryos yield and pregnancy rates were compared in the following matched cycles where total gonadotropin dosage was the same: Gonadotropins alone (G) vs. CCþG (n¼36), LZ þ G vs. G (n¼13), and CC þG vs. LZ þG (n¼8). RESULTS: CCþG increased the oocyte yield by 66% compared to G (5.25 vs. 3.16, p<0.01) and increased the embryo number from 1.69 1.83 to 2.31 1.66 (p¼0.11). Similarly, LZþ G increased the oocyte yield by 69% compared to G (5.79 vs. 3.42, p<0.05) and increased the average embryo number from 1.65 2.24 to 3.81 2.64 (p<0.05). In a smaller group of women who had received both combinations in random order, the oocyte yield of LZþG was greater than that of CCþG (5.5 1.77 vs. 2.93 1.74, p < 0.01). The embryo yield was also increased with LZþ G, compared to CCþG (2.35 1.18 vs. 1.25 þ1.39, p<0.05). While there were biochemical pregnacy rates
S34
Abstracts
Letrozole only patients
Antagonist (N¼24)
Micro-Flare (N¼42)
P value
Age (yrs) Cycle cancellation (%) FSH/hMG (IUs) E2 day of hCG (pg/ml) Follicle14mm Grade 1-2 embryos Oocytes (#) 2PN (#) ICSI (%) Embryos transferred Implantation Rate (%) Clinical PR (%) Ongoing PR (%)
38.9 2.5 20.8 (5/24)
37.3 2.8 16.7 (7/42)
0.03 0.67
4612 1167 716 410 5.4 2.5 3.1 2.4 9.1 4.9 5.1 2.5 45.8 (11/24) 3.1 1.4 8.3 (4/48) 12.5 (3/24) 4.2 (1/24)
4925 1609 894 601 5.9 2.9 1.4 1.2 7.7 4.8 3.1 2.7 57.1 (24/42) 1.8 1.2 20.6 (13/63) 19.0(8/42) 9.5(4/42)
0.48 0.25 0.75 <0.01 0.34 <0.01 0.38 <0.01 0.07 0.50 0.43
CONCLUSIONS: We have previously demonstrated that the addition of letrozole to conventional COH/IVF stimulation was associated with a statistically significant benefit in cycle and pregnancy parameters in poor responders (Kapoor; FS 2007). The aim of the current study was to attempt to determine whether this benefit was mediated by an increase in endogenous hypothalamic gonadotropins via the release from negative estrogenic feedback, or by altering the local ovarian environment. Both groups had similar cycle characteristics, suggesting that letrozole’s benefit is mediated at the ovarian level and not primarily at the hypothalamus. As there is rapid desensitization of the hypothalamic-pituitary axis in MDF protocols, we speculate that accumulation of intra-ovarian androgens by aromatase blockade may locally increase FSH receptivity and potentiate IVF stimulation (Mitwally; FS 2002). It is noteworthy that more embryos of higher grade were available for transfer in the Let-Ant group. Our findings corroborate the benefits of letrozole in poor responder protocols. This study demonstrates that letrozole’s benefit is not impacted by either agonist or antagonist protocols. Supported by: None.
Vol. 90, Suppl 1, September 2008
Variable Age (yrs) Cycle cancellation (%) FSH/hMG (IUs) E2 day of HCG (pg/ mL) FollicleR14mm Oocytes (#) 2PNs (#) ICSI (%) Grade 1-2 embryos Embryos transferred Implantation Rate (%) Clinical PR (%) Ongoing PR (%)
Conventional IVF (Cycles¼87)
Letrozole IVF (Cycles¼66)
P value
37.5 2.7 56.3 (49/87)
37.9 2.8 18.2 (12/66)
0.38 <0.01
3915 1183 858 634
4811 1461 830 543
<0.01 0.76
3.5 3.0 7.2 3.2 4.0 2.4 42.5 (37/87) 2.1 1.4 2.7 1.1 4.9 (5/102) 5.6 (5/87) 4.6 (4/87)
5.7 2.7 8.2 4.8 3.8 2.8 53.1 (35/66) 2.0 1.9 2.2 1.4 14.0 (17/121) 16.7 (11/66) 15.2 (10/66)
<0.01 0.26 0.72 0.20 0.40 0.06 0.02 0.03 0.03
CONCLUSIONS: We have previously reported in poor responders that the addition of letrozole to IVF cycles decreases cancellation rates and improves ongoing pregnancy rates (PR) (Kapoor; F&S 2007). The current report represents an expanded data set and now shows significance for improved implantation and clinical pregnancy rates. The fact that there is a statistically significant improvement in implantation rates further validates the use of letrozole in poor responders. A prospective randomized study is indicated to further define the potential beneficial effect of letrozole in ovarian stimulation protocols. Supported by: None.
Monday, November 10, 2008 4:45 pm
(BP) which favored the cycles of LZ þ G (3 BP) and CC þ G (2 BP), ongoing clinical pregnancy rates were too low for valid comparisons and were 1 with CC, 2 with G and 1 with LZþG. CONCLUSIONS: In poor responders, the addition of CC or LZ to gonadotropin treatment significantly enhanced the oocyte and embryo yield. The data suggest that the addition of LZ may be somewhat more efficacious than CC, although this is preliminary. The overall pregnancy rates in this group of women, nevertheless, is poor. Supported by: None.
