Abstract
According to a number of high-quality studies, intrauterine insemination (IUI) with homologous semen should be the first choice of treatment in the case of moderate male factor subfertility. IVF and ICSI are clearly over-used in this selected group of infertile couples. The limited value of IUI in infertility treatment, as mentioned in the 2013 NICE guidelines, was surely a premature statement and should be adapted to the actual literature. Oxidative stress and high sperm DNA damage is associated with lower pregnancy rates after IUI. Concerning clinical outcome, there is no clear evidence of any sperm preparation technique to be superior. More evidence-based data are becoming available on different variables influencing the success rates after IUI. It can be expected that these findings may lead to a better understanding and use of IUI in the near future.
13.1 Introduction
Infertility is a universal health issue and it has been estimated that 8–12% of couples worldwide are infertile, with 9% currently cited as the probable global average and remarkably similar between more and less developed countries [1].
Assisted reproductive technologies (ART) are considered as an established therapy for the treatment of infertility in a multitude of clinical conditions. They embrace a wide scope of techniques of which intrauterine insemination (IUI), in vitro fertilization (IVF), and intra-cytoplasmic sperm injection (ICSI) are the most popular.
IUI is easy to learn, requires less equipment, and is less expensive and less invasive than IVF/ICSI, with a reasonable success rate within three or four cycles. It is associated with reduced psychological burden and the couple compliance is usually good with a low drop-out rate. In addition, the risk of ovarian hyperstimulation syndrome (OHSS) is reduced and the rate of multiple pregnancies is also lower when performed with natural cycles, clomiphene citrate, or low-dose Human Menopausal Gonadotropins (HMG) stimulation protocols. It is a safe and easy treatment with minimal risks and monitoring.
Nevertheless, the use of AIH (artificial insemination with homologous sperm) as a first-line treatment in case of unexplained and mild/moderate male infertility remained controversial until very recently. This was caused by a lack of prospective randomized trials and large prospective cohort studies as a result of the low budget linked to IUI when compared to the budget associated with other methods of assisted reproduction such as IVF and ICSI. Therefore, large multicentre trials organized by the pharmaceutical industry are not available on the IUI scene, for obvious reasons.
To find out which couples can benefit from AIH in case of male infertility we need to investigate the power of different semen parameters in predicting success after AIH. Huge differences in methodology in semen analysis worldwide make it difficult to draw some conclusions, although the World Health Organization tried to standardize the performances of semen analysis and related procedures in order to reduce variation in the results obtained. A literature search on this topic remains frustrating due to the ongoing lack of standardization in interpretation of semen results.
Based on the results of an ESHRE Capri workshop in 2009, IUI was considered to be a poor substitute for IVF and responsible for a significant rate of high-order multiple births. The recommendations were made in the absence of proper trials and live birth data were not available [2]. It was also not mentioned that the high rate of multiple pregnancies was mostly seen outside Europe and due to the use of high doses of gonadotrophins, especially in the USA.
The NICE guidelines [3] recommended that IUI should not be used in cases of unexplained and moderate male subfertility. According to these guidelines “expectant management was recommended as the first line option and IUI has a very limited value in infertility care.” It is well known that the NICE guidelines were being constructed by using the data of a few studies with obvious shortcomings and not taking into account the HFEA data showing an UK average pregnancy rate of 13% per cycle for IUI in 2011 and 2012 [4– 7]. Ignoring these guidelines, surveys performed in the UK showed that 96% of fertility clinics continued to offer IUI – despite the NICE recommendations [8, 9].
Since then, a number of excellent randomized trials have been published supporting the value of IUI in unexplained and mild/moderate male subfertility cases. In a multicentre randomized noninferiority trial in the Netherlands, the effectiveness of IVF with single embryo transfer or IVF in a modified natural cycle was compared with the effectiveness of IUI-OS (ovarian stimulation) with a healthy live birth as the main outcome parameter [10].
