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Male Factor Infertility

Lesson 7 of 9


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Types of Azoospermia

Azoospermia is a catch-all term used to describe situations where the lab finds no sperm during the semen analysis. This impacts 1% of all males in the US and comprises 10 – 20% of the male factor infertility cases. Unlike with varicocele, there is more agreement on how to treat these patients. An important fact to highlight is that many men / couples trying to conceive with azoospermia do not need to use donor sperm. Most patients with azoospermia do in fact have sperm and it's simply a matter of producing or retrieving it.

For sperm not to be produced, typically one of three things has gone awry:

  • Pre-testicular azoospermia: The testicles were not stimulated to produce sperm (2% of azoospermia cases)

  • Testicular azoospermia: the testicles were stimulated but unable to produce sperm (60% of cases)

  • Post-testicular azoospermia: the testicles produced sperm but none was ejaculated (35 – 40% of cases).

Pre-Testicular Azoospermia

Typically, pre-testicular azoospermia is driven by a hormone imbalance. In this case there is a breakdown in the hypothalamus, the portion of the brain that monitors hormone activity, or in the pituitary, the gland in the body that takes signals from the hypothalamus to secrete more or less of a hormone. The end result is that hormones that are required for producing sperm (FSH, LH, or testosterone) are not being properly produced.

Often pre-testicular azoospermia is highly treatable without IVF and, if the azoospermia is the result of lifestyle factors (namely poor diet, weight gain, or steroid use), it can be reversed. Men are often given FSH and LH supplements to make up for their inability to produce either, and if the man is taking testosterone (which we’ll address in the next chapter), he’ll be tapered off gently so as not to cause a psychological downswing. In about 90% of cases, men begin ejaculating sperm after 6 months of treatment and many couples can avoid undergoing IUI or IVF to conceive.

Testicular Azoospermia (Non-obstructive Azoospermia)

In this situation, the man’s body is producing the proper amount of hormones, but the testicles are not reacting properly to the hormones and are not producing sperm. Clinicians also refer to this as non-obstructive azoospermia as, by all accounts, there is nothing physically blocking sperm production and ejaculation.

Unfortunately, this is probably the hardest type of male factor infertility to treat.

Diagnosing testicular azoospermia can be either relatively painless, or more complex. If the man has smaller testicles and records an elevated FSH or LH level, most clinicians can confidently label the issue as testicular azoospermia.

However, if those FSH or LH levels read normally, it may be unclear if the issue is testicular in nature, or the result of some blockage (which will address next). If the reproductive urologist cannot find a physical obstruction, then they may need to perform a testicular biopsy to confirm the issue is testicular in nature.

Testicular azoospermia comes in a variety of types, some treatable, and others not. As we mentioned in the last chapter, if the issue is related to a varicocele that has damaged the testicles, varicocele surgery then IVF with ICSI has shown reasonably good results.

Finally, if a person is thought to have testicular azoospermia, it’s critical they undergo karyotype and Y-chromosome microdeletion testing to detect any genetic complication.

Retrieving Sperm with TESE & MicroTESE

In some cases of testicular azoospermia, the testicles can still produce sperm that are mature and, in that case, through an invasive procedure – either TESE or MicroTESE – those sperm can be retrieved directly from the testicles for use in IVF with ICSI. Currently, the American Urological Association and American Society for Reproductive Medicine guidelines recommend MicroTESE specifically for non-obstructive azoospermia.

When sperm must be surgically retrieved from the testicles, IVF is a requirement. That’s because ICSI (Intracytoplasmic Sperm Injection) is a requirement. ICSI is the process of injecting a single sperm directly into a woman’s egg. When sperm are surgically retrieved from the testicle, so few are available that only fertilization with ICSI stands a chance of working. ICSI can only be done by having the woman’s eggs, and man’s sperm, available in the lab, which means undergoing IVF is a necessity.

If sperm is retrieved, the American Urological Association believes 25 – 30% of patients will ultimately end up with a live birth from IVF with ICSI.

