The Revolution in Male Infertility - ICSI

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Since the first recorded use of frozen sperm for insemination in 1953, the breakthroughs in fertility had been mostly confined to treatments for female infertility. However, in the last decade, a technique known as Intra-cytoplasmic sperm injection – ICSI for short – has transformed treatment for male infertility so much so that there are almost no men who are completely unable to father children.

The first use of ICSI in humans was announced in 1992 – since then, ICSI has completely revolutionized male infertility treatment, yet it is not without its risks and shortcomings. It raises serious moral concerns surrounding our genetics, biology, and even fatherhood. Furthermore, it does not fully address the needs of pre-pubertal patients who are in need of fertility preservation options. To better understand these concerns, it is important to understand the difference between conventional In-vitro fertilization (IVF) and IVF with ICSI. 

 

In-vitro fertilization, which translates to “in-glass” fertilization, occurs in much the same way natural conception does. Eggs are mixed with millions of sperm in a carefully controlled vessel, and the sperm flood around the egg until one of them penetrates its protective barrier, locking all the other sperm out. Just as in natural conception, this requires a very high sperm-to-egg ratio, and therefore this option will not help males with moderate to severe infertility to conceive.

 

Efforts to reduce the sperm-to-egg ratio needed for IVF led to the development of ICSI – in contrast to conventional IVF, ICSI only needs a sperm-to-egg ratio of 1-to-1. The process begins in the same way as conventional IVF; eggs are collected from the woman by hyper-stimulating her ovaries, and a sperm sample is collected through ejaculate or testicular sperm extraction (TESE – a method of sperm extraction directly from the testicles) for more severe cases. However, once these samples have been collected, instead of mixing them together, a single sperm is selected for implantation into the egg. This sperm is drawn up into an extremely thin pipette which is then pushed through the egg’s outer wall, allowing the sperm to be released into the center of the egg, where it should hopefully achieve fertilization. 

 

By reducing the number of sperm needed to fertilize an egg to just one (although in practicality more than one sperm cell is required, just not millions), a vast number of men who were previously unable to father children – including those due to genetic causes – now have the option to. This represents a huge leap forward for the field of fertility, but it comes at a cost.


Considerations for Fatherhood

The use of ICSI has been well established in a variety of conditions, such as vasectomy, cancers, or injury – all conditions that have no documented effects on the future health of the offspring. Its efficacy has led to it gaining ground over conventional IVF – an increasing number of IVF cycles now utilize ICSI even in cases where male infertility is not thought to be significant factor, as it raises the overall success rate of IVF cycles. However, the use of ICSI for persistent, natural causes of infertility can be a cause of concern. Although many of the specific causes of severe male infertility remain unknown, it is estimated that almost 50% of cases may be due to contributing genetic factors, and there are over 30 known genetic diseases that will cause infertility in men. 

Throughout history, men afflicted by such diseases were faced with the tragic realization that they would never father children of their own, yet their infertility also created a barrier to the hereditary transmission of such illnesses. With the advent of ICSI, most of these men are now capable of fathering children – and many are choosing to do so. The main concern of these men is the chance of passing their condition to their offspring. Technologies such as pre-implantation genetic screening (PGD) allow the selection of embryos that do not carry the problematic gene. However, the technology is limited, as its application depends on the nature of the particular genetic condition. For conditions caused by a single dominant gene, it is relatively easy to screen and eliminate the embryos with the malfunctioning gene. For conditions caused by a pair of recessive genes – such as in the case of cystic fibrosis – affected fathers will inevitably pass one of the genes to their child. Said child must be vigilant as to whether their partners may be carriers as well when they seek to have children of their own. 

 

Furthermore, there are many heritable genetic defects that do not carry the same severe consequences to overall health yet will cause severe refractory infertility. One of the most common, a microdeletion in the azoospermia factor (AZF) region – specifically region AZFc– causes severe infertility, yet TESE may yield enough sperm to pursue ICSI. Many men diagnosed with AZFc choose to have children through ICSI, and unavoidably pass on the mutation to their offspring, thus too becoming infertile. AZF deletions are relatively common in cases of severe male infertility, and thus clinics will often screen severely infertile patients for the genetic defect. Those found to have the defect are presented the choice of continuing with ICSI with full knowledge of the consequences, yet one study found that almost four-fifths of prospective parents decided to pursue ICSI regardless

 

The moral consequences of such decisions cannot be taken lightly. Men with diseases such as cystic fibrosis (or other deadly genetic illnesses) who choose to have children must also consider the impact of their likely early death on their prospective children, as most of these men do not live to see past 40. Children with inherited AZFc microdeletions will experience their infertility as an established fact, and parents of such children will face hard decisions on how and when to tell them. Furthermore, the cumulative societal effect of conceiving infertile children through ICSI may become problematic. A study in the reputable journal Nature Genetics estimated that, if 90% of men that are infertile due to genetic causes fathered children through ICSI, the rate of male infertility due to a genetic basis could increase to 6.7% of all men in 10 generations. Due to barriers in accessibility and cost, this dire situation is unlikely, yet still illuminates a probable trend as assisted-reproduction technologies such as ICSI become more ubiquitous in society. 

 

Without a doubt, ICSI has been an incredibly helpful tool that has allowed many hopeful parents to fulfill their dreams and conceive a child of their own. Almost always, children born through ICSI are healthy and live normal lives. Nonetheless, many couples may be faced with tough decisions about the degree of control they will have over their children’s genetic characteristics and their willingness to expose their offspring to potentially risky conditions.