- Email: [email protected]
Can timing improve therapeutic donor insemination fecundability?
Editor' $ corner FERTILITY AND STERILITY Copyright
©
1991 The American Fertility Society
Vol. 55, No.5. May 1991
Printed on acid-free paper in US.A.
Can timing improve therapeutic donor insemination fecundability?
Sander S. Shapiro, M.D. Section of Reproductive Endocrinology Department of Obstetrics and Gynecology University of Wisconsin-Madison Madison, Wisconsin
Received February 14, 1991. Reprint requests: Sander S. Shapiro, M.D., University Hospital, 600 Highland Avenue, H4/630 esc, Madison, Wisconsin 53792. Vol. 55, No.5, May 1991
Therapeutic donor insemination (TDI) has become a widely accepted means of overcoming male factor infertility. Survey data suggests that the frequency of TDI conceptions more than doubled in the United States between 19771 and 1987. 2 It is estimated that as many as 23,000 infants conceived with donor sperm were born in 1987. Over this same 10-year period a trend toward the more frequent use of cryopreserved sperm has been documented. Clinical convenience and commercial availability recommended the use of frozen specimens rather than fresh semen. Balancing these advantages, in the eyes of many practitioners, was a substantially lower fecundability rate. During the 1980s practitioners weighed the relative merits of fresh and frozen semen and individually selected a preferred therapeutic regimen. Then in 1988 everything changed. The universal recognition that TDI could become a vehicle for the spread of human immunodeficiency virus (HIV) infection prompted government and professional organizations to promulgate a policy of frozen, quarantined semen use. Since that recommendation was enunciated, essentially all TDI has been carried out with quarantined specimens; fresh semen use has been abandoned. A result of this change, in addition to minimizing the potential for HIV infection, has been to lengthen the therapeutic process and substantially increase consumer costs. Coincidentally, it has stimulated efforts aimed at improving fecundability from frozen semen TDI. Investigations into the effects of sperm cryopreservation have identified substantial histologic and chemical changes, diminished postthaw survival, and diminished life span and alterations in functional capacity. Research efforts have provided improved cryopreservation methods and semen extenders that modestly increased postthaw survival and suggested directions for further advancement. 3 Despite these alterations, frozen semen fecundability is currently only about one-half that obtainable with the use of fresh specimens. Further efforts towards an improved cryopreservation technology are obviously needed. Available clinical evidence suggests a direct correlation between numbers of sperm inseminated and success during TDI.4 Optimum sperm insemination numbers have been determined for some farm species but are not presently known for humans. It is likely that the numbers of sperm applied during frozen semen therapy are frequently suboptimal. 5 Care in donor selection and restrictions on the proportion of semen extender used for cryopreservation offer potential avenues to increase sperm numbers and thereby improve fecundability rates. The extent to which such strategies can increase success rates will not, however, be known until they are evaluated in systematic clinical trials. Shapiro
Editor's Corner
869
The window of opportunity for fertilization in humans is narrow; probably 12 to 18 hours after ovulation. This restriction is dictated by the ovum, sperm having a much longer functional postejaculatory life. As a result, insemination of fresh sperm at 48-hour intervals assures that sufficient numbers will be available in the immediate postovulatory period. Such is not thought to be the case when short-lived, frozen sperm are inseminated with this same frequency. Either more frequent or better timed inseminations could assure that optimal numbers of sperm approach ova during their critical fertilization period. Given the present limitations of cryopreservation and our minimal appreciation for optimal sperm numbers, a more immediate and practical means of improving fecundability might be attained through enhanced insemination timing. To that end, a number of methods for the prediction/ identification of ovulation have been considered. Of the several currently available methods, serial ovarian ultrasound scanning has been deemed the most reliable for real-time ovulation detection. 