Using Fresh or Frozen Surgically-Retrieved Sperm

With MicroTESE (one of the surgical approaches), sperm can be retrieved from the testicle in about 60% of cases. When sperm is retrieved it can either be used immediately (which is known as “fresh” sperm) or after it has been frozen and later thawed (known as “frozen” sperm).

Teams from Stanford and The University Illinois – Chicago conducted a meta-analysis to determine if one approach was superior and came to the conclusion whether a couple used fresh or frozen testicular sperm made no difference amongst non-obstructive azoospermatic men.

While the results may appear to be somewhat similar, it’s important to recognize that the processes of using fresh or frozen testicular sperm in an IVF process are nothing alike.

When the couple plans to use fresh sperm, the woman’s eggs must be immediately available to be fertilized with the retrieved sperm. Often that means her eggs need to be retrieved at the same time as the sperm is retrieved, which entails the woman begins and commits to her IVF cycle weeks, or even months, in advance. This places pressure on the couple

What’s more, these married processes requires tremendous coordination between the reproductive urologist and fertility clinic to make sure the eggs and sperm are available at the same time and that the sperm is retrieved, processed and ready for fertilization in quick succession. This places pressure on the clinicians.

On the other hand, when a couple chooses to freeze their surgically-retrieved sperm, they plan to wait to inseminate the woman’s eggs. That means those eggs do not need to be available at the time of sperm retrieval, and so the woman is not forced to start her cycle, and have her eggs retrieved, on specific dates. This alleviates pressure on the couple and on the clinicians involved.

If the couple elected to use fresh sperm, but no sperm is retrieved during the surgical procedure, the woman has already started her costly IVF cycle. She can still have her eggs retrieved, but they must be frozen until the couple waits for sperm to become available. Many clinics are not experienced in freezing and thawing eggs and there is a risk that when those eggs need to be thawed, some will not survive.

Rather, had the couple elected to freeze their sperm, the woman would not have been forced to begin her IVF cycle to sync up with the sperm retrieval. If that sperm retrieval yields no sperm, and the couple decides to move forward using donor sperm, they could try using the donated sperm in a less costly, less invasive IUI procedure instead of starting with IVF.

On the other hand, freezing and thawing sperm carries additional risk.

First is the risk the frozen sperm does not properly thaw. When the teams at Stanford and The University of Illinois – Chicago combed through the literature, they noted that roughly 90% of retrieved testicular sperm properly thawed after it was frozen, which is likely reassuring.

The second underlying fear is that the retrieved sperm undergoes damage when it is frozen and thawed. While there is literature to suggest that is the case, the Stanford and Illinois – Chicago findings that the success rates were comparable should address some of this concern.

Undergoing Additional, or Avoiding Needless, Sperm Retrievals

Unfortunately, in about 70% of microTESE retrievals on men with non-obstructive azoospermia, there is only enough sperm retrieved to do ICSI on one batch of eggs. If the fertilized eggs do not lead to a live birth through IVF, and the couple plans to try again, the man typically must undergo another sperm retrieval (and, of course, a woman will have to undergo another egg retrieval).

There are circumstances where the odds may be low that a surgical sperm retrieval will yield any sperm. This may happen in circumstances of prior negative sperm extraction, certain prior cancer treatments including stem cell transplants, and certain genetic conditions like AZFa or AZFb deletions. While in some cases (such as previous cancer treatment) a successful retrieval may be possible, a discussion with your doctor about how worthwhile the procedure may be is warranted. Alternatives in these circumstances might include using a sperm donor or adoption.

Comparing TESE And MicroTESE

As we’ve covered, in many circumstances for testicular azoospermia (as well as post-testicular azoospermia, which we’ll cover next), the reproductive urologist needs to surgically retrieve sperm directly from the testicle. There are a variety of methods to do this, and the one that’s utilized should depend on the skill of the available urologist, and the risk to the patient.

