Midland Fertility Services, Third Floor, Centre House, Aldridge, WS9 8LT, UK
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Abstract |
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Key words: clomiphene/FSH/HCG/intrauterine insemination/LH surge/natural cycle
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Introduction |
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Materials and methods |
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Intrauterine insemination was performed either in natural cycles or with ovarian stimulation. In stimulated cycles, patients received clomiphene citrate (50100 mg) (Merrel Dow, Uxbridge, UK) orally from day 1 or 2 of the menstrual cycle for 5 days, or gonadotrophins [urofollitrophin high purity (uFSH HP)/follitrophin alpha (rFSH)] (Metrodin HP or Gonal F; Serono Laboratories, Welwyn Garden City, UK), usually 150300 IU on alternate days starting on day 3 of the menstrual cycle.
Patients who had ovarian stimulation were first scanned on day 3 of their menstrual cycle. Other patients had their first scan on days 911. Thereafter, patients either stopped stimulation, continued on alternate days, or had a daily injection depending on the size of the recruited follicles. Serial transvaginal ultrasound scans were continued until the dominant follicle was >15 mm, whereupon patients tested their urine each morning (using the second morning sample) with a commercial urinary LH dipstick (Clear Plan One Step; Unipath Ltd, Bedford, UK) and returned for a repeat scan on the day the LH test was positive. Patients were offered HCG injection on the day of the LH surge on the understanding that its value has not yet been proven. Depending on the patient's choice, an intramuscular injection of 5000 IU HCG (Pregnyl; Organon, Cambridge, UK) was given at the time of the visit and IUI planned for the following morning approximately 2430 h later (Cohlen et al., 1998). Alternatively, when the dominant follicle was >17 mm and the LH test was negative, 5000 IU HCG was administered i.m. that evening, and IUI planned for 40 h later. IUI was performed when the largest follicle was >17 mm and there were no more than three follicles with mean diameter >14 mm present in total. IUI was performed once in every cycle. If ovarian response exceeded these criteria the cycle was either abandoned or, following the administration of HCG, converted to in-vitro fertilization (IVF).
For IUI, either fresh semen (obtained by masturbation) or frozen donor semen was used. The cryopreserved sperm samples were thawed at room temperature. Liquefied semen was added to 12 ml of Medicult IVF medium (Medicult, Copenhagen, Denmark) and then layered onto the top of Pure Sperm gradient (NidaCon International AB, Gothenburg, Sweden) which consisted of 0.5 ml each at a lower layer of 100%, a middle layer of 80%, and an upper layer of 50%. Samples were centrifuged at 300 g for 35 min. The pellet was removed, resuspended in 2 ml of Medicult IVF medium, and centrifuged for 10 min. The supernatant was removed down to 0.2 ml and used for insemination. This final sample contained motile spermatozoa and was resuspended by drawing it up and down the pipette. One drop of this sample was placed on a Horwell Counting Chamber for an estimation of sperm concentration and motility, and the motile sperm count (sperm concentrationxpercentage motile spermatozoa) was calculated.
Patients were routinely scanned (not included in the number of scans performed per treatment cycle in the analysis) before IUI, and evidence of ovulation recorded: an irregularly shaped follicle with marked reduction in size, with or without fluid in the periovulatory area; disappearance of the previously seen follicle; or the presence of a corpus luteum. The cervix was exposed with a bivalve speculum and cleaned with a dry sterile swab or a swab soaked in phosphate-buffered saline. The loaded catheter was passed gently through the cervix and 0.2 ml sperm sample injected high into the uterine cavity. The luteal phase was not routinely supported pharmacologically in our IUI programme, even in stimulated cycles.
A pregnancy test was performed 2 weeks after IUI and, if positive, patients underwent ultrasound scanning 2 weeks later to establish the number of gestation sacs and embryonic viability, and to exclude ectopic pregnancy. Clinical pregnancy was defined as the presence of an intrauterine gestation sac with yolk sac, fetal pole and fetal heart pulsations.
Statistical analysis was performed on an IBM-compatible computer, using the statistical package SPSS for Windows 6.1 program. Between-group differences were analysed with chi-square test and Fisher's exact test for categorical data, and analysis of variance (ANOVA) for continuous variables. When ANOVA revealed a difference within the three treatment groups, the Bonferroni multiple comparisons procedure was done as a post-hoc comparison to determine which means were significantly different from each other. Statistical significance was set at P < 0.05.
