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Optimizing stimulation protocols in IVF cycles using the GnRH antagonist
Keith Hill, Brian Barnett, James Douglas, Alfred Rodriguez, Samuel Chantilis, Marius Meintjes. Presbyterian Hosp ARTS Program, Dallas, TX. Objective: It is suggested by some that blastocyst transfers should be performed for all patients, regardless of age and embryo quality. However, the majority of blastocyst programs maintains that pregnancy outcomes can be optimized by the “rescue” transfer of some embryos at earlier stages of development. The objectives of this study were to evaluate if clinical- or multiple pregnancy outcomes are compromised under the following circumstances and, if so, if it could be related to age. The two circumstances would be when 1) embryos are transferred at the cleavage stage when supernumary embryos are available for selection or when 2) embryos are cultured to the blastocyst stage for transfer when limited numbers of quality embryos are available at the cleavage stages. Design: Data were prospectively collected for all embryo transfers over a 4-year period. Patients using non-ejaculated sperm, gestational carriers or ⬎40 years of age were not included. The age groups evaluated were 1) ⱕ 34, 2) 35-37, 3) 38-40 and 4) donor-oocyte cycles. Within the age categories, treatment groups included day of transfer (day 3 vs., day 5) and the number of quality embryos (ⱖ6 cells with ⬍15% fragmentation) available on day 3 (ⱕ3 embryos vs., ⱖ4 embryos for all age groups except for ages 38 to 40; ⱕ4 vs., ⱖ5). Materials and Methods: Standard IVF and ICSI procedures were used for fertilization. Fertilized embryos were cultured in microdrops under oil using a G-1/G-2 sequential culture system. Differences in endpoints were detected with a Chi-square analysis or a t-test. Results: See tables
a,b Values in columns within age groups with different superscripts are different. 2 , p ⬍ 0.001.
Objective: There is an increasing evidence supporting the role of a regulated cytokine network in the ovulatory process. In humans, it has been shown that follicular fluid (FF) exerts chemotactic activity toward granulocytes and that activity is related to the outcome of in vitro fertilization (IVF) treatment. IL-6 is a regulator of inflammation and immunity, which may be a physiologic link between the endocrine and the immune systems. It also modulates secretion of other cytokines, promotes T-cell activation and B-cell differentiation. The objective of this study was to investigate the role of IL-6 in the periovulatory FF during IVF cycles. Design: A prospective study Materials and Methods: Follicular fluid from 112 women was obtained while they underwent oocyte retrieval for IVF. The indications for IVF were endometriosis in 31 patients, idiopathic infertility in 15, tubal-factor infertility in 21, ovarian-factor infertility in 15, and 30 patients with male-factor infertility. We measured the concentrations of IL-6 in FF using quantative ELISA kits and compared the levels among women who became pregnant and those who did not. Results: Fifty-two patients achieved pregnancy where 60 did not. Both pregnant and non-pregnant patients were comparable regarding age, parity, ovarian stimulation parameters, fertilization rates, and embryo freezing rates (table). Levels of FF IL-6 were significantly higher in pregnant compared to non-pregnant cycles (p ⫽ 0.0005).
Conclusions: Lower levels of IL-6 in the periovulatory FF appear to be associated with a negative outcome in IVF treatment. IL-6 may be a biological marker that affects folliculogenesis, oocyte quality, and/or implantation.
Wednesday, October 15, 2003 2:30 P.M. O-253
a,b Values in columns within embryo quality groups with different superscripts are different. 2, p ⬍ .04.
Conclusion: The expected higher implantation- and pregnancy rates for blastocyst transfers for all patient age groups are partly due to the selection of better prognosis patients for blastocyst transfer. Blastocyst transfers significantly curtailed triplet pregnancy rates for patients ⱕ37 years of age. It appears to be beneficial to all older patients to have embryos transferred on day 5, regardless of the number of quality embryos on day 3. No evidence could be found to suggest that older patients would be compromised by extended culture of low numbers of quality day-3 embryos. Surprisingly, a 3-embryo day-3 transfer can only be justified in patients ⱕ34 years of age in this program, provided that a ⬎10% triplet pregnancy rate is acceptable.
Wednesday, October 15, 2003 2:15 P.M. O-252 Assessment of the predictive value of follicular fluid IL-6 in IVF cycles. Mohamed A. Bedaiwy, Tommaso Falcone, Jeffery M. Goldberg, Marjan Attaran, Kurt Miller, Ashok Agarwal. Cleveland Clin Fdn, Cleveland, OH.