IUI-OS seemed to be noninferior compared to the two alternative strategies of IVF, with a reasonably and comparable low multiple birth rate. By investigating the direct healthcare costs in the same cohort of patients, IUI turned out to be the most cost-effective strategy for heterosexual couples with mild male factor or unexplained infertility with a poor prognosis of becoming pregnant through normal coitus [11].
Farquhar and colleagues [12] published the results of an RCT in which 201 couples with 3–4 years unexplained infertility were randomized to receive three cycles of IUI or expectant management. A live birth rate of 31% with IUI and 9% with expectant management was observed, a threefold difference in outcome.
According to the literature it is obvious that we are over-using IVF to treat unexplained and moderate male infertility. Evidence-based data in 2019 clearly indicate that promoting IVF and ICSI to result in pregnancy “as quick as possible” ignores the advantages of IUI completely in cases of mild or moderate male factor infertility.
13.2 Factors Influencing AIH Outcome in Male Subfertility
Many different factors can influence the success rates in IUI programmes. We give an overview of the most important factors associated with AIH outcome.
13.2.1 Semen Quality
As mentioned before, there is a worldwide lack of standardization in interpretation of semen samples. Despite the use of various external quality control systems and the WHO laboratory manuals to improve the value of semen examinations, the results remain poor. Consequently, the value of semen parameters in predicting ART outcome is difficult to interpret when reviewing the literature.
We performed a structured review to investigate the threshold levels of sperm parameters above which IUI pregnancy outcome is significantly improved or the cut-off values reaching substantial discriminative performance in an IUI programme [13].
In 20 selected articles, the IMC (Inseminating Motile Count or the number of motile sperm inseminated) was cited as an important predictive parameter, in 8 out of 20 studies a cut-off value of 1 million was mentioned, in 4 studies between 1 and 2 million, and in 5 studies the authors calculated a threshold value of 5 million. Sperm morphology using strict criteria was the second-most cited sperm parameter. In 11 out of 15 studies, 4% normal forms were reported as the best cut-off value. When utilizing these cut-off values of sperm morphology and IMC, there is poor sensitivity for predicting who will conceive but a high specificity for predicting failure to conceive with IUI. The TMSC (Total Motile Sperm Count before sperm washing) was also reported to be an important predictive parameter in 10 papers, with a cut-off value of 5 million in 5 papers and 10 million in 5 papers [13] (Table 13.I).
Table 13.1 According to a structured review [13], the success rate of AIH is improved with a morphology score of more than 4% normal forms, an IMC of more than 1 million, a TMSC of more than 5 million, and an initial total motility of more than 30%
| Sperm morphology using strict criteria | >4 % |
| Inseminating Motile Count (IMC) | >1 million |
| Total Motile Sperm Counts (TMSC) | >5 million |
| Total Motility in native sample (TM) | >30 % |
Already in 1997 we published the results of a study examining the predictive value of sperm parameters in an AIH programme. We observed that an IMC of 1 million was at a reasonable threshold level above which IUI can be performed with acceptable pregnancy rates. Overall, sperm morphology and IMC were of no prognostic value using ROC curve analysis. Sperm morphology turned out to be a valuable prognostic parameter in predicting IUI success if the IMC was less than 1 million (area under ROC curve: 77.6%). The cumulative live birth rate (CLBR) after three IUI cycles was 13.6% if the IMC was less than 1 million, significantly different from the group with an IMC of less than 1 million (22.4%, p < 0.05). Considering only patients with IMC of less than 1 million and sperm morphology more than 4%, the CLBR was 21.9%, comparable with the CLBR of all cycles with a normal semen sample or an IMC of more than 1 million [14] (Figure 13.1). The proposed algorithm for male subfertility we have used in our centre since 1998 is shown in Figure 13.2.
Figure 13.1 Cumulative live birth rate after three inseminations (IUIs) with partner’s semen (IMC = Inseminating Motile Count; Morph = sperm morphology using strict criteria) [14].
Figure 13.2 Proposed algorithm for male subfertility treatment at the Genk Institute for Fertility Technology since 1998 [14].
