- Email: [email protected]
ICSI patients
MATERIALS AND METHODS: 103 patients with at least two failed cycles of IVF or ICSI treatment after gonadotropin stimulation in downregulated cycles were included in this study at our tertiary care infertility clinic. The reason for infertility was tubal or male factor. Blood samples were taken from each patient in the middle of the cycle after failed ART therapy. Quantitative and qualitative analysis of plasma amino acid profiles was performed in all patients using high-performance liquid chromatography. The average number of aspirated oocytes per cycle was compared between patients with low and normal L-arginine levels by statistical evaluation (Mann-Whitney test). RESULTS: In 90 patients (87%) a decreased level of plasma L-arginine was measured (normal range: 70⫺130 mol/l). The proportion of Larginine in the aminogram was also reduced below the 5th percentile (2.22%) in 60 patients (58%). The average number of aspirated oocytes per cycle was significantly lower in patients with decreased absolute and relative levels of plasma L-arginine (4.00 vs 6.75 oocyctes per cycle, p⫽0.01; 4.34 vs 6.75 oocytes per cycle, p⫽0.028). CONCLUSION: Plasma L-arginine levels may play a role in patients suffering from recurrent failure of ART especially by poor response. Supported by: Christian-Lauritzen-Institut.
Wednesday, October 20, 2004 2:30 P.M. O-306 Transdermal testosterone application: Effects on the ovarian responsiveness to FSH for low responders to controlled hyperstimulation. J. N. Hugues, N. Massin, J. Galey-Fontaine, C. Coussieu, H. Bry-Gauillard, I. Cedrin-Durnerin. Center for Reproductive Medicine Jean Verdier Hospital University Paris XIII, Bondy, France; Center for Reproductive Medicine, Bondy, France; Laboratory of Hormonal Biochemistry, Paris cedex 4, France. OBJECTIVE: Some evidence exists in humans that androgens may synergistically act with FSH to promote the early follicular recruitment which is critical in ART program. The purpose of this study was to assess whether women with previous low response to FSH could benefit from androgen application. DESIGN: A prospective, randomized, double blind study was conducted. MATERIALS AND METHODS: Forty-nine women were included if they met the following criteria : (i) low response defined as estradiol ⬍ 1200 pg/mL and oocytes ⱕ 5 in a previous cycle and (ii) evidence for decreased ovarian reserve according to day 3 hormonal measurements. For the study cycle, women were randomized to receive either transdermal application of testosterone (10 mg/ day) or placebo during 15 days prior to FSH treatment. For each patient the same agonist or antagonist protocol and similar FSH daily doses were used in both the previous and the study cycles. Oocyte retrieval was performed if at least 3 follicles ⱖ15 mm were detected. A paired analysis comparing the previous cycle and the study cycle was performed. Results are expressed as mean ⫾ SEM. RESULTS: Testosterone (n ⫽ 24) and placebo (n ⫽ 25) treated groups were comparable regarding age, basal hormonal level on day 3 (including testosterone) and ovarian response in the previous cycle. Testosterone gel application resulted in a significant increase in plasma testosterone levels at day 1 of the stimulation (1.7 ⫾ 0.2 vs 0.6 ⫾ 0.03 ng/mL in the placebo group, p⬍0.0001). Oocyte retrieval was performed in 16 cycles (67%) in the testosterone group and in 20 cycles (80%) in the placebo group (p⫽0.45). Comparison of the previous and the study cycles for both treatment groups show that FSH doses, follicle numbers, plasma estradiol peak values and oocyte numbers were not significantly different. However, paired comparison between the study and the previous cycles shows that testosterone application was associated with a higher number of metaphase 2 oocytes (3.8 ⫾ 0.8 vs 2.3 ⫾ 0.2, p⫽0.05) as well as embryos (2.6 ⫾ 0.7 vs 1.6 ⫾ 0.2, NS). In contrast, these parameters were not different in the placebo treated patients (3.3 ⫾ 0.4 vs 2.7 ⫾ 0.2 ; 1.9 ⫾ 0.2 vs 1.8 ⫾ 0.2, respectively). Four clinical pregnancies were observed in the testosterone group (pregnancy rate per transfer 33%) and one in the placebo group (6%). No adverse effects were observed during transdermal testosterone application. CONCLUSION: This study addresses the issue of the potential effect of androgen administration on ovarian responsiveness to FSH in humans. Testosterone gel application to low responder women may improve the
FERTILITY & STERILITY威
number of metaphase 2 oocytes. However, further studies are needed to extend the evaluation of this therapeutic effect and to optimize the regimen of testosterone administration. Supported by: None