6 Unfortunately, expense and inconvenience have inhibited its widespread application as a TDI timing device. Similar indictments discourage use of serial serum luteinizing hormone (LH) sampling, the second most accurate timing method. Hence, clinicians were left with a group of timing techniques of limited prospective value until commercial urine LH assay kits became available. These tests promised a degree of accuracy, cost containment, and efficiency that they were enthusiastically incorporated into many TDI protocols. Only later were studies designed to evaluate their efficacy in TDI undertaken. Reports of these investigations have, so far, provided only marginal encouragement for what has become a widespread practice. Barrat et al. 7 compared retrospective basal body temperature (BBT) timing with a urinary LH test during frozen semen TDI. Subjects (n = 53), who were randomly assigned, received one insemination if in the BBT group and two (surge day and + 1 day) when in the LH group. Fecundability rates during the 230 insemination cycles were relatively low and statistically indistinguishable, with the LH group being only slightly better (0.04 vs 0.07). The difference was so small that a cohort of 378 subjects would have been necessary to demonstrate significance. Kossoy et al. B performed a similar comparative study obtaining almost identical rates with the two timing methods. Unfortunately their paper did not contain a description of how insemination times were related to predicted 870
Shapiro
Editor's Corner
ovulation times. They implied that their high minimum motility criteria for postthaw samples provided sufficient numbers of long-term surviving sperm to overcome any variance in timing that may have occurred. The potential importance of a relationship between estimated day of ovulation and day of insemination can be inferred from a study by Centola et al. 9 That group either inseminated subjects once, on the day after a urinary LH rise, or twice, beginning on the day of a rise. Fecundability was significantly better in the group inseminated for 2 days (0.21 vs 0.06). Whether this difference resulted from the difference in initial insemination timing or the single versus two insemination part of the protocol is not apparent. The relatively high fecundability rate (0.21) obtained is, nevertheless, provocative. In an effort to determine whether LH timing could improve upon fecundability attained through BBT timing, Federman et al. 1O undertook a randomized study comparing a single insemination performed on the day after the LH surge and two inseminations based on past BBT experience. That study, involving 60 subjects (262 cycles) produced a fecundability rate of 0.12 with LH monitoring and 0.05 using BBTs, a difference that was not statistically significant. In the present issue ofthis journal, Odem et alY report the results of a very similar study. Their findings, fecundability of 0.06 with LH monitoring and 0.13 using BBT timing, and their conclusions are, however, the reverse of Federman's. Logic, predicated on our present understanding of sperm cryopreservation, would suggest that improved timing ought to produce improved fecundability. The limitations of retrospective BBT analysis for ovulation prediction are well known as is the rather high correlation between the urinary LH surge and ovulation. Yet, taken together, the studies cited here do not offer a ringing endorsement of the LH assay over BBTs for TDI timing. Wherein lies the explanation for this incongruity between logic and data? Either our presumptions concerning the relative importance of insemination timing or the way in which we use what we know about ovulation for timing is wrong. Clearly what is needed is a systematic, experimental dissection of this therapeutic conundrum. From a monetary perspective, such an endeavor is certainly warranted for, as Odem et alY and others have indicated, the cost of TDI is substantial (approximately $3,997 to the individual and $72,000,000 to the health care system). UnforFertility and Sterility
tunately, to evaluate the multiple variables that impact upon insemination fecundability, a considerably larger study cohort is required than can be gathered at a single site. A consortium such as those involved in cancer therapy trials would be the most effective way to approach this problem. TDI, being rather less glamorous and inherently less sensational, this problem is unlikely to evoke Congressional action or National Institutes of Health sponsored study. Other modes for planning, administration, and financing need to be developed. One that could prove effective is an association between "interest groups" within The American Fertility Society and the manufacturers of commercially available assay kits. Certainly these for profit companies have a vested interest in establishing the relative utility of their products. Correspondingly, the Society has, as one of its missions, the identification and promotion of good medical practice. The establishment of an administrative vehicle to facilitate investigations of therapeutic efficacy seems well within the Society's purview. It is quite likely that a combination of accurate ovulation prediction and temporally specific insemination or temporally determined multiple inseminations can substantially improve fecundability rates. Efforts towards determining the right combination have a high probability of being productive within a short time. The promise implicit in the findings of Centola et a1. 9 make it likely that the commercial distribution of LH assay kits will increase. Society members' concerns about improving TDI, although evident, will not translate into effective multicenter action without some financial underwriting. It stands to reason that those who hold
