Assisted reproductive technology FERTILITY AND STERILITY
Vol. 57, No.2, February 1992
Copyright 0 1992 The American Fertility Society
Printed on
acid~free
paper in U.S.A.
A prospective, randomized trial comparing two different intrauterine insemination regimens in controlled ovarian hyperstimulation cycles*
Kaylen M. Silverberg, M.D. t Julia V. Johnson, M.D.:j: David L. Olive, M.D.
William N. Burns, M.D. Robert S. Schenken, M.D.
Department of Obstetrics and Gynecology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas
Objective: To compare a single periovulatory intrauterine insemination (lUI) with a regimen employing two lUIs, one before ovulation and one after ovulation, in patients undergoing controlled ovarian hyperstimulation with human menopausal gonadotropins (hMG) combined with human chorionic gonadotropin (hCG). Design: A randomized, prospective trial. Participants: Thirty-one consecutive patients undergoing 49 cycles of controlled ovarian hyperstimulation/IUI were studied in a tertiary care setting. Main Outcome Measures: Ovulation was determined sonographically. The establishment of a clinical pregnancy was defined by either ultrasonographic verification of cardiac activity within an intrauterine fetus, or histologic confirmation of trophoblast in a surgical specimen. Results: Clinical pregnancies developed in 2 of 23 cycles in the single insemination group, compared with 12 of the 23 cycles in the double insemination group. Cycle fecundity was significantly higher for group II (0.522) than for group I (0.087) patients (P = 0.003). Conclusion: In hMG/hCG cycles, two lUIs timed as described above are superior to one periovulatory insemination. Fertil Steril 1992;57:357-61 Key Words: Intrauterine insemination, gonadotropins, fertility, ovulation induction, human menotropins, prospective study
The combination of controlled ovarian hyperstimulation and intrauterine insemination (lUI) is gaining acceptance as a treatment for a variety of fertility disorders. The advantages of this form of therapy are that it is less expensive and invasive Received May 16, 1991; revised and accepted September 25, 1991. * Presented at the 46th Annual Meeting of The American Fertility Society, Washington, D.C., October 13 to 18, 1990. t Reprint requests: Kaylen M. Silverberg, M.D., Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7836. :j: Present address: Department of Obstetrics and Gynecology, University of Vermont Medical School, Burlington, Vermont.
Vol. 57, No.2, February 1992
than other assisted reproductive technologies while affording similar monthly fecundity rates (1). Various methods of timing lUI in natural cycles have been described (2). These include the use of basal body temperature (BBT) charts, urine luteinizing hormone (LH) monitoring, evaluation of cervical mucus, and ultrasonography. Although there is no consensus regarding the optimal time for lUI, most agree that lUI should be performed either before ovulation or during the periovulatory period (2). In contrast to natural cycles monitored with urine LH detection kits, the use of human chorionic gonadotropin (hCG) as an ovulation trigger in cycles of controlled ovarian hyperstimulation may afford the opportunity to define a relatively narrow window oftime during which the first ovulation should occur.
Silverberg et al.