Wednesday, October 20, 2004 2:45 P.M. O-307 Aromatase inhibitor letrozole improves implantation rate in poor responder IVF/ICSI patients. L. Moreno, A. Guille´ n, A. Pacheco, A. Mifsud, L. Duque, J. A. Garcia-Velasco. Instituto Valenciano de Infertilidad, Madrid, Spain. OBJECTIVE: Recent studies have shown that androgens in addition to serving as precursors for ovarian estrogen synthesis, also have a fundamental trophic role in primate ovarian follicular development by augmentation of FSH receptor expression on granulosa cells. This mechanism may explain the frequent hyperresponse to ovarian stimulation of PCO patients. The objective of this pilot study is to assess if aromatase inhibition with letrozole improves ovarian response and cycle outcome in a low responder series undergoing controled ovarian hyperstimulation for IVF in comparison with a control group. DESIGN: Case-control study MATERIALS AND METHODS: 147 patients with a previous poor response to standard long protocol (less than four follicles ⱖ16 mm and/or serum E2ⱕ 500 pg/ml on the day of hCG administration) were included and divided in two groups: 76 patients (control group) received high doses FSH/hMG stimulation protocol starting on day 3 of menstrual cycle. A GnRH antagonist was administered to avoid premature ovulation starting when leading follicles reached 14 mm in mean diameter. On the other hand 71 patients (study group) also received a similar protocol with GnRH antagonist but with the addition of letrozole 2.5 mg/day administered from stimulation days 1 through 5. Follicular fluid and blood samples were obtained for all patients the day of egg retrieval. Chi square and student‘s t test were used as appropiate and pⱕ 0.05 was considered significant. RESULTS: Patients were comparable in terms of age (37.4 vs 36.5), body mass index (23.2 vs 22.5) and day 3 serum FSH, LH and estradiol levels. No significant differences among groups were found in terms of days of stimulation (8.9 vs 9.3), mean FSH/hMG dose administered (3804.6 vs 3627.4), mean serum E2 levels the day hCG (813.5 vs 770.04), endometrial thickness (9.8 vs 9.6) and cancelation rate (19.7 vs 15.5%). Despite no difference was found in the number of mature follicles (3.3 vs 3.7), the oocyte retrieved resulted significantly higher in the study group (4.3 vs 6.1, p : 0.033). Interestingly, we found a marked difference in the implantation rate resulting significantly higher in the letrozole group (9.4 vs 25%, p :0.009). There was a clinically relevant higher pregnancy rate in the letrozole group (41.6% vs 28.9%) but values did not reach statistical significance, probably due to sample size. CONCLUSION: We have shown that aromatase inhibition with letrozole significantly improves implantation rate in low responder patients undergoing IVF cycle in comparison with a control group. A randomized trial is mandatory to validate this hypothesis. Supported by: None
Wednesday, October 20, 2004 3:00 P.M. O-308 Comparison of GnRH agonist and antagonist protocols for controlled ovarian hyperstimulation (COH) in poor response IVF patients. N. J. Winston, M. Puccini, L. Nelson, H. Scoccia. University of Illinois at Chicago, Chicago, IL. OBJECTIVE: The cancellation rate in IVF cycles, due to poor response to COH, is reported to be up to 30%. Various COH protocols have been tried in poor responders, but no clear cut data exists to determine which protocols are the most appropriate. We compared two protocols for COH in poor responders with the objective of improving their stimulation and live birth rate.
S123
Wednesday, October 20, 2004 2:30 P.M. O-306 Transdermal testosterone application: Effects on the ovarian responsiveness to FSH for low responders to controlled hyperstimulation. J. N. Hugues, N. Massin, J. Galey-Fontaine, C. Coussieu, H. Bry-Gauillard, I. Cedrin-Durnerin. Center for Reproductive Medicine Jean Verdier Hospital University Paris XIII, Bondy, France; Center for Reproductive Medicine, Bondy, France; Laboratory of Hormonal Biochemistry, Paris cedex 4, France. OBJECTIVE: Some evidence exists in humans that androgens may synergistically act with FSH to promote the early follicular recruitment which is critical in ART program. The purpose of this study was to assess whether women with previous low response to FSH could benefit from androgen application. DESIGN: A prospective, randomized, double blind study was conducted. MATERIALS AND METHODS: Forty-nine women were included if they met the following criteria : (i) low response defined as estradiol ⬍ 1200 pg/mL and oocytes ⱕ 5 in a previous cycle and (ii) evidence for decreased ovarian reserve according to day 3 hormonal measurements. For the study cycle, women were randomized to receive either transdermal application of testosterone (10 mg/ day) or placebo during 15 days prior to FSH treatment. For each patient the same agonist or antagonist protocol and similar FSH daily doses were used in both the previous and the study cycles. Oocyte retrieval was performed if at least 3 follicles ⱖ15 mm were detected. A paired analysis comparing the previous cycle and the study cycle was performed. Results are expressed as mean ⫾ SEM. RESULTS: Testosterone (n ⫽ 24) and placebo (n ⫽ 25) treated groups were comparable regarding age, basal hormonal level on day 3 (including testosterone) and ovarian response in the previous cycle. Testosterone gel application resulted in a significant