54. ICSI for Male Factor Infertility
5.1. Oligoasthenoteratozoospermia
4.1. Oligoasthenoteratozoospermia
Although ICSI should be encouraged mainly in severe male infertility, it can be challenging to establish when a male factor is compulsory for the ICSI technique. Standard semen assessment is performed to confirm the severity of male infertility and advise ICSI, but it is well reported that sperm analysis has limitations; for example, it does not assess the function and physiology of the sperm, and genetic or epigenetic assessment
[83][34]. Sperm number, morphology, and motility are typically evaluated to decide on the ICSI procedure rather than standard IVF insemination
[84][35]. It is worth mentioning that high-quality studies investigating pregnancy outcomes and live birth rate (LBR) between ICSI and IVF in couples with oligoasthenoteratozoospermia are still missing. However, a study published in 2005 by Shuai and collaborators explored these concerns. The
authorscholars observed no differences between the two insemination procedures (IVF and ICSI) in fertilization, implantation, and pregnancy rates in couples undergoing ART with men diagnosed with moderate oligoasthenoteratozoospermia
[85][36]. Sperm morphology is another parameter broadly used to choose for ICSI. In 1986, Kruger and colleagues suggested using strict criteria for sperm abnormalities and advising ICSI when the proportion of normal sperm in the ejaculate was <4%
[86][37]. Additional studies confirmed this evidence and proposed that at least 5% of sperm is needed to be morphologically normal to obtain an acceptable fertilization rate using standard IVF
[87,88][38][39]. Therefore, ICSI rather than IVF has been routinely recommended in patients with reduced sperm morphology (<5%)
[89][40].
5.2. Azoospermia
4.2. Azoospermia
The term azoospermia indicates the absence of sperm cells in the ejaculate. It affects around 1% of the general male population and about 15% of infertile men
[93][41]. There are two different types of azoospermia: obstructive and non-obstructive. In obstructive azoospermia, normal and complete spermatogenesis is typically found, and sperm can be surgically collected from the testis
[94][42]. By contrast, non-obstructive azoospermia is associated with the testicular alterations that result in the failure of sperm production. Typical testicular histopathological features in males with non-obstructive azoospermia include germ cell aplasia, maturation arrest, or hypospermatogenesis. The procedures mostly applied to collect sperm from azoospermic patients are percutaneous acquisition and open surgery
[95][43]. Following sperm retrieval, ICSI can be applied to achieve oocyte fertilization
[96][44].
5.3. Antisperm Antibodies
4.3. Antisperm Antibodies
The presence of seminal antisperm antibodies (ASAs) is typically associated with a gap or rupture of the blood–testis barrier in the reproductive tract, which can be linked with several conditions
[97][45]. However, elevated levels of ASAs in semen samples are observed in about 5–12% of men undergoing ART, and might negatively affect fertility, reducing sperm motility, capacitation, acrosome reaction, and oocyte sperm bounding
[98][46].
5.4. ICSI and Sperm DNA Fragmentation (SDF)
4.4. ICSI and Sperm DNA Fragmentation (SDF)
DNA fragmentation test is applied to assess the breakage of DNA strands inside the sperm head. This diagnostic test can predict fertility and normal embryo development and pregnancy outcomes than routine semen analysis parameters
[99,100][47][48]. With the use of probes, sperm DNA breaks can be deeply scrutinized and quantified with the aid of fluorescence/optical microscopy or flow cytometry
[100][48]. Sperm DNA fragmentation (SDF) is generally induced by oxidative stress resulting from environmental and lifestyle factors such as smoking, genital tract infections, obesity, and nutrition
[101][49]. Moreover, SDF is frequently detected in men with infertility issues (e.g., varicocele), and it is more prevalent in those individuals than in fertile counterparts
[102,103][50][51]. Scientific evidence indicates that a high level of SDF impairs the probabilities of success following ART
[104,105][52][53].
