- Email: [email protected]
The effect of multiple cycles in oocyte donors
American Journal of Obstetrics and Gynecology (2005) 192, 1382–4
www.ajog.org
The effect of multiple cycles in oocyte donors Akas Jain, MD,* Jared C. Robins, MD, Daniel B. Williams, MD, Michael A. Thomas, MD Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Cincinnati Medical Center, Cincinnati, Ohio Received for publication August 30, 2004; revised November 19, 2004; accepted December 7, 2004
KEY WORDS Oocyte donor In vitro fertilization Controlled ovarian hyperstimulation
Objective: The purpose of this study was to determine whether multiple controlled ovarian hyperstimulation cycles in oocyte donors affect the ovarian response, the oocytes retrieved, or the pregnancy rates. Study design: A retrospective chart review of repeat donor in vitro fertilization cycles between 1992 and 2003 at the University of Cincinnati Center for Reproductive Health was performed. The variables that were examined included the peak estradiol level, the length of stimulation, the number of follicles O15 mm, the amount of gonadotropins that were used, the number of oocytes that were retrieved and inseminated, the average number of cells per embryo at the time of transfer, and the clinical pregnancy rates. Results: A total of 107 in vitro fertilized donor oocyte cycles were analyzed, of which 45 young healthy women underwent at least 2 cycles and 17 women underwent 3 cycles. Donors who underwent a second or third cycle demonstrated no differences in the cycle parameters that were observed. Conclusion: Repeated controlled ovarian hyperstimulation cycles in a donor population does not demonstrate a diminished ovarian response to exogenous gonadotropins. Oocyte donors can undergo up to 3 stimulation cycles without a negative affect on the ovarian response to gonadotropins, the number of mature oocytes retrieved, the embryo quality, or the clinical pregnancy rate. Ó 2005 Elsevier Inc. All rights reserved.
Oocyte donation has become a standard mode of therapy for the treatment of many causes of infertility, which include premature ovarian failure, decreased ovarian function, recurrent pregnancy loss, cases with maternal genetic abnormalities, or recurrent unsuccessful in vitro fertilization (IVF) attempts.1,2 Because there are more potential donor oocyte recipients than donors, many centers have used the same oocyte donor for more than 1 cycle. There have been case series of young, * Reprint requests: Akas Jain, MD, 3450 Wayne Ave, #23D, Bronx, NY 10467. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.12.038
healthy IVF donors who repeated up to 9 cycles of controlled ovarian hyperstimulation (COH).3 Diamond et al4 discussed the possible blunting effect of ovarian response in consecutive COH cycles such that higher doses of gonadotropins may be required to achieve follicular maturation. Concern exists that there is intercycle variability in subsequent IVF cycles. It is unknown whether the same subject will require higher doses of gonadotropins to achieve the same clinical outcomes. The purpose of this study was to determine whether repeating COH cycles of oocyte donors may have an effect on ovarian response, embryo quality, or pregnancy rates.
Jain et al Table I
1383 Outcome data for cycles 1 and 2
Variable
Cycle 1 (n = 45)
Cycle 2 (n = 45)
P value
Donor age (y)* Peak estradiol level (pg/mL)* Days of stimulation (n)* Mature follicles O15 mm (n)* Total oocytes retrieved (n)* Mature oocytes inseminated (n)* Stage of embryo development at transfer (n of cells)* Total ampules used (n)* Pregnancy rate (%)
26.5 2349.6 10.9 11.5 15.9 15.0 6.7
27.2 2278.6 11.2 11.4 16.6 15.2 6.5
NS NS NS NS NS NS NS
G G G G G G G
0.67 151.3 0.27 0.69 0.96 0.95 0.32
30.3 G 1.1 55.5
G G G G G G G
0.66 185.4 0.33 0.81 1.18 1.06 0.34
31.0 G 1.35 47.6
NS NS
NS, Not significant. * Data are given as mean G SEM.
Table II
Cycle outcome data from donors who received 3 cycles
Variable
Cycle 1 (n = 17)
Cycle 2 (n = 17)
Cycle 3 (n = 17)
P value
Donor age (y)* Peak estradiol level (pg/mL)* Days of stimulation (n)* Follicles O15mm (n)* Total oocytes retrieved (n)* Mature oocytes inseminated (n)* Stage of embryo development at transfer (n of cells)* Total ampules used (n)* Pregnancy rate (%)
26.5 2498.3 11.6 11.0 13.8 12.7 7.22
27.1 2688.2 10.5 10.4 17.6 16.4 6.02
28.2 2768.5 10.8 11.4 19.9 19.6 6.88
NS NS NS NS NS NS NS
G G G G G G G
4.3 903.6 1.7 5.8 4.3 6.8 1.8
31.9 G 8.3 56.7
G G G G G G G
4.0 1100.8 1.0 4.53 8.2 7.6 1.7
31.8 G 8.95 52.9
G G G G G G G
4.5 994.6 1.3 5.1 9.3 8.8 1.7
36.2 G 14.4 52.9
NS NS
NS, Not significant. * Data are given as mean G SEM.