lUI after hCG
357
Theoretically, this should allow more precision in the timing of lUI in relation to ovulation. Despite this and the widespread combination of controlled ovarian hyperstimulationjlUI for the treatment of infertility, no studies have prospectively evaluated different lUI regimens during controlled ovarian hyperstimulation. We therefore designed a prospective, randomized study to compare the efficacy of a single lUI performed in the periovulatory period with one lUI performed before ovulation and a second lUI performed after ovulation. MATERIALS AND METHODS
Thirty-one consecutive patients undergoing 49 cycles of controlled ovarian hyperstimulation combined with lUI at the Center for Reproductive Medicine, Humana Women's Hospital-South Texas were studied. Diagnoses by cycle included ovulatory dysfunction (n = 14), unexplained infertility (n = 7), male factor (n = 2), treated endometriosis (n = 3), cervical factor (n = 1), and two or more infertility factors (n = 22). Husband's semen was used in 40 cycles, and cryopreserved donor semen was used in 9 cycles as treatment for severe male-factor infertility. Three days after the onset of menses, patients underwent transvaginal sonography with an ATL Ultramark 4 equipped with a 5-MHz endovaginal probe (Advanced Technology Laboratories, Bothell, W A). Ovarian stimulation using human menopausal gonadotropin (hMG, Pergonal; Serono Laboratories, Inc., Randolph, MA) was initiated if the largest follicle was 100%. The hMG dosage was increased by 75 IU whenever serial E 2 levels rose by 1 X 106 motile spermatozoa are inseminated into the uterus (9). Every insemination performed in our study contained at least 1 X 106 motile spermatozoa with a range of 1 X 106 to 124 X 106 , and pregnancy rates (PRs) were not correlated with sperm concentration. This suggests that the number of spermatozoa inseminated in this study is probably not the critical factor. Another possible reason for the higher PR with two inseminations involves the timing of lUI. The significantly higher cycle fecundity afforded by the dual insemination protocol may have resulted because the multiple ovulations in hMG/hCG cycles are sequential over a period of at least several hours (7). Thus, the first insemination would provide sufficient motile spermatozoa proximate to the initially ovulated oocyte(s). The second insemination may provide additional sperm to fertilize those oocytes 360
Silverberg et al.
lUI after hCG
that subsequently ovulate. Because ovulation should rarely occur earlier than 36 hOurb after the hCG injection, most perform a single lUI 32 to 40 hours after administering hCG (1, 9, 10). To date, only one prospective, randomized trial comparing different timing regimens of lUI in controlled ovarian hyperstimulation cycles has been reported (J.C. Barrett and J. Marshall, unpublished observations). The study failed to demonstrate a significant difference in cycle fecundity when comparing a single lUI 30 hours after hCG administration to one at the time of hCG and a second 30 hours later. Overall cycle fecundity in these patients, who received either hMG or clomiphene citrate/hMG, was 0.147. However, as the report appeared only in abstract form, no information regarding patient diagnoses or sperm quality was provided. Further, both inseminations presumably were performed before ovulation. Thus, the findings are not directly comparable with our study, that assesses a single periovulatory lUI to one insemination performed before ovulation combined with a second performed after ovulation of at least one oocyte. It remains possible that either a single preovulatory or postovulatory lUI timed as in our group II patients may have resulted in similar cycle fecundity. Data obtained from natural cycles suggest that fertility is maximal on the day ofthe LH peak, i.e., just before ovulation (11). Similarly, Byrd et al. (8) reported that the optimal time for lUI in natural cycles is 10 to 20 hours after the detection of the endogenous LH surge. This would suggest that the preovulatory lUI is the more important in natural cycles. A retrospective, nonrandomized study employing hMG/hCG and intracervical insemination in 113 cycles suggests that this may also be true in controlled ovarian hyperstimulation cycles (12). Although the timing of intracervical insemination was not well controlled and ovulation was confirmed only by BBT rise, cycle fecundity tended to be higher in the group receiving preovulatory inseminations. If indeed the timing of the first insemination is the critical factor resulting in improved cycle fecundity, the mechanism is likely related to increasing the number of capacitated sperm within the upper genital tract. The method of sperm preparation described herein presumably initiates capacitation, and this process continues after insemination (13). Although the amount of time required for capacitation to occur within the genital tract is unknown, extended in vivo incubation (12 to 36 hours) of sperm may enhance sperm fertilizing capacity (14). This may explain the improved cycle fecundity observed Fertility and Sterility