5.5. Globozoospermia
4.5. Globozoospermia
This condition is described by the entire lack of the acrosomal vesicle in the sperm head, with alteration of the nuclear membrane, and midpiece defects, resulting in a round-shaped sperm head. It is an uncommon condition involving a small percentage of infertile men (about 0.1%)
[111][54]. Despite having normal sperm count and motility, globozoospermic sperm cannot fertilize the oocyte: therefore, ICSI remains the favorable option available.
65. Use of ICSI for Couples with Partners Having Semen Analysis within Reference Ranges
One of the first Cochrane review papers was published in 2004 by van Rumste and collaborators to investigate whether ICSI improves LBR compared to IVF in couples whose male partners had semen analysis within reference ranges. The authorscholars showed a significantly higher fertilization rate in the IVF group but no difference in pregnancy, miscarriage, or LBR than ICSI insemination [113][55]. Subsequently, Bhattacharya and co-workers performed a multicenter randomized controlled study comparing clinical outcomes after ICSI or traditional IVF in couples with male partners having semen assessment within references ranges. The study randomly assigned 415 couples and was performed in four UK IVF units. Their results showed that the fertilization rate was higher with IVF than with ICSI (58% versus 47%; p = 0.0001). Standard IVF insemination provided an implantation rate of 30% compared to 22% for ICSI (p = 0.03). No significant difference was observed regarding the clinical pregnancy rate between IVF and ICSI (33% and 26%, respectively). Moreover, the overall laboratory time used was significantly shorter with IVF than with ICSI (22.9 min versus 38.1) [114][56]. Dang and co-workers reported similar results. They randomized 1064 patients undergoing ART to ICSI technique (n = 532) or standard IVF insemination (n = 532). After the first embryo transfer, LBR was 35% in the ICSI group versus 31% for couples assigned to conventional IVF (p = 0.27). They found higher TFF with IVF (6%) than with ICSI (5%). The study concluded that in couples undergoing ART with a male partner having so-called normal semen parameters, ICSI did not increase LBR compared with conventional IVF [115][57].
76. Contemporary Use (and Overuse) of ICSI
Since its first use almost 30 years ago, the application of ICSI as a fertilization method has raised steadily, even though the percentage of infertile couples with severe male factors has not increased
[125][58]. Thus, it seems evident that currently, ICSI is applied broadly, even though there is no clear evidence of its benefit in couples without male factor infertility
[113,114,123,125,126][55][56][58][59][60]. Boulet and collaborators analyzed data on ART between 1996 and 2012 and reported increased use of ICSI from 36.4% in 1996 to 76.2% in 2012, even though male-factor infertility remained unchanged at about 36% of cycles
[118][61]. Another trial published by Dyer and colleagues analyzing the worldwide data on ART performed between 2008 and 2010 found that ICSI was used as a fertilization method in about 67% of about 4.5 million cycles completed
[123][59]. However, there is considerable variation according to countries; in Asia, ICSI is applied in about 55% of the treatments, 65% of cases in Europe, 85% of patients in Latin America, and almost 100% of patients in the Middle East
[123][59]. Moreover, in a large retrospective study performed in Australia between 2002 and 2013, analyzing about 585 thousand ART cycles, the
authorscholars did not report any improvement when ICSI was used rather than standard IVF insemination for couples without obvious male infertility. They observed an LBR of about 10% lower with ICSI than IVF
[122][62]. On this basis, one should ask why is ICSI preferred to standard IVF in routine practice for cases without a clear male factor? Possible factors to justify the broad ICSI application related to a general notion that ICSI reduces the risk of TFF. Naturally, fertilization failure is problematic to any couple undergoing ART; especially when counseling is not available and the physician is the person involved in delivering this bad news. In addition, in private settings, where the couple needs to pay for the treatment, the failed fertilization also represents a remarkable burden for the couple who will need to bear the costs of another cycle. The debate is ongoing
[115][57] and the Practice Committee of the American Society for Reproductive Medicine (ASRM) has recently produced a committee opinion paper recommending against the extensive use of ICSI in couples undergoing MAR cycles without confirmed male factor infertility
[124][63].