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Results |
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Discussion |
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The overall clinical pregnancy rate in this study was 16% per cycle. The rates of 12.1% and 16.9% achieved with the use of homologous and donor semen respectively were consistent with those cited in earlier reports (Dickey et al., 1991; Hurd et al., 1993
; Fuh et al., 1997
), but lower than that of another (Pittrof et al., 1996
). That poor result was achieved when IUI was performed with homologous semen in natural cycles irrespective of the indication for treatment (Irianni et al., 1990
; DiMarzo et al., 1992
), was borne out by the results of our study. In addition, our results were in agreement with a previous report (Cohlen et al., 1998
) that cycles in which >10x106 motile spermatozoa were inseminated resulted in a lower pregnancy rate. This would suggest that subtle female factors may also be contributing to the sub-fertility in such cases.
It is perhaps not surprising that the mean cycle day of treatment was less, and the mean diameter of the leading follicle smaller, in cycles where HCG injection was administered before the LH surge (Martinez et al., 1991). In contrast to the findings by Fuh et al. (1997), these variables did not affect the treatment outcome in this group (Fuh et al. 1997
). The mean number of follicles >14 mm present on the day of the LH surge (or HCG administration) was significantly higher in group 3 compared with that in groups 1 and 2. However, this difference was no longer apparent when the number of follicles recruited in the three groups was analysed in relation to the type of stimulation used. Therefore, this variable is unlikely to account for the higher (but not significantly better) pregnancy rate seen in group 3 in the different stimulation protocols. It was a disadvantage that significantly more transvaginal scans were performed in patients in group 3. This was true only for the data from the subset of those who had treatment without stimulation, but it did not influence the pregnancy rate when donor semen was used. Only few patients used their partner's semen for treatment in a natural cycle for meaningful statistical comparison.
In artificial insemination, it has always been known that some form of timing is necessary to achieve an optimal pregnancy rate (Allen et al., 1985). In IUI, unlike timed intercourse, most authorities agree that the timing of insemination needs to be more precise and closer to the actual time of ovulation. The ability to determine the most opportune time of insemination would make performing a single insemination more cost-effective (Martinez et al., 1991
). This is supported by the findings in this study, where 17% compared with a 5% clinical pregnancy rate was achieved in cycles where there was evidence of ovulation at the time of IUI (Table IV
).
The results of this study confirm the previous report by Pittrof et al. (1996) that when HCG is used to time IUI, the prior detection of a spontaneous LH surge does not affect the pregnancy rate (Pittrof et al., 1996). Whereas it is routine in our unit for patients to test their urine daily for an LH surge once a dominant follicle is identified, this was done in less than half of the treatment cycles presented (Pittrof et al., 1996
). Our result is at variance with the findings by Fuh et al. (1997), who concluded that a significantly higher pregnancy rate was achieved if a spontaneous LH surge occurred before HCG administration, especially where administration of HCG was delayed for 820 h after an observed LH surge (Fuh et al., 1997
). It is reasonable to expect a better pregnancy rate in IUI if imminent ovulation, as ascertained by the detection of an LH surge, occurs before injecting HCG to ensure and time ovulation more precisely. Several reasons could be put forward to explain why this strategy should improve the treatment outcome in IUI: an improvement in the accuracy of timing because of the known oocyte release after HCG injection; the presence of an LH surge is an indication that the final process of natural follicular maturation has commenced and that ovulation is imminent; the likelihood that ovulation could be triggered in the presence of an immature follicle(s) is avoided; luteinized unruptured folliclewhich occurs in up to 9% of cycles in women with unexplained infertility (Daly et al., 1985
)as a cause of treatment failure is avoided; occult ovulatory dysfunction (Tummon et al., 1988
; Daly, 1989
) may be corrected; urinary LH assays may not correlate completely with ultrasound findings in the identification of ovulation (Shoupe et al., 1989
); and wide variance in the temporal identification of the LH surge has been found using several commercial LH kits (Vermeah et al., 1987
). Despite these, we could not establish any benefit in waiting for a spontaneous LH surge before administering HCG in the presence of a mature follicle(s) in this study. Although this was true for cycles in which homologous semen and stimulation with clomiphene citrate and gonadotrophins were used, the number of cycles involved did not allow for proper statistical comparison. With donor semen, performing IUI in a natural cycle gives a good pregnancy rate, whether the timing of treatment is by LH surge alone or by administration of HCG before or after the LH surge. We could not evaluate the time interval between the LH surge and HCG administration because there were too many missing data for meaningful statistical comparison. It is therefore not possible to comment on the impact of this variable on the treatment outcome. Following a demonstration of the LH surge, all patients had their IUI treatment within 30 h. Fuh et al. (1997) in their study concluded that the longer the time interval (up to 20 h) between the LH surge and subsequent HCG administration, the better the pregnancy rate (up to 3038%) (Fuh et al., 1997
). Although in this studyunlike our owngonadotrophins were used in virtually every treatment cycle, this assertion needs to be investigated further. However, our result is in agreement with their findings that the timing of IUI based on the LH surge is not critical to the achievement of pregnancy.