in our study in which insemination is performed 18 rather than 2 hours before the first ovulation. Nevertheless, our study design did not compare a single preovulatory lUI to a single postovulatory lUI as timed in group II patients. Therefore, the possibility remains that either the second lUI or the combination is responsible for our results. The cycle fecundity in group II is at the upper range of success rates reported for hMGjlUI cycles (1,9, 15). In addition to the timing of insemination described above, another factor that may account for this is our individualized regimen of hMG stimulation. Although our stimulation protocol is widely used, it differs significantly from that of previous controlled ovarian hyperstimulationjlUI studies (1, 3,9, 15). Finally, with respect to the use of donor spermatozoa, it appears that donor samples exhibiting good post-thaw motility can be used without experiencing a significant decrease in cycle fecundity, as compared with fresh sperm. This finding confirms the results reported in two recent studies (8, 16). We conclude that, using fresh or cryopreserved sperm, two lUIs timed as described above are superior to a single periovulatory lUI in cycles of controlled ovarian hyperstimulation with hMG. Acknowledgments. We gratefully acknowledge Mrs. Joanne Wright and Mrs. Patsy Oertli for the diligent preparation of this manuscript. REFERENCES 1. Dodson WC, Whitesides DB, Hughes CL Jr, Easley HA III, Haney AF. Superovulation with intrauterine insemination in the treatment of infertility: a possible alternative to gamete intrafallopian transfer and in vitro fertilization. Fertil Steril 1987;48:441-5. 2. Allen NC, Herbert CM III, Maxson WS, Rogers BJ, Diamond MP, Wentz AC. Intrauterine insemination: a critical review. Fertil Steril 1985;44:569-80.
Vol. 57, No.2, February 1992
3. Serhal PF, Katz M, Little V, Woronowski H. Unexplained infertility-the value of Pergonal superovulation combined with intrauterine insemination. Fertil Steril 1988;49:602-6. 4. Corson SL, Batzer FR, Gocial B, Maislin G. Intrauterine insemination and ovulation stimulation as treatment of infertility. J Reprod Med 1989;34:397-406. 5. Y ovich JL, Matson PL. The treatment of infertility by the high intrauterine insemination of husband's washed spermatozoa. Hum Reprod 1988;3:939-43. 6. Tredway DR, Chan P, Henig I, Gullett A, Cheatwood M. Effectiveness of stimulated menstrual cycles and Percoll sperm preparation in intrauterine insemination. J Reprod Med 1990;35:103-8. 7. Silverberg KM, Olive DL, Burns WN, Johnson JV, Groff TR, Schenken RS. Follicular size at the time of human chorionic gonadotropin administration predicts ovulation outcome in human menopausal gonadotropin -stimulated cycles. Fertil Steril 1991;56:296-300. 8. Byrd W, Bradshaw K, Carr B, Edman C, Odom J, Ackerman G. A prospective randomized study of pregnancy rates following intrauterine and intracervical insemination using frozen donor sperm. Fertil Steril1990;53:521-7. 9. Dodson WC, Haney AF. Controlled ovarian hyperstimulation and intrauterine insemination for treatment of infertility. Fertil Steril 1991;55:457-67. 10. Taylor PJ, Kredentser JV. Washed intrauterine insemination-indications and success. Int J FertiI1989;34:378-84. 11. Barrett JC, Marshall J. The role of conception on different days of the menstrual cycle. Popul Stud 1969;23:455-9. 12. Kemmann E, Pasquale S. Timing and frequency of artificial insemination in women under menotropin therapy. Fertil SteriI1985;44:271-3. 13. Sher G, Knutzen VK, Stratton CJ, Montakhab MM, Allenson SG. In vitro sperm capacitation and transcervical intrauterine insemination for the treatment of refractory infertility: phase I. Fertil Steril 1984;41:260-4. 14. Huszar G, DeCherney A. The role of intrauterine insemination in the treatment of infertile couples: the Yale experience. Semin Reprod EndocrinoI1987;5:11-21. 15. Remohi J, Gastaldi C, Patrizio P, Gerli S, Ord T, Asch RH, et al. Intrauterine insemination and controlled ovarian hyperstimulation in cycles before GIFT. Hum Reprod 1989;4: 918-23. 16. Hammond MG, Jordan S, Sloan CS. Factors affecting pregnancy rates in a donor insemination program using frozen semen. Am J Obstet Gynecol 1986;155:480-5.
