1 Infertility Unit, Department of Obstetrics and Gynaecology, University of Milan and 2 Reproductive Unit, Istituto Scientifico San Raffaele, Milan, Italy
3 To whom correspondence should be addressed at: Infertility Unit, Department of Obstetrics and Gynaecology, University of Milan, Via Manfredo Fanti 6, 20122, Milan, Italy. e-mail: ragni{at}telemacus.it
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Abstract |
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Key words: GnRH antagonist/intrauterine insemination/ovulation induction/recombinant FSH
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Introduction |
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The considerable human and financial costs of multiple births thus warrant a re-evaluation of the protocols of ovarian stimulation. In this context, a new class of drugs, the GnRH antagonists, recently have become commercially available and are now at an advanced stage of clinical development. These drugs cause a prompt and reversible suppression of gonadotrophin secretion, thus preventing spontaneous ovulation (Huirne and Lambalk, 2001). Their precise role in the armamentarium of drugs for ovarian stimulation remains to be clarified. In particular, considering that a premature LH surge, a condition that may interfere with the adequate timing of IUI, has been reported to occur frequently in stimulated cycles (Cohlen et al., 1998
), it might be hypothesized that these drugs may have a role in this specific context. We have conducted a randomized study comparing two different protocols using GnRH antagonists associated with IUI in order to determine the best protocol that may ensure a decrease in multiple birth risk on one hand and an acceptable pregnancy rate on the other.
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Materials and methods |
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After inclusion in the study, patients underwent a transvaginal ultrasonography on day 3 of the cycle and were randomized by means of a previously computer-generated list into two groups. Sealed opaque envelopes contaning treatment allocation were opened after ultrasonographic scan. Women were enrolled only for one cycle of treatment. All subjects started the therapy from the third day of the cycle. The therapeutic protocol of the study is illustrated in Figure 1. Patients in group A were administered recombinant FSH (rFSH; Puregon®, Organon, The Netherlands) 50 IU per day, whereas those included in group B were treated with rFSH 50 IU on alternate days. Ovarian stimulation in both groups was monitored by daily transvaginal ultrasound scans starting from the eighth day of the cycle (fifth day of ovarian stimulation).The GnRH antagonist Ganirelix (Orgalutran®, Organon, The Netherlands) at a dose of 0.25 mg per day was started from the day in which a follicle 14 mm in mean diameter was visualized until administration of 5000 IU of HCG (leading follicle with a mean diameter
18 mm). If a leading follicle with a mean diameter
18 mm was detected at the first transvaginal ultrasound scan at the eighth day of the cycle, HCG was administrated the same day without prescribing GnRH antagonist. No luteal phase supplementation was prescribed since we previously have demonstrated a normal hormonal luteal profile in patients treated with rFSH and GnRH antagonists (Ragni et al., 2001
). To further prevent multiple gestations, the cycle was cancelled if the total number of follicles with a mean diameter
15 mm visualized at the time of HCG injection was >2. Insemination was performed 34 h after HCG administration. Serum levels of estradiol were assessed daily starting on the first day of GnRH antagonist until the day of HCG administration. Serum levels of progesterone were determined at 0, +2, +4, +6, +8, +10 and +12 days after HCG administration. Finally, LH levels were evaluated on the day of HCG injection. All hormonal assessments were obtained retrospectively and did not influence clinical decisions regarding ongoing cycles. Serum was obtained from blood samples after centrifugation at 800 g for 10 min at room temperature and then stored at 20°C until assessment. All samples were evaluated simultaneously. Commercially available immunoassays for in vitro quantitative determination (Roche Diagnostics GmbH, Mannheim, Germany) were used to assess serum levels of progesterone, estradiol and LH.
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Results |
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Discussion |
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This study suggests that 50 IU of rFSH daily represents the lower dose of gonadotrophins to use that may presumably ensure a decrease of multiple birth risk on one hand and an acceptable pregnancy rate on the other. Further changing the dose of gonadotrophins to 50 IU on alternate days is associated with a further increase in the percentage of mono-ovulatory cycles and thus with a hypothetical lower risk of multiple birth, but also with an unacceptable drop in the success rate. Indeed, the percentage of patients with only one follicle with a mean diameter 16 mm increased from 53.3 to 78.8%, whereas the pregnancy rate decreased from 34.4 to 5.9%. In this context, it has to be noted that, although the worth in terms of follicular growth of a regimen with low dose on alternate days has been documented previously (Buckler et al., 1999
), the appropriateness of this scheme in the presence of a GnRH antagonist has not been demonstrated. Since administration of the antagonist may suppress endogenous FSH secretion, it might be hypothesized that this effect may cause a transient insufficiency of FSH levels in the alternate dose regimen. On the other hand, it is worthwhile noting that serum peak levels of estradiol did not differ between patients randomized to receive rFSH daily and those receiving it on alternate days, thus indirectly supporting that follicular development is not significantly impaired in women treated on alternate days.