Material and methods A retrospective analysis of donors who have undergone multiple IVF cycles at the University of Cincinnati Center for Reproductive Health between 1992 and 2003 was performed. This included a total of 107 cycles comprised of 45 subjects who had undergone at least 2 cycles and 17 subjects who underwent 3 cycles. Donor selection was anonymous and was contingent on a normal physical examination, noncontributory medical history, and family history void of congenital anomaly or genetic predisposition to disease. Standard infectious disease screening, karyotype, and comprehensive pyschologic evaluation was performed; each donor was given informed consent regarding all risks of COH and the process of oocyte retrieval and donation. Oocyte donors underwent standard IVF stimulation with gonadotropins after cycle down-regulation with leuprolide acetate. Human chorionic gonadotropin (10,000 IU) was administered when at least 2 to 3 follicles were R18 mm in mean diameter. This was followed by transvaginal oocyte retrieval and subsequent embryo transfer to the recipient.
Peak estradiol level, the ampules of medication that were used, and the number of days of stimulation were examined. Outcome variables included the number of follicles that were found to be R15 mm on transvaginal ultrasonography, the total number of oocytes that were retrieved and inseminated per cycle, the average number of cells per embryo that were transferred, and the clinical pregnancy rate by cardiac activity on ultrasound examination. Continuous independent variables were analyzed with analysis of variance or the Wilcoxon signed-rank test. Dependent variables were standardized to cycle 1.
Results Tables I and II show that oocyte donors who underwent 2 or 3 COH cycles did not show a significant difference in age at the time of retrieval, the peak estradiol concentration at the time of human chorionic gonadotropin administration, the days of gonadotropin stimulation, the follicle size R15 mm, the total number of oocytes that were retrieved, the number of mature
1384 oocytes that were inseminated, the number of blastomeres at the time of transfer, the total number of gonadotropin ampules that were used, and the clinical pregnancy rate.
Comment Although there is limited information regarding the effects of repeated COH cycles on young healthy donors, this issue has been addressed in non-donor patients who received ovarian stimulation. Silverberg et al5 compared consecutive versus alternating ovarian stimulation cycles in 50 subjects and discovered that a significantly higher total dose of human menopausal gonadotropin was required in the second consecutive cycle but that fecundity rates and follicle development were not impaired. In another comparison of the ovarian response of 50 subjects who underwent 2 consecutive COH cycles, Diamond et al4 found similar peak estradiol levels and doses of human menopausal gonadotropin in both cycles, but one third of the anovulatory women did not meet the criteria for human chorionic gonadotropin administration in the second cycle. These studies raise suspicion of a detrimental effect of consecutive ovarian hyperstimulation cycles. In contrast, our study demonstrated that cycle variables did not change significantly when oocyte donors underwent either 2 or 3 cycles. Therefore, the use of gonadotropins in a repeated fashion did not have an effect on the future cohort of follicles that were later
Jain et al recruited. This finding may be due to the young age of the donors who were recruited and the relative short interval between treatment cycles, as demonstrated by the mean age per cycle of the donors. Opsahl et al6 observed a similar response in oocyte donors who underwent up to 6 COH cycles. This group also did not observe a difference in cycle parameters if the donor underwent intervals between cycles that were as short as 2 months or O12 months. Therefore, we conclude that oocyte donors can be invited for up to 3 cycles without a negative effect on ovarian response to gonadotropins, number of mature oocytes retrieved, embryo quality, or pregnancy rates.
References 1. Remohi J, Gartner B, Gallardo E, Yalil S, Simon C, Pellicer A. Pregnancy and birth rates after oocyte donation. Fertil Steril 1997;67:717-23. 2. Rosenwaks Z. Donor eggs: their application in modern reproductive technologies. Fertil Steril 1987;47:895-909. 3. Caligara C, Navarro J, Vargas G, Simon C, Pellicer A, Remohi J. The effect of repeated controlled ovarian stimulation in donors. Hum Reprod 2001;16:2320-3. 4. Diamond MP, DeCherney AH, Hill GA, Nero F, Wentz AC. Response to repetitive cycles of ovulation induction in the same women. J In Vitro Fertil Embryo Transf 1987;4:251-5. 5. Silverberg KM, Klein NA, Burns WN, Schenken RS, Olive DL. Consecutive versus alternating cycles of ovarian stimulation using human menopausal gonadotropin. Hum Reprod 1992;7:940-4. 6. Opsahl MS, Blauer KL, Black SH, Dorfmann A, Sherins RJ, Schulman JD. Pregnancy rates in sequential in vitro fertilization cycles by oocyte donors. Obstet Gynecol 2001;97:201-4.