Silverberg et al.
lUI after hCG
361
Vol. 57, No.2, February 1992
Copyright 0 1992 The American Fertility Society
Printed on
acid~free
paper in U.S.A.
A prospective, randomized trial comparing two different intrauterine insemination regimens in controlled ovarian hyperstimulation cycles*
Kaylen M. Silverberg, M.D. t Julia V. Johnson, M.D.:j: David L. Olive, M.D.
William N. Burns, M.D. Robert S. Schenken, M.D.
Department of Obstetrics and Gynecology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas
Objective: To compare a single periovulatory intrauterine insemination (lUI) with a regimen employing two lUIs, one before ovulation and one after ovulation, in patients undergoing controlled ovarian hyperstimulation with human menopausal gonadotropins (hMG) combined with human chorionic gonadotropin (hCG). Design: A randomized, prospective trial. Participants: Thirty-one consecutive patients undergoing 49 cycles of controlled ovarian hyperstimulation/IUI were studied in a tertiary care setting. Main Outcome Measures: Ovulation was determined sonographically. The establishment of a clinical pregnancy was defined by either ultrasonographic verification of cardiac activity within an intrauterine fetus, or histologic confirmation of trophoblast in a surgical specimen. Results: Clinical pregnancies developed in 2 of 23 cycles in the single insemination group, compared with 12 of the 23 cycles in the double insemination group. Cycle fecundity was significantly higher for group II (0.522) than for group I (0.087) patients (P = 0.003). Conclusion: In hMG/hCG cycles, two lUIs timed as described above are superior to one periovulatory insemination. Fertil Steril 1992;57:357-61 Key Words: Intrauterine insemination, gonadotropins, fertility, ovulation induction, human menotropins, prospective study
The combination of controlled ovarian hyperstimulation and intrauterine insemination (lUI) is gaining acceptance as a treatment for a variety of fertility disorders. The advantages of this form of therapy are that it is less expensive and invasive Received May 16, 1991; revised and accepted September 25, 1991. * Presented at the 46th Annual Meeting of The American Fertility Society, Washington, D.C., October 13 to 18, 1990. t Reprint requests: Kaylen M. Silverberg, M.D., Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7836. :j: Present address: Department of Obstetrics and Gynecology, University of Vermont Medical School, Burlington, Vermont.
Vol. 57, No.2, February 1992
than other assisted reproductive technologies while affording similar monthly fecundity rates (1). Various methods of timing lUI in natural cycles have been described (2). These include the use of basal body temperature (BBT) charts, urine luteinizing hormone (LH) monitoring, evaluation of cervical mucus, and ultrasonography. Although there is no consensus regarding the optimal time for lUI, most agree that lUI should be performed either before ovulation or during the periovulatory period (2). In contrast to natural cycles monitored with urine LH detection kits, the use of human chorionic gonadotropin (hCG) as an ovulation trigger in cycles of controlled ovarian hyperstimulation may afford the opportunity to define a relatively narrow window oftime during which the first ovulation should occur.
Silverberg et al.