An important and unexpected finding of this study is that we have documented the possibility of achieving a remarkably high clinical pregnancy rate per initiated cycle (34.4%, 95% CI 17.751.1%) combining low dose gonadotrophins and GnRH antagonists. In idiopathic subfertility and in male subfertility, the two major indications for IUI after standard ovarian stimulation, pregnancy rates from 2.3 to 27.4% and from 3.9 to 13.6% per cycle, respectively, have been reported (Goverde et al., 2000). In a recent large randomized clinical trial aimed to assess the efficacy of IUI, the pregnancy rate per cycle was found to be 8.7% (Guzick et al., 1999
). This specific study enrolled 932 couples and currently represents the largest prospective series available on this topic. The reported success rate in previous series specifically using low-dose gonadotrophin without GnRH antagonist in IUI cycles ranged from 9.8 to 25.7% (Balasch et al., 1994
; Gregoriou et al., 1995
; Healy et al., 2003
). The strict criteria used to recruit patients in our study, notably an age below 38 years and the absence of previous IUI, may at least in part explain the high success rate observed. On the other hand, it is unlikely that these criteria, which are frequently employed for studies on this topic, may be solely responsible for the observed results. In this context, it might be speculated that the concomitant use of GnRH antagonist may play a critical role. In particular, this drug may allow optimal timing for insemination in relation to ovulation. In this regard, it is worthwhile noting that a premature LH surge, a condition that may interfere with the adequate timing of IUI, has been reported to occur in 24% of stimulated cycles (Cohlen et al., 1998
). On the other hand, it also has to be considered that the much lower pregnancy rate observed in the group treated on alternate days which also used the GnRH antagonist suggests that the success rate of the daily regimen may be due to a better follicular development rather than to the use of the antagonist. A prospective trial where daily 50 IU of rFSH is used with or without GnRH antagonist may help to clarify this issue. Considering costs associated with the use of this drug, such a study may be of value in view of future cost-effectiveness analyses. Finally, considering the relatively small number of cases enrolled in this study, it cannot be excluded that an alpha error may also play a role in explaining the extremely high pregnancy rate observed. It has to be noted, however, that the binomial distribution statistical model used to determine the 95% CI of the pregnancy rate indicates that the lower limit of this interval is 17.7% and, thus, that the rate of success should be at least above this still considerably high percentage. Larger trials are, however, warranted to define more precisely the pregnancy rate associated with this protocol.
Reducing the number of multifetal gestations that result from ovarian stimulation with or without IUI is one of the most important challenges in reproductive medicine (Dickey, 2003). Several strategies to prevent multiplets have been proposed. Mild ovarian stimulation, supernumerary follicle aspiration, coasting, conversion to IVF, selective abortion and application of strict cancellation criteria are all possible solutions (Rosenwaks and Chung, 2003
). Cost-effectiveness and cost-benefit analyses of these different strategies remain to be conducted. In this study, we have evaluated a strategy that combined a protocol of mild ovarian stimulation with the application of strict cancellation criteria. Indeed, cycles were cancelled if three or more follicles with a mean diameter
15 mm were present. Considering specifically patients who received 50 IU of rFSH daily, the cancellation rate was found to be 6.3%. This percentage appears to be appealing, considering that it has been reported that the consequence of reducing high-order multiple pregnancies using cancellation criteria would be to interrupt one-third of superovulation induction cycles (Rosenwaks and Chung, 2003
). The effectiveness of this protocol in preventing multiple gestation cannot be reliably assessed in the present study due to the insufficient sample size. However, some observations suggest that this risk may be low. First, all 11 pregnancies achieved using this scheme were found to be singleton. Secondly, the extremely reduced total number of follicles with a mean diameter
11 mm and the low serum peak levels of estradiol observed strongly support that patients are presumably not exposed to a relevant risk (Dickey, 2003
; Fritz and Ory, 2003
). These two variables have indeed been demonstrated to be the two most significant variables correlated with the risk of multiple births in a large series of women undergoing ovarian stimulation (Gleicher et al., 2000
). In this specific study, serum peak levels of estradiol in women with a twin pregnancy or a high-order multiple pregnancy (
3) were 1458 ± 922 pg/ml and 1482 ± 583 pg/ml, respectively. These levels were therefore much higher than those observed in our study (<300 pg/ml for both treatment groups). Similarly, total numbers of follicles were 17.2 ± 10.1 and 25.3 ± 11.3 in women who developed a twin pregnancy and a high-order multiple pregnancy, respectively. Again, these means were markedly higher than those observed in our study (2.4 ± 2.0 and 1.5 ± 0.7 follicles for patients treated with rFSH daily or on alternate days, respectively).
A protocol employing rFSH 50 IU daily and a GnRH antagonist might become an attractive new possibility for ovarian stimulation in IUI cycles once its effectiveness in terms of pregnancy rate and risk of multiple birth has been confirmed in a larger series.
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Submitted on May 6, 2003; resubmitted on July 22, 2003; accepted on September 29, 2003.