Monday, November 10, 2008 5:00 pm O-93 LETROZOLE CAN BE USED IN COMBINATION WITH GnRH AGONISTS IN POOR RESPONDERS WITHOUT NEGATING ITS BENEFICIAL EFFECTS. M. Kapoor, A. J. Polotsky, C. Benadiva, M. P. Leondires, S. S. Richilin, J. M. Hurwitz. OB/GYN, Danbury Hospital, Danbury, CT; OB/GYN, Albert Einstein College of Medicine, Bronx, NY; OB/GYN, University of Connecticut, Farmington, CT; Reproductive Medicine Associates of Connecticut, Norwalk, CT. OBJECTIVE: To compare agonist and antagonist protocols and the role of letrozole in IVF for poor responders. DESIGN: Retrospective cohort study. MATERIALS AND METHODS: 55 patients defined as poor responders based on previous COH/IVF performance (at least 1 previous cycle with %4 mature follicles or estradiol (E2) %500 pg/mL) were treated with letrozole 5mg/day on cycle days (CD) 2-6 in addition to either an antagonist FSH/ hMG protocol (Let-Ant) or a microdose flare FSH/hMG protocol (Let-MDF). MDF was started on CD3 and gonadotropin injections were started on CD4. Ovarian stimulation and oocyte retrieval were performed according to established protocols. RESULTS: Mean SD, unless indicated.
O-92
TABLE
DOES THE ADDITION OF CLOMIPHENE CITRATE OR LETRAZOLE TO GONADOTROPIN TREATMENT ENHANCE THE OOCYTE YIELD IN POOR RESPONDERS UNDERGOING ANTAGONIST IVF CYCLES? V. P. Jovanovic, M. M. Guarnaccia, D. H. Kort, M. V. Sauer, R. A. Lobo. REI/OB-GYN, Columbia University Medical Center, New York, NY; REI/OB-GYN, Center for Womens Reproductive Care, New York, NY. OBJECTIVE: To determine whether the addition of clomiphene citrate (CC) or letrazole (LZ) enhance the oocyte and embryo yield of poor responders undergoing antagonist IVF cycles; and whether one regimen may be superior to the other. DESIGN: Retrospective analysis of matched IVF antagonist cycles in women who had received more than one of the treatment regimens. MATERIALS AND METHODS: Between 2006-2008 we identified 423 cycles of poor responding women who underwent gonadotropin treatment (450-600 IU/day) alone or in combination with either CC or LZ; as well as women who have undergone gonadotropin treatment combined with both CC and LZ in sequential cycles. The sequential treatments were carried out within a 3-4 month time frame. The women studied were 41.1 2.2 years old, with FSH values of 9.5 4.5 mIU/ml and where characterized by prior poor responses, having % 3 mature follicles during prior gonadotropin therapy. CC 100 mg/day or letrazole 5 mg/day were given for the first 5 days of gonadotropin therapy starting on cycle day 2. A standard IVF antagonist protocol was followed otherwise. Responses of oocyte yield, maximum E2, embryos yield and pregnancy rates were compared in the following matched cycles where total gonadotropin dosage was the same: Gonadotropins alone (G) vs. CCþG (n¼36), LZ þ G vs. G (n¼13), and CC þG vs. LZ þG (n¼8). RESULTS: CCþG increased the oocyte yield by 66% compared to G (5.25 vs. 3.16, p<0.01) and increased the embryo number from 1.69 1.83 to 2.31 1.66 (p¼0.11). Similarly, LZþ G increased the oocyte yield by 69% compared to G (5.79 vs. 3.42, p<0.05) and increased the average embryo number from 1.65 2.24 to 3.81 2.64 (p<0.05). In a smaller group of women who had received both combinations in random order, the oocyte yield of LZþG was greater than that of CCþG (5.5 1.77 vs. 2.93 1.74, p < 0.01). The embryo yield was also increased with LZþ G, compared to CCþG (2.35 1.18 vs. 1.25 þ1.39, p<0.05). While there were biochemical pregnacy rates
S34
Abstracts
Letrozole only patients
Antagonist (N¼24)
Micro-Flare (N¼42)
P value
Age (yrs) Cycle cancellation (%) FSH/hMG (IUs) E2 day of hCG (pg/ml) Follicle14mm Grade 1-2 embryos Oocytes (#) 2PN (#) ICSI (%) Embryos transferred Implantation Rate (%) Clinical PR (%) Ongoing PR (%)
38.9 2.5 20.8 (5/24)
37.3 2.8 16.7 (7/42)
0.03 0.67
4612 1167 716 410 5.4 2.5 3.1 2.4 9.1 4.9 5.1 2.5 45.8 (11/24) 3.1 1.4 8.3 (4/48) 12.5 (3/24) 4.2 (1/24)
4925 1609 894 601 5.9 2.9 1.4 1.2 7.7 4.8 3.1 2.7 57.1 (24/42) 1.8 1.2 20.6 (13/63) 19.0(8/42) 9.5(4/42)
0.48 0.25 0.75 <0.01 0.34 <0.01 0.38 <0.01 0.07 0.50 0.43
CONCLUSIONS: We have previously demonstrated that the addition of letrozole to conventional COH/IVF stimulation was associated with a statistically significant benefit in cycle and pregnancy parameters in poor responders (Kapoor; FS 2007). The aim of the current study was to attempt to determine whether this benefit was mediated by an increase in endogenous hypothalamic gonadotropins via the release from negative estrogenic feedback, or by altering the local ovarian environment. Both groups had similar cycle characteristics, suggesting that letrozole’s benefit is mediated at the ovarian level and not primarily at the hypothalamus. As there is rapid desensitization of the hypothalamic-pituitary axis in MDF protocols, we speculate that accumulation of intra-ovarian androgens by aromatase blockade may locally increase FSH receptivity and potentiate IVF stimulation (Mitwally; FS 2002). It is noteworthy that more embryos of higher grade were available for transfer in the Let-Ant group. Our findings corroborate the benefits of letrozole in poor responder protocols. This study demonstrates that letrozole’s benefit is not impacted by either agonist or antagonist protocols. Supported by: None.
Vol. 90, Suppl 1, September 2008