Merviel and colleagues [15] reported the data of a retrospective analysis of 1,038 AIH cycles performed between 2002 and 2005 in a single university medical centre, aiming to determine the predictive factors for pregnancy after AIH. According to their results, a TMSC of 5 million or more could be used as a threshold value above which AIH is more successful.
According to Lemmens and colleagues [16], AIH is especially relevant for couples with moderate male factor infertility. They observed a positive relationship for less than or equal to 4% of morphologically normal spermatozoa (odds ratio [OR] 1.39) and a moderate IMC (5–10 million; OR 1.73). Low IMC values showed a negative relation (≤1 million; OR 0.42). In the multivariable model, however, the predictive power of these sperm parameters was rather low. These data were based on the results of a retrospective, observational study with logistic regression analyses of 4,251 first AIH cycles in 1,166 couples visiting the fertility laboratory for their first AIH episode.
Comparable results were obtained in a prospective cohort study of 1,401 AIH cycles in 556 couples in our AIH programme in Genk [17]. Univariate statistical analysis revealed female and male age, male smoking, female body mass index, ovarian stimulation, and inseminating motile count (IMC) as covariates significantly influencing CPR (clinical pregnancy rate) per cycle. Multivariate GEE analysis (generalized estimating equations) revealed that the only valuable prognostic covariates included female age, male smoking, and infertility status (i.e. primary/secondary infertility). IMC showed a significant curvilinear relationship, with first an increase and then a decrease in pregnancy rate, with the best results for an IMC of between 5 and 10 million [17].
Moolenaar and colleagues [18] made use of a computer-simulated cohort of subfertile women to examine the cost-effectiveness of AIH compared to IVF and ICSI. The base-case calculation was centred on a 30-year-old woman with a regular menstrual cycle, normal fallopian tubes, and a partner with a pre-wash TMSC between 0 and 10 million. A 30-year-old woman was selected because previous studies of pregnancy probabilities according to pre-wash TMSC were based on couples in whom the woman had a mean age near 30 years. Three different treatment options were investigated: AIH with and without controlled ovarian stimulation, IVF, and ICSI. The main outcome was expected live birth; secondary outcomes were cost per couple and the incremental cost-effectiveness ratio. If only cost per live birth is considered for each treatment, above a pre-wash TMSC of 3 million, AIH seemed to be less costly than IVF and below a pre-wash TMSC of 3 million, ICSI is less costly.
13.2.2 Male Age
Increased male age seems to be associated with a decline in semen volume, sperm motility, and sperm morphology but not with sperm concentration. Semen parameters start to decline after 35 years of age. Male fertility was found to decrease substantially in the late 30s and continues to decrease after age 40 [19]. Nevertheless, in contrast to female fertility, male fertility is maintained until very late in life. Age-dependent decrease of fertility in couples is usually attributed to female ageing, which makes studies on a male age effect difficult. In addition to female age, other confounders such as reduced coital frequency and an increasing incidence of erectile dysfunction may play an important role as well. It seems that for natural conception, paternal age has a limited effect whenever the female partner is young. Time to pregnancy is longer with advancing age of men. However, when the female partner too is of age, then a synergistic adverse effect of paternal age is observed.
The more invasive the treatment, the less important the effect of male age; success rates of IVF or ICSI are not affected by male age. On the other hand, the success rate of intra-uterine insemination (IUI) is affected by male age, probably because IUI requires sperm of much higher quality compared to IVF and ICSI [19]. According to the actual literature, paternal age has no impact on IUI success rates as long as the female partner is less than 35 years.
On the other hand, oxidative stress-induced mtDNA damage and nuclear DNA damage in ageing men may put them at a higher risk for transmitting multiple genetic and chromosomal defects. Paternal age above 40 years seems to be a risk factor for spontaneous abortion.
