FERTILITY AND STERILITY威 VOL. 82, NO. 1, JULY 2004 Copyright ©2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A.
RESPONSES
Timing of intrauterine insemination: where are we? Guido Ragni, M.D., Edgardo Somigliana, M.D., and Walter Vegetti, M.D. Infertility Unit, Department of Obstetrics and Gynecology, University of Milan, Milan, Italy
Correct timing of insemination remains a controversial aspect of IUI cycles associated with ovarian hyperstimulation. Although it is currently believed that insemination at 32–38 hours after hCG administration provides the best results, clinical evidence supporting this conclusion is scarce. Double insemination might be an alternative, effective strategy, but studies on this topic are few, heterogeneous, and controversial. (Fertil Steril威 2004;82:25– 6. ©2004 by American Society for Reproductive Medicine.)
Intrauterine insemination with controlled ovarian hyperstimulation is one of the treatment modalities offered most often to couples with unexplained or mild male factor subfertility. Its effectiveness, particularly in couples with unexplained infertility, has been recently demonstrated (1, 2). However, many aspects of the treatment that could optimize the rate of success remain to be defined. For example, a recently debated issue is the correct timing of insemination.
Received January 27, 2004; revised and accepted January 27, 2004. Reprint requests: Guido Ragni, M.D., Infertility Unit, Department of Obstetrics and Gynecology, University of Milan, Via Manfredo Fanti 6, Milan 20122, Italy (FAX: 39-02-57994302; Email:
[email protected]). 0015-0282/04/$30.00 doi:10.1016/j.fertnstert.2004. 01.028
Spermatozoa survive for a limited period in the female reproductive tract, and oocytes are fertilizable for only 12–16 hours (3). Unfortunately, timing of ovulation varies considerably and might also depend on the ovarian hyperstimulation regimen used. According to a World Health Organization probit analysis of natural cycles, ovulation takes place from 24 to 56 hours after the onset of the LH surge, with a mean time of 32 hours (4). In stimulated cycles, ovulations usually begin ⱖ36 hours after hCG administration and are sequential over several hours (5). However, it has been shown that after induction with clomiphene citrate, a certain number of oocytes can be fertilized as early as 12 hours after hCG administration (6). Moreover, a premature LH surge, a condition that might interfere with the adequate timing of insemination, has been reported to occur in 24% of stimulated cycles with gonadotropins (7). Despite this detailed information regarding the timing of ovulation, few data are currently available from a clinical perspective. Specifically, although it is cur-
rently believed that insemination at 32–38 hours after hCG administration would provide the best results, clinical evidence supporting this conclusion is scarce. Randomized trials specifically designed to establish the optimal timing of the insemination are warranted. An alternative proposed strategy to solve the problem of correct timing is to increase the number of inseminations from one to two per cycle. The rationale of this approach is to provide sufficient motile spermatozoa at different times of ovulation. Results from only four published randomized, prospective studies specifically designed to address this point are controversial (8 –11). Two of them have documented an increase in the probability of achieving pregnancy with a double-insemination strategy (8, 10), whereas the other two have failed to show any difference (9, 11). Meta-analyses are warranted to shed light on the debate. However, it has to be noted that the use of this type of analysis in this context is hampered by the extreme clinical heterogeneity of available studies (12). Indeed, at least three major variables that differ from one study to the other might influence the optimum timing of insemination. First, it cannot be excluded that the indication of treatment (mild male subfertility, cervical factor, unexplained subfertility) might play a role (11). For example, a double-insemination protocol at 12–36 hours in couples with mild male factor might lead to an insufficient number of spermatozoa at the second (and probably more important) insemination be25
cause a 24-hour interval might be insufficient for adequate recovery of spermatozoa in this subgroup of patients (13). Second, the stimulation protocol might play a major role. In particular, the use of antiestrogens, such as clomiphene citrate rather than gonadotropins, and the dose of both gonadotropins and hCG might influence the optimum timing of insemination. The recently proposed use of GnRH antagonist in the armamentarium of drugs to be used in superovulation induction associated with IUI might further complicate the debate in this field (14). In this regard, it is worth noting that, as recently debated in the January 2003 issue of Fertility and Sterility, a gold standard for ovulation stimulation is currently unavailable. As a consequence, regimens used vary significantly from one center to another. Finally, a third aspect to be considered is the precise timing for double insemination. For example, in the study performed by our group, IUIs at 12–34 hours but not at 34 – 60 hours proved effective in increasing the probability of success (10). Combining results from these two protocols to draw conclusions as to the utility of double insemination might lead to underestimating its benefit. Overall, we believe that, although meta-analyses represent a valid tool to elucidate debated issues, the reduced number of available randomized studies and the heterogeneity of protocols used