increase in plasma testosterone levels at day 1 of the stimulation (1.7 ⫾ 0.2 vs 0.6 ⫾ 0.03 ng/mL in the placebo group, p⬍0.0001). Oocyte retrieval was performed in 16 cycles (67%) in the testosterone group and in 20 cycles (80%) in the placebo group (p⫽0.45). Comparison of the previous and the study cycles for both treatment groups show that FSH doses, follicle numbers, plasma estradiol peak values and oocyte numbers were not significantly different. However, paired comparison between the study and the previous cycles shows that testosterone application was associated with a higher number of metaphase 2 oocytes (3.8 ⫾ 0.8 vs 2.3 ⫾ 0.2, p⫽0.05) as well as embryos (2.6 ⫾ 0.7 vs 1.6 ⫾ 0.2, NS). In contrast, these parameters were not different in the placebo treated patients (3.3 ⫾ 0.4 vs 2.7 ⫾ 0.2 ; 1.9 ⫾ 0.2 vs 1.8 ⫾ 0.2, respectively). Four clinical pregnancies were observed in the testosterone group (pregnancy rate per transfer 33%) and one in the placebo group (6%). No adverse effects were observed during transdermal testosterone application. CONCLUSION: This study addresses the issue of the potential effect of androgen administration on ovarian responsiveness to FSH in humans. Testosterone gel application to low responder women may improve the
FERTILITY & STERILITY威
number of metaphase 2 oocytes. However, further studies are needed to extend the evaluation of this therapeutic effect and to optimize the regimen of testosterone administration. Supported by: None
Wednesday, October 20, 2004 2:45 P.M. O-307 Aromatase inhibitor letrozole improves implantation rate in poor responder IVF/ICSI patients. L. Moreno, A. Guille´ n, A. Pacheco, A. Mifsud, L. Duque, J. A. Garcia-Velasco. Instituto Valenciano de Infertilidad, Madrid, Spain. OBJECTIVE: Recent studies have shown that androgens in addition to serving as precursors for ovarian estrogen synthesis, also have a fundamental trophic role in primate ovarian follicular development by augmentation of FSH receptor expression on granulosa cells. This mechanism may explain the frequent hyperresponse to ovarian stimulation of PCO patients. The objective of this pilot study is to assess if aromatase inhibition with letrozole improves ovarian response and cycle outcome in a low responder series undergoing controled ovarian hyperstimulation for IVF in comparison with a control group. DESIGN: Case-control study MATERIALS AND METHODS: 147 patients with a previous poor response to standard long protocol (less than four follicles ⱖ16 mm and/or serum E2ⱕ 500 pg/ml on the day of hCG administration) were included and divided in two groups: 76 patients (control group) received high doses FSH/hMG stimulation protocol starting on day 3 of menstrual cycle. A GnRH antagonist was administered to avoid premature ovulation starting when leading follicles reached 14 mm in mean diameter. On the other hand 71 patients (study group) also received a similar protocol with GnRH antagonist but with the addition of letrozole 2.5 mg/day administered from stimulation days 1 through 5. Follicular fluid and blood samples were obtained for all patients the day of egg retrieval. Chi square and student‘s t test were used as appropiate and pⱕ 0.05 was considered significant. RESULTS: Patients were comparable in terms of age (37.4 vs 36.5), body mass index (23.2 vs 22.5) and day 3 serum FSH, LH and estradiol levels. No significant differences among groups were found in terms of days of stimulation (8.9 vs 9.3), mean FSH/hMG dose administered (3804.6 vs 3627.4), mean serum E2 levels the day hCG (813.5 vs 770.04), endometrial thickness (9.8 vs 9.6) and cancelation rate (19.7 vs 15.5%). Despite no difference was found in the number of mature follicles (3.3 vs 3.7), the oocyte retrieved resulted significantly higher in the study group (4.3 vs 6.1, p : 0.033). Interestingly, we found a marked difference in the implantation rate resulting significantly higher in the letrozole group (9.4 vs 25%, p :0.009). There was a clinically relevant higher pregnancy rate in the letrozole group (41.6% vs 28.9%) but values did not reach statistical significance, probably due to sample size. CONCLUSION: We have shown that aromatase inhibition with letrozole significantly improves implantation rate in low responder patients undergoing IVF cycle in comparison with a control group. A randomized trial is mandatory to validate this hypothesis. Supported by: None
Wednesday, October 20, 2004 3:00 P.M. O-308 Comparison of GnRH agonist and antagonist protocols for controlled ovarian hyperstimulation (COH) in poor response IVF patients. N. J. Winston, M. Puccini, L. Nelson, H. Scoccia. University of Illinois at Chicago, Chicago, IL. OBJECTIVE: The cancellation rate in IVF cycles, due to poor response to COH, is reported to be up to 30%. Various COH protocols have been tried in poor responders, but no clear cut data exists to determine which protocols are the most appropriate. We compared two protocols for COH in poor responders with the objective of improving their stimulation and live birth rate.
S123