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Middle East Fertility Society, Vol. 10, No. 1, 2005, pp. 39-42 DEBATE The current role of intrauterine insemination for the treatment of male factor and unexplained infertility Willem Ombelet, MD, PhD Genk Institute for Fertility Technology Schiepse Bos 6 3600 Genk Belgium Email: willem.ombelet@pandora.be Related Articles: mf05003,mf05004,mf05005, and mf05006Code Number: mf05007 Approximately 10 to 15 % of women will receive infertility treatment during their lifetime and of all subfertile couples, only 1-2 % will undergo treatment with assisted reproductive technologies (ART). Artificial insemination with husband's semen (AIH) has been used in clinical medicine for more than 200 years in the treatment of infertile couples. The first documented application of AIH was done in London in the 1770s by John Hunter. A patient with severe hypospadias was advised to collect the semen ( which escaped during coitus ) in a warmed syringe and inject the sample into the vagina. J.M.Sims reported his findings of postcoital tests and 55 inseminations in the mid 1800s but only after the introduction of sperm donation artificial insemination became very popular. For many years homologous artificial inseminations were only indicated in cases of physiologic and psychologic dysfunction, such as retrograde ejaculation, vaginismus, hypospadias and impotence. With the routine use of post-coital tests other indications were added such as hostile cervical mucus and immunologic causes with the presence of antispermatozoal antibodies in the cervical mucus. The term AIH covers a wide range of different techniques. Washed or unwashed semen can be used and inseminated at various levels in the female reproductive tract. The insemination can be done intravaginally, intracervically, pericervically using a cap, intrauterine, intratubal or directly intraperitoneal. Most studies refer to intrauterine inseminations (IUI) which seems to be an easy and better way of treatment. The rationale for the therapy of artificial insemination is the increase of gamete density at the site of fertilization. The theoretic advantage of IUI over intravaginal techniques may be due to the increasing number of sperm arriving at the fertilization site, even when sperm or cervical mucus abnormalities are present. The increasing use of AIH in idiopathic and male infertility is mainly the result of the refinement of techniques for the preparation of washed motile spermatozoa as they were used in IVF procedures, finally resulting in a post-wash fraction containing a high number of motile spermatozoa with a better sperm morphology. For ART, success in subfertility treatment is generally described as pregnancy rate per treatment cycle (IVF, ICSI, IUI). On the other hand, it is important to be aware of the complex weave of secondary issues to consider such as neonatal outcome, short and long term infant morbidity and maternal complications, all of them closely linked to the higher incidence of multiple pregnancies after treatment with assisted reproductive techniques. Consequently, ART (especially IVF and ICSI) accounts for 0.4-0.8% of the total health care costs in the USA compared to 0.08 - 0.16 % in the Nordic countries. This can only be explained by the lower incidence of multiples in Scandinavian countries. When male subfertility is found in couples with longstanding infertility, IVF and ICSI are not the only treatment options. From a theoretic point of view, increasing the number of motile spermatozoa at the site of fertilization with intrauterine insemination, especially when sperm quality is suboptimal, should increase the probability of conception. In two meta-analyses, Cohlen et al (1) showed that in case of male subfertility and compared to natural conception, IUI is an effective treatment option. It also seems that cycle fecundity drops after the third or fourth IUI cycle (2,3). The remaining couples seem not to benefit of this method of treatment and should be advised to consider a treatment with IVF and /or ICSI. According to Cohlen et al. (4), IUI should only be applied in couples that have a reasonable perspective in achieving an reasonable ongoing pregnancy after IUI and couples should make the decision themselves in dialogue with their physicians. But the question remains: what is a reasonable success-rate. Although ICSI is the most successful treatment option per cycle in most cases of moderate and severe male subfertility, more simple methods of assisted reproduction such as IUI have to be weighed against ICSI not only taking into account the immediate success rate but also the cost-effectiveness of the different strategies. IUI is less invasive, less stressful, less expensive and more cost-effective compared to IVF / ICSI. A number of studies has been performed which focuses on the cost-effectiveness of IUI when compared to IVF (5,6,7). In all studies, three IUI's were as successful, but much cheaper compared to one IVF/ICSI cycle. The effectiveness of IUI was also reported in a large retrospective analysis of almost 10 000 IUI-cycles in which male factor subfertility was associated with a unexpected high pregnancy rate of 8.2 % per cycle in a population with an average female age of 39 years (8). In the selection of couples to be treated with IUI or IVF/ICSI, it would of course be interesting to establish cut-off values of semen parameters above which IUI is a real alternative for IVF/ICSI in male subfertility. We previously demonstrated that in a selected group of patients with normal ovarian response to clomiphene (CC)-stimulation, individual sperm parameters including inseminating motile count (IMC or number of motile spermatozoa after washing procedure) and sperm morphology turned out to be