www.ajog.org
The effect of multiple cycles in oocyte donors Akas Jain, MD,* Jared C. Robins, MD, Daniel B. Williams, MD, Michael A. Thomas, MD Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Cincinnati Medical Center, Cincinnati, Ohio Received for publication August 30, 2004; revised November 19, 2004; accepted December 7, 2004
KEY WORDS Oocyte donor In vitro fertilization Controlled ovarian hyperstimulation
Objective: The purpose of this study was to determine whether multiple controlled ovarian hyperstimulation cycles in oocyte donors affect the ovarian response, the oocytes retrieved, or the pregnancy rates. Study design: A retrospective chart review of repeat donor in vitro fertilization cycles between 1992 and 2003 at the University of Cincinnati Center for Reproductive Health was performed. The variables that were examined included the peak estradiol level, the length of stimulation, the number of follicles O15 mm, the amount of gonadotropins that were used, the number of oocytes that were retrieved and inseminated, the average number of cells per embryo at the time of transfer, and the clinical pregnancy rates. Results: A total of 107 in vitro fertilized donor oocyte cycles were analyzed, of which 45 young healthy women underwent at least 2 cycles and 17 women underwent 3 cycles. Donors who underwent a second or third cycle demonstrated no differences in the cycle parameters that were observed. Conclusion: Repeated controlled ovarian hyperstimulation cycles in a donor population does not demonstrate a diminished ovarian response to exogenous gonadotropins. Oocyte donors can undergo up to 3 stimulation cycles without a negative affect on the ovarian response to gonadotropins, the number of mature oocytes retrieved, the embryo quality, or the clinical pregnancy rate. Ó 2005 Elsevier Inc. All rights reserved.
Oocyte donation has become a standard mode of therapy for the treatment of many causes of infertility, which include premature ovarian failure, decreased ovarian function, recurrent pregnancy loss, cases with maternal genetic abnormalities, or recurrent unsuccessful in vitro fertilization (IVF) attempts.1,2 Because there are more potential donor oocyte recipients than donors, many centers have used the same oocyte donor for more than 1 cycle. There have been case series of young, * Reprint requests: Akas Jain, MD, 3450 Wayne Ave, #23D, Bronx, NY 10467. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.12.038
healthy IVF donors who repeated up to 9 cycles of controlled ovarian hyperstimulation (COH).3 Diamond et al4 discussed the possible blunting effect of ovarian response in consecutive COH cycles such that higher doses of gonadotropins may be required to achieve follicular maturation. Concern exists that there is intercycle variability in subsequent IVF cycles. It is unknown whether the same subject will require higher doses of gonadotropins to achieve the same clinical outcomes. The purpose of this study was to determine whether repeating COH cycles of oocyte donors may have an effect on ovarian response, embryo quality, or pregnancy rates.
Jain et al Table I
1383 Outcome data for cycles 1 and 2
Variable
Cycle 1 (n = 45)
Cycle 2 (n = 45)
P value
Donor age (y)* Peak estradiol level (pg/mL)* Days of stimulation (n)* Mature follicles O15 mm (n)* Total oocytes retrieved (n)* Mature oocytes inseminated (n)* Stage of embryo development at transfer (n of cells)* Total ampules used (n)* Pregnancy rate (%)
26.5 2349.6 10.9 11.5 15.9 15.0 6.7
27.2 2278.6 11.2 11.4 16.6 15.2 6.5
NS NS NS NS NS NS NS
G G G G G G G
0.67 151.3 0.27 0.69 0.96 0.95 0.32
30.3 G 1.1 55.5
G G G G G G G
0.66 185.4 0.33 0.81 1.18 1.06 0.34
31.0 G 1.35 47.6
NS NS
NS, Not significant. * Data are given as mean G SEM.
Table II
Cycle outcome data from donors who received 3 cycles
Variable
Cycle 1 (n = 17)
Cycle 2 (n = 17)
Cycle 3 (n = 17)
P value
Donor age (y)* Peak estradiol level (pg/mL)* Days of stimulation (n)* Follicles O15mm (n)* Total oocytes retrieved (n)* Mature oocytes inseminated (n)* Stage of embryo development at transfer (n of cells)* Total ampules used (n)* Pregnancy rate (%)
26.5 2498.3 11.6 11.0 13.8 12.7 7.22
27.1 2688.2 10.5 10.4 17.6 16.4 6.02
28.2 2768.5 10.8 11.4 19.9 19.6 6.88
NS NS NS NS NS NS NS
G G G G G G G
4.3 903.6 1.7 5.8 4.3 6.8 1.8
31.9 G 8.3 56.7
G G G G G G G
4.0 1100.8 1.0 4.53 8.2 7.6 1.7
31.8 G 8.95 52.9
G G G G G G G
4.5 994.6 1.3 5.1 9.3 8.8 1.7
36.2 G 14.4 52.9
NS NS
NS, Not significant. * Data are given as mean G SEM.