S96
Abstracts
Optimizing stimulation protocols in IVF cycles using the GnRH antagonist. Alan B. Copperman, Benjamin Sandler, Tanmoy Mukherjee, Lawrence Grunfeld, Paul Bergh, Richard T. Scott Jr. Mount Sinai Sch of Medicine, New York, NY; Reproductive Medicine Assoc of New York, New York, NY; Reproductive Medicine Assoc of New Jersey, Morristown, NJ. Objective: As experience accumulates using the third-generation GnRH antagonist ganirelix (Antagon), it is imperative that we study factors unique to the follicular dynamics and identify factors that might optimize its use in IVF cycles. Design: Non-randomized comparison. Materials and Methods: One thousand seven hundred seventy-three women underwent IVF using the GnRH antagonist over a three year period at Reproductive Medicine Associates of New York and Reproductive Medicine Associates of New Jersey. Controlled ovarian hyperstimulation using a combination of recombinant follicle stimulating hormone (rFSH) and human Menopausal Gonadotropin (hMG) were initiated in split doses beginning on the third day of the menstrual cycle for patients whether or not they were pretreated with oral contraceptive. Ganirelix acetate (250 g/day) was started when the lead follicle reached 14mm. Routinely, an “add-back” of 75 IU of hMG was introduced on the first day of antagonist. Human chorionic gonadotropin (hCG) was administered at the discretion of the treating physician, but was normally given when two follicles reached a greatest diameter of 18mm. The size of the lead follicle at the time of hCG was recorded. For comparison, down regulation cycles using leuprolide acete were analyzed.
Vol. 80, Suppl. 3, September 2003
Results: The clinical pregnancy rate significantly increased in a linear fashion from 5 to 9 days of gonadotropin stimulation as determined by linear regression analysis (P⬍0.001) at which time clinical pregnancy rates plateaued. No pregnancies were observed with 16 or 17 days of gonadotropin stimulation. These results suggest that clinical pregnancy rates improve with increased duration of gonadotropin stimulation, at least up to 9 days. In a second retrospective analysis, we compared pregnancy rates with administration of hCG when the lead follicle diameter was 16 to 17 mm, 18 to 19 mm, or greater than 20 mm. The results are presented in graphic comparison and compared to an unmatched cohort of down-regulation patients.
hormonally diagnosed women with PCOS (LH mean value ⱖ 6 ⫾1.8 IU/mL and FSH mean value ⱕ 7⫾1.2 IU/mL) were compared to a control group of 181 women without PCOS. On cycle day 3, serum levels of AMH, FSH, estradiol (E2), inhibin B (INHB), and LH were measured within the two months before the procedure of ART. We compared between the two patients groups the age, serum levels of each hormone, number of retrieved oocytes, number of embryos obtained at day two and the rate of ongoing pregnancy .Statistical analysis was computed for each parameter in all patients groups. Results: Among the 232 women with PCOS, the AMH serum levels in 79 pregnant patients (mean age: 34.9⫾1.2 yrs) and in 153 non pregnant patients (mean age: 35.16⫾1.3 yrs) were respectively 3.09⫾1.2 and 1.96⫾0.8 ng/mL (P- value ⱕ0.00005), INHB serum levels were 75.2⫾12.2 and 74.18⫾14.2 pg/mL (P- value ⫽ 0.01), E2 serum levels were 24.1⫾14 and 25.9⫾15 pg/mL and the FSH serum levels were 6.28⫾1.1 and 6.58 ⫾1.15 IU/mL (P- value ⱕ0.05). The mean age and E2 serum levels were not statistically different between the pregnant and non pregnant women. The number of retrieved oocytes (7,9⫾4.2) and embryos (5,8⫾3.1) was higher in the pregnant group compared to the non pregnant group (respectively 6.5⫾3.5 and 5⫾2.8). Among the control patients group (58 pregnant and 123 non pregnant patients) the AMH serum levels respectively 2.15⫾1.7 and 0.97⫾1.3 ng/mL (P- value ⱕ 0.005) were less correlated to the number of retrieved oocytes or embryos or to the number of ongoing pregnancies than in the studied group. Conclusion: AMH serum levels at day 3 seems to be a good predictive factor to the outcome of ART in women with PCOS.