of little prognostic value in predicting success for the group as a whole (9). However, sperm morphology becomes a very useful predictive tool in a subgroup of patients with an IMC of less than 1 million. In terms of therapeutic strategy, this implies that above a cut-off value of 1 million motile spermatozoa recovered after washing, CC-IUI can be promoted as a first-line therapy with an acceptable cumulative ongoing pregnancy rate (OPR) of 24 % after three cycles. Furthermore, in cases with less than 1 million motile spermatozoa, CC-IUI remains important as a first-line option provided the sperm morphology score is 4 % or more. In order to investigate the reported threshold levels of sperm parameters above which IUI pregnancy outcome is significantly improved, we performed a literature search by means of a Medline search for the period from 1983 until 2002 (10). According to this review, inseminating motile count (IMC) and sperm morphology are the most valuable sperm parameters to predict IUI outcome. A trend towards increasing conception rates with increasing inseminating motile count was found. However, the cut-off value above which IUI seems to be successful ranges from 0.3 to 20 million. This finding once again highlight the importance of other confounding factors influencing success after subfertility treatment such as female age, duration of subfertility etc. Our analysis also confirmed the results of a previous reported meta-analysis showing a significant improvement in pregnancy rates above the 4 % threshold for strict criteria (11). According to our medline search, the cut-off level for total sperm motility before sperm preparation ranged between 30 and 50 %. Two other parameters influencing the pregnancy rate after IUI were the hypo-osmotic swelling (HOS) test (threshold: > 50 %) and sperm DNA fragmentation (threshold: < 12 %). On the other hand, there is also a widespread belief among fertility specialists that an increased use of artificial insemination with controlled ovarian stimulation (COH) will lead to an uncontrolled increase in multiple pregnancies. A retrospective analysis of 363 187 deliveries in Flanders (Belgium) between 1997 and 2002 showed that of all multiple pregnancies following ovarian stimulation, IVF/ICSI was performed in 66.7 %, controlled ovarian stimulation and timed coitus (COH-TC) in 23.7 % and COH-IUI in 9.6 % of cases. Concerning the different treatment procedures, the multiple birth rate was 27.2 % for IVF, 25.7 % for ICSI, 13.7 % for COH-IUI and 9.7 % for COH-TC respectively. These data show that the criticism mentioned in some reports about the high risk for multiple pregnancies following non-IVF assisted reproduction can easily be solved by using low dose hormonal stimulation. According to our data, IVF and ICSI remain the most important contributors to the high incidence of multiple gestation following ART. Nevertheless, the major complication of assisted reproductive technologies remains the high incidence of multiple pregnancies, not only for IVF and ICSI, but also for non-IVF procedures such as ovarian hyperstimulation with or without artificial insemination. The rationale behind the use of ovarian hyperstimulation in IUI is the increase of the number of oocytes available for fertilisation and to correct subtle unpredictable ovulatory dysfunction. Other advantages of superovulation are the enhanced opportunity for oocyte capture, fertilisation and implantation. On the other hand, the risk for ovarian hyperstimulation syndrome and especially multiple pregnancies is increased. Consequently, careful monitoring remains essential and cancellation of the insemination procedure, rescue IVF and follicular aspiration before ovulation are reasonable options when three or more follicles of a diameter greater than or equal to 15 mm are present. Natural cycle IUI should be offered more frequently and one should consider that ovulation induction may also be achieved with clomiphene citrate (CC), a good first line option since ovulation can be induced in about 50-70 % of cases, with a low multiple pregnancy rate of 6 to 8 % (2,9,12). Gonadotrophins are necessary in clomiphene-resistant cases and yield better pregnancy rates compared to CC, but at the expence of a higher multiple pregnancy rate of more than 15 % in most studies. Low dosage gonadotrophins protocols are being tested and seem to result in a lower multiple birth rate without influencing the ongoing pregnancy rate too much (13,14). In the near future we have to study the value of supplementation of culture media with reactive oxygen species (ROS) scavengers to improve the results after IUI. Until now, no study investigated the possible role of antioxidants in culture media or as a dietary supplement on success rates in IUI cycles. It should be further investigated whether treating spermatozoa with solutions containing antioxidants during sperm preparation can improve pregnancy rates with IUI, especially in male subfertility cases. In conclusion, IUI should be promoted as the best first-line treatment in almost all cases of mild and moderate male subfertility provided at least one tube is patent and an IMC of more than 1 million can be obtained after sperm preparation. After three or four unsuccessful attempts, IVF or ICSI should be advised. Surprisingly and despite evidence-based arguments, most infertility centers still neglect the possibility of using IUI as a first line treatment. Data from Australia and New Zealand clearly show that almost 80 % of centers are convinced of the cost-effectiveness of IUI in male subfertility cases, but nearly a third of centers still promote IVF as a first-line treatment even with patent tubes and normal semen (15). REFERENCES
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