Material and methods A retrospective analysis of donors who have undergone multiple IVF cycles at the University of Cincinnati Center for Reproductive Health between 1992 and 2003 was performed. This included a total of 107 cycles comprised of 45 subjects who had undergone at least 2 cycles and 17 subjects who underwent 3 cycles. Donor selection was anonymous and was contingent on a normal physical examination, noncontributory medical history, and family history void of congenital anomaly or genetic predisposition to disease. Standard infectious disease screening, karyotype, and comprehensive pyschologic evaluation was performed; each donor was given informed consent regarding all risks of COH and the process of oocyte retrieval and donation. Oocyte donors underwent standard IVF stimulation with gonadotropins after cycle down-regulation with leuprolide acetate. Human chorionic gonadotropin (10,000 IU) was administered when at least 2 to 3 follicles were R18 mm in mean diameter. This was followed by transvaginal oocyte retrieval and subsequent embryo transfer to the recipient.
Peak estradiol level, the ampules of medication that were used, and the number of days of stimulation were examined. Outcome variables included the number of follicles that were found to be R15 mm on transvaginal ultrasonography, the total number of oocytes that were retrieved and inseminated per cycle, the average number of cells per embryo that were transferred, and the clinical pregnancy rate by cardiac activity on ultrasound examination. Continuous independent variables were analyzed with analysis of variance or the Wilcoxon signed-rank test. Dependent variables were standardized to cycle 1.
Results Tables I and II show that oocyte donors who underwent 2 or 3 COH cycles did not show a significant difference in age at the time of retrieval, the peak estradiol concentration at the time of human chorionic gonadotropin administration, the days of gonadotropin stimulation, the follicle size R15 mm, the total number of oocytes that were retrieved, the number of mature
1384 oocytes that were inseminated, the number of blastomeres at the time of transfer, the total number of gonadotropin ampules that were used, and the clinical pregnancy rate.
Comment Although there is limited information regarding the effects of repeated COH cycles on young healthy donors, this issue has been addressed in non-donor patients who received ovarian stimulation. Silverberg et al5 compared consecutive versus alternating ovarian stimulation cycles in 50 subjects and discovered that a significantly higher total dose of human menopausal gonadotropin was required in the second consecutive cycle but that fecundity rates and follicle development were not impaired. In another comparison of the ovarian response of 50 subjects who underwent 2 consecutive COH cycles, Diamond et al4 found similar peak estradiol levels and doses of human menopausal gonadotropin in both cycles, but one third of the anovulatory women did not meet the criteria for human chorionic gonadotropin administration in the second cycle. These studies raise suspicion of a detrimental effect of consecutive ovarian hyperstimulation cycles. In contrast, our study demonstrated that cycle variables did not change significantly when oocyte donors underwent either 2 or 3 cycles. Therefore, the use of gonadotropins in a repeated fashion did not have an effect on the future cohort of follicles that were later
Jain et al recruited. This finding may be due to the young age of the donors who were recruited and the relative short interval between treatment cycles, as demonstrated by the mean age per cycle of the donors. Opsahl et al6 observed a similar response in oocyte donors who underwent up to 6 COH cycles. This group also did not observe a difference in cycle parameters if the donor underwent intervals between cycles that were as short as 2 months or O12 months. Therefore, we conclude that oocyte donors can be invited for up to 3 cycles without a negative effect on ovarian response to gonadotropins, number of mature oocytes retrieved, embryo quality, or pregnancy rates.
References 1. Remohi J, Gartner B, Gallardo E, Yalil S, Simon C, Pellicer A. Pregnancy and birth rates after oocyte donation. Fertil Steril 1997;67:717-23. 2. Rosenwaks Z. Donor eggs: their application in modern reproductive technologies. Fertil Steril 1987;47:895-909. 3. Caligara C, Navarro J, Vargas G, Simon C, Pellicer A, Remohi J. The effect of repeated controlled ovarian stimulation in donors. Hum Reprod 2001;16:2320-3. 4. Diamond MP, DeCherney AH, Hill GA, Nero F, Wentz AC. Response to repetitive cycles of ovulation induction in the same women. J In Vitro Fertil Embryo Transf 1987;4:251-5. 5. Silverberg KM, Klein NA, Burns WN, Schenken RS, Olive DL. Consecutive versus alternating cycles of ovarian stimulation using human menopausal gonadotropin. Hum Reprod 1992;7:940-4. 6. Opsahl MS, Blauer KL, Black SH, Dorfmann A, Sherins RJ, Schulman JD. Pregnancy rates in sequential in vitro fertilization cycles by oocyte donors. Obstet Gynecol 2001;97:201-4.