In conclusion, our results show that there is no benefit in waiting for the LH surge in the presence of a mature follicle when donor semen is used for IUI in a natural cycle. Similar clinical pregnancy rates per cycle could be achieved in this group of patients, irrespective of whether HCG, the LH surge, or both are used to time IUI. With this strategy, further monitoring to detect the LH surge is avoided and treatment planned for a time convenient to the patient. Two sources of bias in our study are worth mentioning. Firstly, the design of our study is retrospective; hence it does not represent the best evidence. Secondly, patients were allowed to choose their treatment but the reasons for their choice have not been analysed; hence the possible effect on the outcome is uncertain. Nevertheless, this report adds to the debate concerning the effectiveness of the administration of HCG before or after an LH surge versus LH surge alone in IUI. What is now needed is a prospective randomized studythat takes into consideration the confounding variables mentioned in this studyto determine whether in the presence of a mature follicle there is any benefit in waiting for the LH surge before administering HCG in patients having IUI.
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Acknowledgments |
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Notes |
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References |
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Berger, T., Marrs, R.P. and Moyer, D.L. (1985) Comparison of techniques for selection of motile spermatozoa. Fertil. Steril., 43, 268273.[ISI][Medline]
Burr, R.W., Siegberg, R., Flaherty, S.P. et al. (1996) The influence of sperm morphology and the number of motile sperm inseminated on the outcome of intrauterine insemination combined with mild ovarian stimulation. Fertil. Steril., 65, 127132.[ISI][Medline]
Cohlen, B.J., te Velde, E.R., Scheffer, G. et al. (1993) The pattern of the luteinizing hormone surge in spontaneous cycles is related to the probability of conception. Fertil. Steril., 60, 413417.[ISI][Medline]
Cohlen, B.J., te Velde, E.R., van Kooiji, R.J. et al. (1998) Controlled ovarian hyperstimulation and intrauterine insemination for treating male sub-fertility: a controlled study. Hum. Reprod., 13, 15531558.[Abstract]
Curie-Cohen, M., Luttrell, L. and Shapiro, S. (1979) Current practice of artificial insemination by donor in the United States. N. Engl. J. Med., 300, 585590.[Abstract]
Daly, D.C. (1989) Treatment validation of ultrasound-defined abnormal follicular dynamics as a cause of infertility. Fertil. Steril., 51, 5157.[ISI][Medline]
Daly, D.C., Soto-Albors, C., Walter, C. et al. (1985) Ultrasonographic assessment of luteinized unruptured follicle syndrome in unexplained infertility. Fertil. Steril., 43, 6265.[ISI][Medline]
Deaton, J.L., Clark, R.R., Pittaway, D.E. et al. (1997) Clomiphene citrate ovulation induction in combination with a timed intrauterine insemination: the value of urinary luteinizing hormone versus human chorionic gonadotrophin timing. Fertil. Steril., 68, 4347.[ISI][Medline]
Dickey, R.P., Olar, T.T., Taylor, S.N. et al. (1991) Relationship of follicle number, serum estradiol, and other factors to birth rate and multiparity in human menopausal gonadotrophin induced intrauterine insemination cycles. Fertil. Steril., 56, 8992.[ISI][Medline]
DiMarzo, S.J., Kennedy, J.F., Young, Ph.E. et al. (1992) Effect of controlled ovarian hyperstimulation on pregnancy rates after intrauterine insemination. Am. J. Obstet. Gynecol., 166, 16071613.[ISI][Medline]
Federman, C.A., Dumesic, D.A., Boone, W.R. et al. (1990) Relative efficiency of therapeutic donor insemination using a luteinizing hormone monitor. Fertil. Steril., 54, 489492.[ISI][Medline]
Fuh, K.W., Wang, X., Tai, A. et al. (1997) Intrauterine insemination: effect of the temporal relationship between the luteinizing hormone surge, human chorionic gonadotrophin administration and insemination on pregnancy rates. Hum. Reprod., 12, 21622166.[Abstract]
Horne, G., Jamaludin, A., Critchlow, J.D. et al. (1998) A 3-year review of intrauterine insemination, using cryopreserved donor spermatozoa and cycle monitoring by urinary or serum luteinizing hormone measurements. Hum. Reprod., 13, 30453048.[Abstract]
Hughes, E.G. (1997) The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: a meta-analysis. Hum. Reprod., 12, 18651872.[Abstract]
Hughes, E.G. and Vandekerckhove, P. (1996) Clomiphene citrate vs. placebo or no treatment. In Unexplained Subfertility. BMJ Publishing Group, Cochrane Library, Oxford. Review number 0002.