Vol. 55, No.5, May 1991
an interest ought to join together to meet this therapeutic need. REFERENCES 1. Curie-Cohen M, Shapiro S: Current practice of artificial insemination by donor in the United States. N Engl J Med 300:585, 1979 2. Shapiro S, Saphire DG, Stone WH: Changes in American A.I.D. practice during the past decade. Int J Fertil 35:284, 1990 3. Prins GS, Weidel L: A comparative study of buffer systems as cryoprotectants for human spermatozoa. Fertil Steril 46: 147, 1986 4. David G, Czyglik F, Mayaux MJ, Schwartz D: The success of AID and semen characteristics: study on 1489 cycles and 192 ejaculates. Int J Androl 3:613, 1980 5. Brown CA, Boone WR, Shapiro SS: Improved cryopreserved semen fecundability in an alternating fresh-frozen artificial insemination program. Fertil Steril 50:825, 1988 6. Shoupe D, Mishell DR, Lacarra M, Lobo RA, Harnstein J, d' Abking G, Moyer D: Correlation of endometrial maturation with four methods of estimating day of ovulation. Obstet Gynecol 73:88, 1989 7. Barratt CL, Cooke S, Chauhan M, Cooke ID: A prospective randomized controlled trial comparing urinary luteinizing hormone dipsticks and basal body temperature charts with timed donor insemination. Fertil Steril 52:394, 1989 8. Kossoy LR, Hill GA, Parker RA, Rogers BJ, Dalglish CS, Herbert CM, Wentz AC: Luteinizing hormone and ovulation timing in a therapeutic donor insemination program using frozen semen. Fertil Steril 160:1169, 1989 9. Centola GM, Mottox JH, Raubertas RF: Pregnancy rates after double versus single insemination with frozen semen. Fertil Steril 54:1089, 1990 10. Federman CA, Dumesic DA, Boone WR, Shapiro SS: Relative efficiency of therapeutic donor insemination using luteinizing hormone monitor. Fertil Steril 54:489, 1990 11. Odem RR, Durso NS, Long CA, Pineda JA, Strickler RC, Gast MS: Therapeutic donor insemination: a prospective randomized study of scheduling methods. Fertil Steril 55: 976, 1991
Shapiro
Editor's Corner
871
©
1991 The American Fertility Society
Vol. 55, No.5. May 1991
Printed on acid-free paper in US.A.
Can timing improve therapeutic donor insemination fecundability?
Sander S. Shapiro, M.D. Section of Reproductive Endocrinology Department of Obstetrics and Gynecology University of Wisconsin-Madison Madison, Wisconsin
Received February 14, 1991. Reprint requests: Sander S. Shapiro, M.D., University Hospital, 600 Highland Avenue, H4/630 esc, Madison, Wisconsin 53792. Vol. 55, No.5, May 1991
Therapeutic donor insemination (TDI) has become a widely accepted means of overcoming male factor infertility. Survey data suggests that the frequency of TDI conceptions more than doubled in the United States between 19771 and 1987. 2 It is estimated that as many as 23,000 infants conceived with donor sperm were born in 1987. Over this same 10-year period a trend toward the more frequent use of cryopreserved sperm has been documented. Clinical convenience and commercial availability recommended the use of frozen specimens rather than fresh semen. Balancing these advantages, in the eyes of many practitioners, was a substantially lower fecundability rate. During the 1980s practitioners weighed the relative merits of fresh and frozen semen and individually selected a preferred therapeutic regimen. Then in 1988 everything changed. The universal recognition that TDI could become a vehicle for the spread of human immunodeficiency virus (HIV) infection prompted government and professional organizations to promulgate a policy of frozen, quarantined semen use. Since that recommendation was enunciated, essentially all TDI has been carried out with quarantined specimens; fresh semen use has been abandoned. A result of this change, in addition to minimizing the potential for HIV infection, has been to lengthen the therapeutic process and substantially increase consumer costs. Coincidentally, it has stimulated efforts aimed at improving fecundability from frozen semen TDI. Investigations into the effects of sperm cryopreservation have identified substantial histologic and chemical changes, diminished postthaw survival, and diminished life span and alterations in functional capacity. Research efforts have provided improved cryopreservation methods and semen extenders that modestly increased postthaw survival and suggested directions for further advancement. 