Wednesday, October 15, 2003 3:00 P.M. O-255 Ejaculatory abstinence less than 3 days results in a higher pregnancy rate (PR) following intrauterine insemination (IUI). Marcus W. Jurema, Andrea D. Damasceno Vieira, Brandon Bankowski, Yulian Zhao, Edward Wallach, Howard Zacur. The Johns Hopkins Medical Institutions, Baltimore, MD; Univ de Brasilia (UdB), Brasilia, Brazil. Conclusions: GnRH antagonists bind to gonadotrope GnRH receptors and compete successfully with endogenous agonist GnRH molecules for receptor occupancy. Follicles are recruited earlier in antagonist cycles (North American Ganrilex Study Group), but it now appears that there is a late difference in follicular dynamics among stimulation protocols, as well. The duration of gonadotropin stimulation associated with acceptable pregnancy rates is fairly broad (9 to 15 days). As the size of the lead follicle increases in GnRH antagonist cycles, a concomitant increase in pregnancy rates occurs. Conversely, patients in agonist down-regulation treatment regimens do not benefit from obtaining larger follicle sizes. Furthermore, it appears that increasing lead follicle size is a more accurate correlator of increasing pregnancy rates than increasing duration of gonadotropin stimulation.
Wednesday, October 15, 2003 2:45 P.M. O-254 Serum anti mullerian hormone as a novel predictive factor of success in art among women with polycystic ovary syndrome? Andre´ Hazout, Anne Marie Junca, Alain Le Meur, Flavien Ternaux, Paul Cohen-Barcie. ART Unit Eylau Muette, Paris, France. Objective: To compare the serum antimullerian hormone (AMH) levels in women with polycystic ovary syndrome (PCOS) and those in women without PCOS, and to define AMH as a predictive factor of success in ART. Design: Retrospective study concerning 413 patients undergoing ART procedure (IVF or ICSI). Materials and Methods: Two hundred thirty-two sonographically and
FERTILITY & STERILITY威
Objective: The duration of ejaculatory abstinence is known to affect sperm concentration and motility, while morphology remains relatively constant. The effect of the abstinence interval on pregnancy outcome is not well characterized since most studies do not consider abstinence as an independent variable. In this study, we examined the influence of the abstinence interval on sperm parameters and pregnancy rates following IUI. Design: Retrospective analysis. Materials and Methods: 410 couples underwent 929 fresh, non-donor IUI cycles performed between June 1999 and October 2002. The influence of the duration of abstinence on the processed sperm parameters (concentration, motility, and total motile sperm [TMS]) and PR was analyzed by Pearson’s correlation. The impact of each of these parameters, including duration of abstinence, on PR was evaluated by stepwise logistic regression. ANOVA and independent t-tests were used to compare means. Results: Duration of abstinence correlated positively with sperm concentration and TMS, but negatively with motility. PR correlated negatively with duration of abstinence (r ⫽ ⫺0.083, p ⬍ 0.05). Logistic regression revealed that only the duration of abstinence had a significant impact on PR. Table 1 shows the PR according to the abstinence interval. There were no differences in male or female age within or between the groups. An abstinence interval of ⱕ 3 days had the highest mean PR (14%), while an interval of 4 to 10 days had a lower mean PR (10%), and an abstinence interval ⬎ 10 days had the lowest mean PR (3%) [Figure 1]. These abstinence interval groups were statistically different from each other (p ⬍ 0.05).
* p ⬍ 0.05 compared to ⬎ 10 days.
S97
a,b Values in columns within age groups with different superscripts are different. 2 , p ⬍ 0.001.
Objective: There is an increasing evidence supporting the role of a regulated cytokine network in the ovulatory process. In humans, it has been shown that follicular fluid (FF) exerts chemotactic activity toward granulocytes and that activity is related to the outcome of in vitro fertilization (IVF) treatment. IL-6 is a regulator of inflammation and immunity, which may be a physiologic link between the endocrine and the immune systems. It also modulates secretion of other cytokines, promotes T-cell activation and B-cell differentiation. The objective of this study was to investigate the role of IL-6 in the periovulatory FF during IVF cycles. Design: A prospective study Materials and Methods: Follicular fluid from 112 women was obtained while they underwent oocyte retrieval for IVF. The indications for IVF were endometriosis in 31 patients, idiopathic infertility in 15, tubal-factor infertility in 21, ovarian-factor infertility in 15, and 30 patients with male-factor infertility. We measured the concentrations of IL-6 in FF using quantative ELISA kits and compared the levels among women who became pregnant and those who did not. Results: Fifty-two patients achieved pregnancy where 60 did not. Both pregnant and non-pregnant patients were comparable regarding age, parity, ovarian stimulation parameters, fertilization rates, and embryo freezing rates (table). Levels of FF IL-6 were significantly higher in pregnant compared to non-pregnant cycles (p ⫽ 0.0005).