For patients with testicular azoospermia, there is one small, single-center study that compares the results of TESE versus MicroTESE. The study, shown below, found that MicroTESE was the superior technique in locating sperm, retrieving sperm and doing so while inflicting less damage. What’s more, in six men’s cases where TESE did not work, microTESE did. When Bernie, another investigator, did a pooled analysis comparing MicroTESE versus TESE, he concluded MicroTESE was 1.5x more likely to result in successful sperm retrieval.

What makes microTESE a more efficient procedure is that it allows the surgeon to project which tubules in the testicle are more likely to contain sperm and thus allows for a more precise, less invasive harvesting of tissue.

On the other hand, microTESE is often more expensive (around 50% more than TESE) and its availability relies on the number of qualified local reproductive urologists who can perform it.

For patients with post-testicular azoospermia who require sperm retrieval, the American Urological Association seems to have no preference on where the retrieval should be from (testicle or epididymis), or the technique used.

As of today, roughly 60% of men undergoing a testicular biopsy for non-obstructive azoospermia will manage to have sperm retrieved and of those, 20 – 30% will go on to have that sperm achieve pregnancy through IVF with ICSI.

Post-Testicular Azoospermia (Obstructive Azoospermia)

Typically, post-testicular azoospermia (also known as obstructive azoospermia) is caused by some sort of blockage, namely a vasectomy, a missing vas deferens, or an infection in the ejaculatory duct. Occasionally, a trans-rectal ultrasound (TRUS) is needed to make a diagnosis.

If it appears the man is missing the vas deferens, there is a meaningful risk he is a carrier for cystic fibrosis, and at this point the couple should undergo genetic carrier screening, consult a genetic counselor, and discuss the risks of conceiving naturally. The couple may ultimately consider undergoing IVF so that they can use PGD (Pre-Implantation Genetic Diagnosis) to test their embryos and assess their risk of leading to the birth of a child with cystic fibrosis.

Microsurgery of the reproductive tract generally has good outcomes in reversing the impact of a vasectomy. Our best data on the subject is from a large sample set (over 1,000 men) and reveals that pregnancy rates (but not necessarily live birth rates) are clearly impacted by the length of time the vasectomy has been in place. However, a major confounder here is that often these studies don’t take into account the age of the female partner, which can meaningfully distort the analysis below.

All the same, these are not easy procedures to perform. They often require a wealth of experience and so it’s important to understand the number of procedures, and outcomes, any urologist has achieved before enlisting their services.

In circumstances where the ejaculatory ducts are blocked, surgery typically results in 50 – 75% of men producing sperm in their semen analysis, and 25% achieving pregnancy without IVF.

Pro Tips

  • It’s important to have your semen analysis taken at a laboratory with a lot of experience and that has the expertise to find rare sperm in a sample when average labs cannot

  • Men with pre-testicular azoospermia also have an elevated risk (but still a low likelihood) of developing pituitary cancer. If there is a pituitary issue, an endocrinology evaluation is appropriate often including brain imaging

  • If you have testicular azoospermia, see a specialist to find out why this might be occurring, to see if it is treatable, and to ensure there is nothing else dangerous to be concerned over

  • If you have testicular azoospermia, it’s critical you go to a fertility clinic that is excellent at ICSI and records ICSI fertilization rates above 80%

  • If you have testicular azoospermia, understand the degree to which your urologist and fertility clinic have worked together in performing a testicular sperm retrieval & IVF with ICSI in concert

  • If you have testicular azoospermia, work with your doctor and clinic to determine whether using fresh or frozen retrieved sperm makes most sense. Probe on their collective track record of using fresh and frozen sperm.

  • If you have testicular azoospermia, discuss with your urologist their ability to perform microTESE in addition to TESE

  • If you have testicular azoospermia, discuss with your doctor if you are the type of patient for whom sperm may be unable to be retrieved (e.g. patients with AZFa or AZFb microdeletions)

  • If your doctor diagnoses a missing vas deferens, make a point to undergo genetic carrier screening for cystic fibrosis and make an appointment with a genetic counselor. It may make sense to consider IVF with PGD to test embryos