lUI after hCG
357
Theoretically, this should allow more precision in the timing of lUI in relation to ovulation. Despite this and the widespread combination of controlled ovarian hyperstimulationjlUI for the treatment of infertility, no studies have prospectively evaluated different lUI regimens during controlled ovarian hyperstimulation. We therefore designed a prospective, randomized study to compare the efficacy of a single lUI performed in the periovulatory period with one lUI performed before ovulation and a second lUI performed after ovulation. MATERIALS AND METHODS
Thirty-one consecutive patients undergoing 49 cycles of controlled ovarian hyperstimulation combined with lUI at the Center for Reproductive Medicine, Humana Women's Hospital-South Texas were studied. Diagnoses by cycle included ovulatory dysfunction (n = 14), unexplained infertility (n = 7), male factor (n = 2), treated endometriosis (n = 3), cervical factor (n = 1), and two or more infertility factors (n = 22). Husband's semen was used in 40 cycles, and cryopreserved donor semen was used in 9 cycles as treatment for severe male-factor infertility. Three days after the onset of menses, patients underwent transvaginal sonography with an ATL Ultramark 4 equipped with a 5-MHz endovaginal probe (Advanced Technology Laboratories, Bothell, W A). Ovarian stimulation using human menopausal gonadotropin (hMG, Pergonal; Serono Laboratories, Inc., Randolph, MA) was initiated if the largest follicle was 100%. The hMG dosage was increased by 75 IU whenever serial E 2 levels rose by 1 X 106 motile spermatozoa are inseminated into the uterus (9). Every insemination performed in our study contained at least 1 X 106 motile spermatozoa with a range of 1 X 106 to 124 X 106 , and pregnancy rates (PRs) were not correlated with sperm concentration. This suggests that the number of spermatozoa inseminated in this study is probably not the critical factor. Another possible reason for the higher PR with two inseminations involves the timing of lUI. The significantly higher cycle fecundity afforded by the dual insemination protocol may have resulted because the multiple ovulations in hMG/hCG cycles are sequential over a period of at least several hours (7). Thus, the first insemination would provide sufficient motile spermatozoa proximate to the initially ovulated oocyte(s). The second insemination may provide additional sperm to fertilize those oocytes 360
Silverberg et al.
lUI after hCG
that subsequently ovulate. Because ovulation should rarely occur earlier than 36 hOurb after the hCG injection, most perform a single lUI 32 to 40 hours after administering hCG (1, 9, 10). To date, only one prospective, randomized trial comparing different timing regimens of lUI in controlled ovarian hyperstimulation cycles has been reported (J.C. Barrett and J. Marshall, unpublished observations). The study failed to demonstrate a significant difference in cycle fecundity when comparing a single lUI 30 hours after hCG administration to one at the time of hCG and a second 30 hours later. Overall cycle fecundity in these patients, who received either hMG or clomiphene citrate/hMG, was 0.147. However, as the report appeared only in abstract form, no information regarding patient diagnoses or sperm quality was provided. Further, both inseminations presumably were performed before ovulation. Thus, the findings are not directly comparable with our study, that assesses a single periovulatory lUI to one insemination performed before ovulation combined with a second performed after ovulation of at least one oocyte. It remains possible that either a single preovulatory or postovulatory lUI timed as in our group II patients may have resulted in similar cycle fecundity. Data obtained from natural cycles suggest that fertility is maximal on the day ofthe LH peak, i.e., just before ovulation (11). Similarly, Byrd et al. (8) reported that the optimal time for lUI in natural cycles is 10 to 20 hours after the detection of the endogenous LH surge. This would suggest that the preovulatory lUI is the more important in natural cycles. A retrospective, nonrandomized study employing hMG/hCG and intracervical insemination in 113 cycles suggests that this may also be true in controlled ovarian hyperstimulation cycles (12). Although the timing of intracervical insemination was not well controlled and ovulation was confirmed only by BBT rise, cycle fecundity tended to be higher in the group receiving preovulatory inseminations. If indeed the timing of the first insemination is the critical factor resulting in improved cycle fecundity, the mechanism is likely related to increasing the number of capacitated sperm within the upper genital tract. The method of sperm preparation described herein presumably initiates capacitation, and this process continues after insemination (13). Although the amount of time required for capacitation to occur within the genital tract is unknown, extended in vivo incubation (12 to 36 hours) of sperm may enhance sperm fertilizing capacity (14). This may explain the improved cycle fecundity observed Fertility and Sterility
in our study in which insemination is performed 18 rather than 2 hours before the first ovulation. Nevertheless, our study design did not compare a single preovulatory lUI to a single postovulatory lUI as timed in group II patients. Therefore, the possibility remains that either the second lUI or the combination is responsible for our results. The cycle fecundity in group II is at the upper range of success rates reported for hMGjlUI cycles (1,9, 15). In addition to the timing of insemination described above, another factor that may account for this is our individualized regimen of hMG stimulation. Although our stimulation protocol is widely used, it differs significantly from that of previous controlled ovarian hyperstimulationjlUI studies (1, 3,9, 15). Finally, with respect to the use of donor spermatozoa, it appears that donor samples exhibiting good post-thaw motility can be used without experiencing a significant decrease in cycle fecundity, as compared with fresh sperm. This finding confirms the results reported in two recent studies (8, 16). We conclude that, using fresh or cryopreserved sperm, two lUIs timed as described above are superior to a single periovulatory lUI in cycles of controlled ovarian hyperstimulation with hMG. Acknowledgments. We gratefully acknowledge Mrs. Joanne Wright and Mrs. Patsy Oertli for the diligent preparation of this manuscript. REFERENCES 1. Dodson WC, Whitesides DB, Hughes CL Jr, Easley HA III, Haney AF. Superovulation with intrauterine insemination in the treatment of infertility: a possible alternative to gamete intrafallopian transfer and in vitro fertilization. Fertil Steril 1987;48:441-5. 2. Allen NC, Herbert CM III, Maxson WS, Rogers BJ, Diamond MP, Wentz AC. Intrauterine insemination: a critical review. Fertil Steril 1985;44:569-80.