Conclusions: Lower levels of IL-6 in the periovulatory FF appear to be associated with a negative outcome in IVF treatment. IL-6 may be a biological marker that affects folliculogenesis, oocyte quality, and/or implantation.
Wednesday, October 15, 2003 2:30 P.M. O-253
a,b Values in columns within embryo quality groups with different superscripts are different. 2, p ⬍ .04.
Conclusion: The expected higher implantation- and pregnancy rates for blastocyst transfers for all patient age groups are partly due to the selection of better prognosis patients for blastocyst transfer. Blastocyst transfers significantly curtailed triplet pregnancy rates for patients ⱕ37 years of age. It appears to be beneficial to all older patients to have embryos transferred on day 5, regardless of the number of quality embryos on day 3. No evidence could be found to suggest that older patients would be compromised by extended culture of low numbers of quality day-3 embryos. Surprisingly, a 3-embryo day-3 transfer can only be justified in patients ⱕ34 years of age in this program, provided that a ⬎10% triplet pregnancy rate is acceptable.
Wednesday, October 15, 2003 2:15 P.M. O-252 Assessment of the predictive value of follicular fluid IL-6 in IVF cycles. Mohamed A. Bedaiwy, Tommaso Falcone, Jeffery M. Goldberg, Marjan Attaran, Kurt Miller, Ashok Agarwal. Cleveland Clin Fdn, Cleveland, OH.
S96
Abstracts
Optimizing stimulation protocols in IVF cycles using the GnRH antagonist. Alan B. Copperman, Benjamin Sandler, Tanmoy Mukherjee, Lawrence Grunfeld, Paul Bergh, Richard T. Scott Jr. Mount Sinai Sch of Medicine, New York, NY; Reproductive Medicine Assoc of New York, New York, NY; Reproductive Medicine Assoc of New Jersey, Morristown, NJ. Objective: As experience accumulates using the third-generation GnRH antagonist ganirelix (Antagon), it is imperative that we study factors unique to the follicular dynamics and identify factors that might optimize its use in IVF cycles. Design: Non-randomized comparison. Materials and Methods: One thousand seven hundred seventy-three women underwent IVF using the GnRH antagonist over a three year period at Reproductive Medicine Associates of New York and Reproductive Medicine Associates of New Jersey. Controlled ovarian hyperstimulation using a combination of recombinant follicle stimulating hormone (rFSH) and human Menopausal Gonadotropin (hMG) were initiated in split doses beginning on the third day of the menstrual cycle for patients whether or not they were pretreated with oral contraceptive. Ganirelix acetate (250 g/day) was started when the lead follicle reached 14mm. Routinely, an “add-back” of 75 IU of hMG was introduced on the first day of antagonist. Human chorionic gonadotropin (hCG) was administered at the discretion of the treating physician, but was normally given when two follicles reached a greatest diameter of 18mm. The size of the lead follicle at the time of hCG was recorded. For comparison, down regulation cycles using leuprolide acete were analyzed.
Vol. 80, Suppl. 3, September 2003
Results: The clinical pregnancy rate significantly increased in a linear fashion from 5 to 9 days of gonadotropin stimulation as determined by linear regression analysis (P⬍0.001) at which time clinical pregnancy rates plateaued. No pregnancies were observed with 16 or 17 days of gonadotropin stimulation. These results suggest that clinical pregnancy rates improve with increased duration of gonadotropin stimulation, at least up to 9 days. In a second retrospective analysis, we compared pregnancy rates with administration of hCG when the lead follicle diameter was 16 to 17 mm, 18 to 19 mm, or greater than 20 mm. The results are presented in graphic comparison and compared to an unmatched cohort of down-regulation patients.