13.2.3 Oxidative Stress
A number of factors are responsible for the low pregnancy rates seen with IUI, including oxidative stress. Oxidative stress occurs when there is excessive generation of reactive oxygen species (ROS) and/or underproduction of protective enzymatic and nonenzymatic antioxidants. ROS, at low levels, are essential for facilitating complex cellular redox interactions and modifying biological molecules, for example, DNA, proteins, and lipids in various cellular organelles. Low levels of ROS can also enhance the ability of human spermatozoa to bind with the zonae pellucida, an effect that is hampered by the addition of the antioxidant vitamin E. Low concentrations of hydrogen peroxide (H2O2), when incubated with spermatozoa, can stimulate sperm capacitation and induce spermatozoa to undergo the acrosome reaction and fuse with other types of ROS (e.g. nitric oxide and superoxide anion (O2) can also promote sperm capacitation and the acrosome reaction) [20].
High levels of seminal ROS are present in 40–80% of unselected infertile men. Seminal ROS commonly occurs in men with varicocele, leukocytospermia, and/or idiopathic infertility. The main sources of ROS are immature sperm and seminal leukocytes [20].
Bungum and colleagues [21] examined the relationship between the results of sperm chromatin structure assay (SCSA) and the outcome of IVF, ICSI, and intrauterine insemination. A total of 387 intrauterine insemination (IUI) cycles were included. SCSA results were expressed as DNA fragmentation index (DFI). Clinical pregnancy rate and delivery rate were significantly higher in the group with DFI less than or equal to 30% than in patients with DFI of more than 30%. In the latter group, the results of ICSI were significantly better than those of IVF.
According to a systematic review performed by Cho and Agarwal [22], current evidence supports the association between high SDF (sperm DNA fragmentation) and poor reproductive outcomes for natural conception and intrauterine insemination.
13.2.4 Semen Preparation Techniques
Sperm preparation techniques (SPTs) should isolate and select sperm cells with intact functional and genetic properties, including normal morphology, minimal DNA damage, and intact cell membranes with functional binding properties [23]. Sperm processing techniques are used to prepare a concentrated volume of highly motile sperm. The handling of semen samples during these procedures may result in excessive generation of ROS. There are two commonly used techniques: density-gradient centrifugation (DGC) and the swim-up technique. The first technique uses centrifugation to separate fractions of spermatozoa based upon their motility, size, and density. The mature, leukocyte-free spermatozoa are separated from the immature immotile sperm and are then centrifuged. However, the process of centrifugation itself can provoke leukocytes to generate high levels of ROS. Double-density gradient centrifugation is especially associated with high levels of ROS. Reducing the centrifugation time rather than the centrifugation force can minimize the generation of ROS and may assist in retrieval of the highest proportion of mature sperm.
The other technique used to prepare semen for IUI is the swim-up technique, in which highly motile sperm are separated based on their natural ability to migrate against gravity. This technique may be inappropriate for semen samples that contain a high concentration of ROS producer cells such as leukocytes, and immature and damaged spermatozoa [23]. A Cochrane review did not find any significant differences in pregnancy rates between these two techniques in the setting of AIH [24].
On the other hand, Ricci and colleagues [25] showed that the DGC technique resulted in higher recovery rates of total motile, progressive motile, and viable sperm than the swim-up technique. Because the most harmful effects of ROS on sperm are seen in motility and viability, it seems plausible that DGC is associated with the least amount of ROS. Unfortunately, no studies have directly assessed the impact of these techniques on ROS generation and the relationship to IUI outcomes.
To conclude, there is insufficient evidence to recommend any specific SPT at this moment. Novel sperm selection methods based on sperm surface charge or nonapoptotic sperm selection show promising results. Selection based on sperm surface charge did not lead to any improvement in fertilization rates or embryo quality following ICSI. The zeta potential method was reported in one study to increase fertilization, implantation, and pregnancy rates, although not significantly.
Nonapoptotic sperm selection by Magnetic Activated Cell Sorting (MACS) resulted in spermatozoa with higher motility and less apoptosis, higher embryo cleavage, and higher pregnancy rates. Fertilization or implantation rates were not higher. More evidence is needed before using them routinely in AIH programmes [23].
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