3 Despite these alterations, frozen semen fecundability is currently only about one-half that obtainable with the use of fresh specimens. Further efforts towards an improved cryopreservation technology are obviously needed. Available clinical evidence suggests a direct correlation between numbers of sperm inseminated and success during TDI.4 Optimum sperm insemination numbers have been determined for some farm species but are not presently known for humans. It is likely that the numbers of sperm applied during frozen semen therapy are frequently suboptimal. 5 Care in donor selection and restrictions on the proportion of semen extender used for cryopreservation offer potential avenues to increase sperm numbers and thereby improve fecundability rates. The extent to which such strategies can increase success rates will not, however, be known until they are evaluated in systematic clinical trials. Shapiro
Editor's Corner
869
The window of opportunity for fertilization in humans is narrow; probably 12 to 18 hours after ovulation. This restriction is dictated by the ovum, sperm having a much longer functional postejaculatory life. As a result, insemination of fresh sperm at 48-hour intervals assures that sufficient numbers will be available in the immediate postovulatory period. Such is not thought to be the case when short-lived, frozen sperm are inseminated with this same frequency. Either more frequent or better timed inseminations could assure that optimal numbers of sperm approach ova during their critical fertilization period. Given the present limitations of cryopreservation and our minimal appreciation for optimal sperm numbers, a more immediate and practical means of improving fecundability might be attained through enhanced insemination timing. To that end, a number of methods for the prediction/ identification of ovulation have been considered. Of the several currently available methods, serial ovarian ultrasound scanning has been deemed the most reliable for real-time ovulation detection. 6 Unfortunately, expense and inconvenience have inhibited its widespread application as a TDI timing device. Similar indictments discourage use of serial serum luteinizing hormone (LH) sampling, the second most accurate timing method. Hence, clinicians were left with a group of timing techniques of limited prospective value until commercial urine LH assay kits became available. These tests promised a degree of accuracy, cost containment, and efficiency that they were enthusiastically incorporated into many TDI protocols. Only later were studies designed to evaluate their efficacy in TDI undertaken. Reports of these investigations have, so far, provided only marginal encouragement for what has become a widespread practice. Barrat et al. 7 compared retrospective basal body temperature (BBT) timing with a urinary LH test during frozen semen TDI. Subjects (n = 53), who were randomly assigned, received one insemination if in the BBT group and two (surge day and + 1 day) when in the LH group. Fecundability rates during the 230 insemination cycles were relatively low and statistically indistinguishable, with the LH group being only slightly better (0.04 vs 0.07). The difference was so small that a cohort of 378 subjects would have been necessary to demonstrate significance. Kossoy et al. B performed a similar comparative study obtaining almost identical rates with the two timing methods. Unfortunately their paper did not contain a description of how insemination times were related to predicted 870
Shapiro
Editor's Corner
ovulation times. They implied that their high minimum motility criteria for postthaw samples provided sufficient numbers of long-term surviving sperm to overcome any variance in timing that may have occurred. The potential importance of a relationship between estimated day of ovulation and day of insemination can be inferred from a study by Centola et al. 9 That group either inseminated subjects once, on the day after a urinary LH rise, or twice, beginning on the day of a rise. Fecundability was significantly better in the group inseminated for 2 days (0.21 vs 0.06). Whether this difference resulted from the difference in initial insemination timing or the single versus two insemination part of the protocol is not apparent. The relatively high fecundability rate (0.21) obtained is, nevertheless, provocative. In an effort to determine whether LH timing could improve upon fecundability attained through BBT timing, Federman et al. 1O undertook a randomized study comparing a single insemination performed on the day after the LH surge and two inseminations based on past BBT experience. That study, involving 60 subjects (262 cycles) produced a fecundability rate of 0.12 with LH monitoring and 0.05 using BBTs, a difference that was not statistically significant. In the present issue ofthis journal, Odem et alY report the results