hormonally diagnosed women with PCOS (LH mean value ⱖ 6 ⫾1.8 IU/mL and FSH mean value ⱕ 7⫾1.2 IU/mL) were compared to a control group of 181 women without PCOS. On cycle day 3, serum levels of AMH, FSH, estradiol (E2), inhibin B (INHB), and LH were measured within the two months before the procedure of ART. We compared between the two patients groups the age, serum levels of each hormone, number of retrieved oocytes, number of embryos obtained at day two and the rate of ongoing pregnancy .Statistical analysis was computed for each parameter in all patients groups. Results: Among the 232 women with PCOS, the AMH serum levels in 79 pregnant patients (mean age: 34.9⫾1.2 yrs) and in 153 non pregnant patients (mean age: 35.16⫾1.3 yrs) were respectively 3.09⫾1.2 and 1.96⫾0.8 ng/mL (P- value ⱕ0.00005), INHB serum levels were 75.2⫾12.2 and 74.18⫾14.2 pg/mL (P- value ⫽ 0.01), E2 serum levels were 24.1⫾14 and 25.9⫾15 pg/mL and the FSH serum levels were 6.28⫾1.1 and 6.58 ⫾1.15 IU/mL (P- value ⱕ0.05). The mean age and E2 serum levels were not statistically different between the pregnant and non pregnant women. The number of retrieved oocytes (7,9⫾4.2) and embryos (5,8⫾3.1) was higher in the pregnant group compared to the non pregnant group (respectively 6.5⫾3.5 and 5⫾2.8). Among the control patients group (58 pregnant and 123 non pregnant patients) the AMH serum levels respectively 2.15⫾1.7 and 0.97⫾1.3 ng/mL (P- value ⱕ 0.005) were less correlated to the number of retrieved oocytes or embryos or to the number of ongoing pregnancies than in the studied group. Conclusion: AMH serum levels at day 3 seems to be a good predictive factor to the outcome of ART in women with PCOS.
Wednesday, October 15, 2003 3:00 P.M. O-255 Ejaculatory abstinence less than 3 days results in a higher pregnancy rate (PR) following intrauterine insemination (IUI). Marcus W. Jurema, Andrea D. Damasceno Vieira, Brandon Bankowski, Yulian Zhao, Edward Wallach, Howard Zacur. The Johns Hopkins Medical Institutions, Baltimore, MD; Univ de Brasilia (UdB), Brasilia, Brazil. Conclusions: GnRH antagonists bind to gonadotrope GnRH receptors and compete successfully with endogenous agonist GnRH molecules for receptor occupancy. Follicles are recruited earlier in antagonist cycles (North American Ganrilex Study Group), but it now appears that there is a late difference in follicular dynamics among stimulation protocols, as well. The duration of gonadotropin stimulation associated with acceptable pregnancy rates is fairly broad (9 to 15 days). As the size of the lead follicle increases in GnRH antagonist cycles, a concomitant increase in pregnancy rates occurs. Conversely, patients in agonist down-regulation treatment regimens do not benefit from obtaining larger follicle sizes. Furthermore, it appears that increasing lead follicle size is a more accurate correlator of increasing pregnancy rates than increasing duration of gonadotropin stimulation.
Wednesday, October 15, 2003 2:45 P.M. O-254 Serum anti mullerian hormone as a novel predictive factor of success in art among women with polycystic ovary syndrome? Andre´ Hazout, Anne Marie Junca, Alain Le Meur, Flavien Ternaux, Paul Cohen-Barcie. ART Unit Eylau Muette, Paris, France. Objective: To compare the serum antimullerian hormone (AMH) levels in women with polycystic ovary syndrome (PCOS) and those in women without PCOS, and to define AMH as a predictive factor of success in ART. Design: Retrospective study concerning 413 patients undergoing ART procedure (IVF or ICSI). Materials and Methods: Two hundred thirty-two sonographically and
FERTILITY & STERILITY威
Objective: The duration of ejaculatory abstinence is known to affect sperm concentration and motility, while morphology remains relatively constant. The effect of the abstinence interval on pregnancy outcome is not well characterized since most studies do not consider abstinence as an independent variable. In this study, we examined the influence of the abstinence interval on sperm parameters and pregnancy rates following IUI. Design: Retrospective analysis. Materials and Methods: 410 couples underwent 929 fresh, non-donor IUI cycles performed between June 1999 and October 2002. The influence of the duration of abstinence on the processed sperm parameters (concentration, motility, and total motile sperm [TMS]) and PR was analyzed by Pearson’s correlation. The impact of each of these parameters, including duration of abstinence, on PR was evaluated by stepwise logistic regression. ANOVA and independent t-tests were used to compare means. Results: Duration of abstinence correlated positively with sperm concentration and TMS, but negatively with motility. PR correlated negatively with duration of abstinence (r ⫽ ⫺0.083, p ⬍ 0.05). Logistic regression revealed that only the duration of abstinence had a significant impact on PR. Table 1 shows the PR according to the abstinence interval. There were no differences in male or female age within or between the groups. An abstinence interval of ⱕ 3 days had the highest mean PR (14%), while an interval of 4 to 10 days had a lower mean PR (10%), and an abstinence interval ⬎ 10 days had the lowest mean PR (3%) [Figure 1]. These abstinence interval groups were statistically different from each other (p ⬍ 0.05).
* p ⬍ 0.05 compared to ⬎ 10 days.
S97