Hurd, W.W., Randolph, J.F., Ansbacher, R. et al. (1993) Comparison of intracervical, intrauterine and intratubal techniques for donor insemination. Fertil. Steril., 59, 339342.[ISI][Medline]
Irianni, F.M., Acosta, A.A., Oehninger, S. and Acosta, M.R. (1990) Evaluation and preparation of spermatozoa for intrauterine insemination: clinical aspects. In Acosta, A.A., Swanson, R.J., Ackerman, S.B. et al. (eds), Human Spermatozoa in Assisted Reproduction. Williams and Wilkins, Baltimore, pp. 265279.
Khalifa, Y., Redgement, C.J., Tsirigotis, M. et al. (1995) The value of single versus repeated insemination in intrauterine donor insemination cycles. Hum. Reprod., 10, 153154.[Abstract]
Manganiello, P.D., Stern, J.E., Stukel, T.A. et al. (1997) A comparison of clomiphene citrate and human menopausal gonadotrophin for use in conjunction with intrauterine insemination. Fertil. Steril., 68, 405412.[ISI][Medline]
Martinez, A.R., Bernadus, R.E., Voorhorst, F.J. et al. (1991) A controlled study of human chorionic gonadotrophin induced ovulation versus urinary luteinizing hormone surge for timing of intrauterine insemination. Hum. Reprod., 6, 12471251.[Abstract]
Ombelet, W., Vandeput, H., Van de Putte, G. et al. (1997) Intrauterine insemination after ovarian stimulation with clomiphene citrate: predictive potential of inseminating motile count and sperm morphology. Hum. Reprod., 12, 14581463.[Abstract]
Patton, P.E., Burry, K.A., Thurmond, A. et al. (1992) Intrauterine insemination outperformed intracervical insemination in a randomized, controlled study with frozen, donor semen. Fertil. Steril., 57, 559564.[ISI][Medline]
Pearlstone, A.C. and Surrey, E.S. (1994) The temporal relation between the urine LH surge and sonographic evidence of ovulation: determinants and clinical significance. Obstet. Gynecol., 83, 184188.[Abstract]
Pittrof, R.U., Shaker, A., Dean, N. et al. (1996) Success of intrauterine insemination using cryopreserved donor sperm is related to the age of the woman and the number of preovulatory follicles. J. Assist. Reprod. Genet., 13, 310313.[ISI][Medline]
Ransom, M.X., Blotner, M.B., Bohrer, M. et al. (1994) Does increasing frequency of intrauterine insemination improve pregnancy rates significantly during superovulation cycles? Fertil. Steril., 61, 303307.[ISI][Medline]
Romeu, A., Monzo, A., Peiro, T. et al. (1997) Endogenous LH surge versus hCG as ovulation trigger after low-dose highly purified FSH in IUI: a comparison of 761 cycles. J. Assist. Reprod. Genet., 14, 518524.[ISI][Medline]
Shoupe, D., Mishell, D.R., LaCarra, M. et al. (1989) Correlation of endometrial maturation with four methods of estimating day of ovulation. Obstet. Gynecol., 73, 8892.[Abstract]
Tomlinson, M.J., Amissah-Arthur, J.B., Thompson, K.A. et al. (1996) Prognostic indicators for intrauterine insemination (IUI): statistical model for IUI success. Hum. Reprod., 11, 18921896.[Abstract]
Tummon, I.S., Maclin, V.M., Radwanska, E. et al. (1988) Occult ovulatory dysfunction in women with minimal endometriosis or unexplained infertility. Fertil. Steril., 50, 716720.[ISI][Medline]
Vermeah, M., Kletzky, O.A., Davajan, V. and Israel R. (1987) Monitoring techniques to predict and detect ovulation. Fertil. Steril., 47, 259264.[ISI][Medline]
Submitted on December 3, 1998; accepted on March 9, 1999.