currently limits the validity of such analyses. The controversy regarding the correct timing of insemination shares a common difficulty with many other issues currently being debated in the field of infertility. Specifically, published studies frequently involve insufficient sample sizes, which impacts the interpretation of results. This major point should be kept in mind by both researchers and readers. In this context, although the success rates of IUI have been reported to vary widely, a 10% rate of success per cycle is reasonably expected to occur in IUI cycles associated with controlled ovarian hyperstimulation (1, 2, 15). Most variants of the procedure that would allow an increase of 5% (i.e., an increase in the rate of success of 50%) have to be considered clinically relevant. Unfortunately, to obtain this frequency of event rate, the calculated sample size becomes prohibitively large. Specifically, on the basis of these assumptions, the number of couples to be enrolled would be 1,370 with use of the commonly accepted twotailed test with probabilities of type I and type II errors set at 0.05 and 0.20, respectively (16). Furthermore, it has to be considered that few studies are accurately designed (17). Methodologic aspects of trials in subfertility have recently been exhaustively reviewed by Daya (18). In particular, it has been pointed out that patients should be enrolled in a trial only for their first cycle of treatment and that a crossover study design should be avoided (18). The application of these recommendations would further reduce the sample size of published studies and thus available information. Never-
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Timing of IUI
theless, we believe that medical progress also arises from widespread participation in the scientific debate. Contributions based on limited numbers of cases are thus also welcome. However, limitations related to the power of a trial should always be clearly discussed in the study, and interpretation of the results should take this limitation into consideration. In conclusion, currently available studies are insufficient to draw firm conclusions as to the optimal timing of insemination and the utility of double insemination. Large multicenter trials and/or meta-analysis based on several and homogeneous studies are warranted to address these issues. References 1. Guzick DS, Carson SA, Coutifaris C, Overstreet JW, Factor-Litvak P, Steinkampf MP, et al. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. N Engl J Med 1999;340: 177–83. 2. Goverde AJ, McDonnell J, Vermeiden JPW, Schats R, Rutten FFH, Schoemaker J. Intrauterine insemination or in-vitro fertilization in idiopathic subfertility and male subfertility: a randomised trial and cost-effectiveness analysis. Lancet 2000;355:13–8. 3. Edwards RG, Brody SA. Principles and practice of assisted human reproduction, 1st ed. Philadelphia: W.B. Saunders, 1995. 4. World Health Organization. Temporal relationships between ovulation and defined changes in the concentration of plasma 17--estradiol, luteinizing hormone, follicle-stimulating hormone and progesterone. Am J Obstet Gynecol 1980;138:383–90. 5. Edwards RG, Steptoe PC. Control of human ovulation, fertilization and implantation. Proc R Soc Med 1974;67:932–5. 6. Templeton AA, Van Look P, Angell RE, Aitken RJ, Lumsden MA, Baird DT. Oocyte recovery and fertilization rates in women at various times after administration of hCG. J Reprod Fertil 1996;76:771–8. 7. Cohlen BJ, Te Velde ER, Van Kooij RJ, Looman CWN, Habbema JDF. Controlled ovarian hyperstimulation and intrauterine insemination for treating male subfertility: a controlled study. 1998;13:1553– 8. 8. Silverberg KM, Johnson JV, Olive DL, Burns WN, Schenken RS. A prospective, randomized trial comparing two different insemination regimens in controlled ovarian hyperstimulation cycles. Fertil Steril 1992;57:357–61. 9. Ransom MX, Blotner MB, Boher M, Corsan G, Kemmann E. Does increasing frequency of intrauterine insemination improve pregnancy rates significantly during superovulation cycles? Fertil Steril 1994;61: 303–7. 10. Ragni G, Maggioni P, Guermandi E, Testa A, Baroni E, Colombo M, et al. Efficacy of double intrauterine insemination in controlled ovarian hyperstimulation cycles. Fertil Steril 1999;72:619 –22. 11. Alborzi S, Motazedian S, Parsanezhad ME, Jannati S. Comparison of the effectiveness of single intrauterine insemination (IUI) versus double insemination per cycle in infertile patients. Fertil Steril 2003;80:595–9. 12. Cantineau AEP, Heineman MJ, Cohlen BJ. Single versus double intrauterine insemination in stimulated cycles for subfertile couples: a systematic review based on a Cochrane review. Hum Reprod 2003;18: 941–6. 13. Hornstein MD, Cohen JN, Thomas PP, Gleason RE, Friedman AJ, Mutter GL. The effect of consecutive day inseminations on semen characteristics in an intrauterine insemination program. Fertil Steril 1992;58:433–5. 14. Ragni G, Alagna F, Brigante C, Riccaboni A, Colombo M, Somigliana E, et al. GnRH antagonists and mild ovarian stimulation for intrauterine insemination: a randomized study comparing different gonadotrophin dosages. Hum Reprod 2004;19:54 –8. 15. Hughes EG. The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: a meta-analysis. Hum Reprod 1997;12:1865–72. 16. Mittendorf R, Arun V, Sapugay AM. The problem of the type II statistical error. Obstet Gynecol 1995;86:857–9. 17. Vail A, Gardener E. Common statistical errors in the design and analysis of subfertility trials. Hum Reprod 2003;18:1000 –4. 18. Daya S. Pitfalls in the design and analysis of efficacy trials in subfertility. Hum Reprod 2003;18:1005–9.
Vol. 82, No. 1, July 2004