Vol. 57, No.2, February 1992
3. Serhal PF, Katz M, Little V, Woronowski H. Unexplained infertility-the value of Pergonal superovulation combined with intrauterine insemination. Fertil Steril 1988;49:602-6. 4. Corson SL, Batzer FR, Gocial B, Maislin G. Intrauterine insemination and ovulation stimulation as treatment of infertility. J Reprod Med 1989;34:397-406. 5. Y ovich JL, Matson PL. The treatment of infertility by the high intrauterine insemination of husband's washed spermatozoa. Hum Reprod 1988;3:939-43. 6. Tredway DR, Chan P, Henig I, Gullett A, Cheatwood M. Effectiveness of stimulated menstrual cycles and Percoll sperm preparation in intrauterine insemination. J Reprod Med 1990;35:103-8. 7. Silverberg KM, Olive DL, Burns WN, Johnson JV, Groff TR, Schenken RS. Follicular size at the time of human chorionic gonadotropin administration predicts ovulation outcome in human menopausal gonadotropin -stimulated cycles. Fertil Steril 1991;56:296-300. 8. Byrd W, Bradshaw K, Carr B, Edman C, Odom J, Ackerman G. A prospective randomized study of pregnancy rates following intrauterine and intracervical insemination using frozen donor sperm. Fertil Steril1990;53:521-7. 9. Dodson WC, Haney AF. Controlled ovarian hyperstimulation and intrauterine insemination for treatment of infertility. Fertil Steril 1991;55:457-67. 10. Taylor PJ, Kredentser JV. Washed intrauterine insemination-indications and success. Int J FertiI1989;34:378-84. 11. Barrett JC, Marshall J. The role of conception on different days of the menstrual cycle. Popul Stud 1969;23:455-9. 12. Kemmann E, Pasquale S. Timing and frequency of artificial insemination in women under menotropin therapy. Fertil SteriI1985;44:271-3. 13. Sher G, Knutzen VK, Stratton CJ, Montakhab MM, Allenson SG. In vitro sperm capacitation and transcervical intrauterine insemination for the treatment of refractory infertility: phase I. Fertil Steril 1984;41:260-4. 14. Huszar G, DeCherney A. The role of intrauterine insemination in the treatment of infertile couples: the Yale experience. Semin Reprod EndocrinoI1987;5:11-21. 15. Remohi J, Gastaldi C, Patrizio P, Gerli S, Ord T, Asch RH, et al. Intrauterine insemination and controlled ovarian hyperstimulation in cycles before GIFT. Hum Reprod 1989;4: 918-23. 16. Hammond MG, Jordan S, Sloan CS. Factors affecting pregnancy rates in a donor insemination program using frozen semen. Am J Obstet Gynecol 1986;155:480-5.
Silverberg et al.
lUI after hCG
361