of a very similar study. Their findings, fecundability of 0.06 with LH monitoring and 0.13 using BBT timing, and their conclusions are, however, the reverse of Federman's. Logic, predicated on our present understanding of sperm cryopreservation, would suggest that improved timing ought to produce improved fecundability. The limitations of retrospective BBT analysis for ovulation prediction are well known as is the rather high correlation between the urinary LH surge and ovulation. Yet, taken together, the studies cited here do not offer a ringing endorsement of the LH assay over BBTs for TDI timing. Wherein lies the explanation for this incongruity between logic and data? Either our presumptions concerning the relative importance of insemination timing or the way in which we use what we know about ovulation for timing is wrong. Clearly what is needed is a systematic, experimental dissection of this therapeutic conundrum. From a monetary perspective, such an endeavor is certainly warranted for, as Odem et alY and others have indicated, the cost of TDI is substantial (approximately $3,997 to the individual and $72,000,000 to the health care system). UnforFertility and Sterility
tunately, to evaluate the multiple variables that impact upon insemination fecundability, a considerably larger study cohort is required than can be gathered at a single site. A consortium such as those involved in cancer therapy trials would be the most effective way to approach this problem. TDI, being rather less glamorous and inherently less sensational, this problem is unlikely to evoke Congressional action or National Institutes of Health sponsored study. Other modes for planning, administration, and financing need to be developed. One that could prove effective is an association between "interest groups" within The American Fertility Society and the manufacturers of commercially available assay kits. Certainly these for profit companies have a vested interest in establishing the relative utility of their products. Correspondingly, the Society has, as one of its missions, the identification and promotion of good medical practice. The establishment of an administrative vehicle to facilitate investigations of therapeutic efficacy seems well within the Society's purview. It is quite likely that a combination of accurate ovulation prediction and temporally specific insemination or temporally determined multiple inseminations can substantially improve fecundability rates. Efforts towards determining the right combination have a high probability of being productive within a short time. The promise implicit in the findings of Centola et a1. 9 make it likely that the commercial distribution of LH assay kits will increase. Society members' concerns about improving TDI, although evident, will not translate into effective multicenter action without some financial underwriting. It stands to reason that those who hold
Vol. 55, No.5, May 1991
an interest ought to join together to meet this therapeutic need. REFERENCES 1. Curie-Cohen M, Shapiro S: Current practice of artificial insemination by donor in the United States. N Engl J Med 300:585, 1979 2. Shapiro S, Saphire DG, Stone WH: Changes in American A.I.D. practice during the past decade. Int J Fertil 35:284, 1990 3. Prins GS, Weidel L: A comparative study of buffer systems as cryoprotectants for human spermatozoa. Fertil Steril 46: 147, 1986 4. David G, Czyglik F, Mayaux MJ, Schwartz D: The success of AID and semen characteristics: study on 1489 cycles and 192 ejaculates. Int J Androl 3:613, 1980 5. Brown CA, Boone WR, Shapiro SS: Improved cryopreserved semen fecundability in an alternating fresh-frozen artificial insemination program. Fertil Steril 50:825, 1988 6. Shoupe D, Mishell DR, Lacarra M, Lobo RA, Harnstein J, d' Abking G, Moyer D: Correlation of endometrial maturation with four methods of estimating day of ovulation. Obstet Gynecol 73:88, 1989 7. Barratt CL, Cooke S, Chauhan M, Cooke ID: A prospective randomized controlled trial comparing urinary luteinizing hormone dipsticks and basal body temperature charts with timed donor insemination. Fertil Steril 52:394, 1989 8. Kossoy LR, Hill GA, Parker RA, Rogers BJ, Dalglish CS, Herbert CM, Wentz AC: Luteinizing hormone and ovulation timing in a therapeutic donor insemination program using frozen semen. Fertil Steril 160:1169, 1989 9. Centola GM, Mottox JH, Raubertas RF: Pregnancy rates after double versus single insemination with frozen semen. Fertil Steril 54:1089, 1990 10. Federman CA, Dumesic DA, Boone WR, Shapiro SS: Relative efficiency of therapeutic donor insemination using luteinizing hormone monitor. Fertil Steril 54:489, 1990 11. Odem RR, Durso NS, Long CA, Pineda JA, Strickler RC, Gast MS: Therapeutic donor insemination: a prospective randomized study of scheduling methods. Fertil Steril 55: 976, 1991
Shapiro
Editor's Corner
871