SART Fertility Experts - Azoospermia

Struggling with male infertility or curious about azoospermia? Join Dr. Josh Halpern and Dr. Joseph Findley as they break down the causes, diagnosis, and treatment options for this often-silent condition. Whether you're a patient, partner, or provider, this episode of SART Fertility Experts offers expert insight, hopeful solutions, and practical advice that could change the course of a fertility journey. Don't miss it—knowledge is the first step to action.

Hello, and welcome to this edition of the SART Fertility Experts podcast. My name is Joseph Findley, and I'm a physician in reproductive endocrinology and infertility at University Hospitals Cleveland Medical Center. Today, I'm joined by Dr. Josh Halpern, who is a board certified and fellowship trained reproductive urologist.

He serves as both the regional medical director in Northeast and Chief Scientific Officer for Posterity Health. He is also on faculty at Northwestern University Feinberg School of Medicine. Welcome.

Thanks, Joseph. Great to be here. And so our topic for today, we'll be discussing azoospermia.

So just to begin, what is azoospermia? So azoospermia is the condition of having no sperm in the ejaculate, simply put. And it's actually a little bit more common than you might think. The prevalence of azoospermia is about 1% to 2% of all men, and about 10% of men who are struggling with fertility.

Now, on the one hand, that doesn't sound like a huge number. On the other hand, 1% to 2% of all men is actually more substantial than a lot of patients might think. And so azoospermia comes in a lot of different flavors, which we'll get into, but it's one of the conditions that we as reproductive urologists see quite often and on a regular basis.

Excellent. So this sounds like it's something that is pretty common in folks who are struggling with infertility, and it sounds like there are things that can be done about it. Is that correct? Absolutely.

It really depends on the cause of azoospermia when we think about how we might treat azoospermia. And so I think we may spend a little bit of time here trying to understand the different types of azoospermia, how patients might present with azoospermia, and what we do as reproductive urologists to get to the bottom of some of those distinctions. Can you walk us through some of those causes? Yes.

So when we think about azoospermia, we typically think about azoospermia in two categories. Obstructive azoospermia, which is azoospermia in the setting of having some sort of blockage, or non-obstructive azoospermia, which is typically a sperm production issue. So obstructive azoospermia typically is the case when a man has a testicle that's capable of making sperm.

His testicles are actually producing sperm most of the time normally, but those sperm are hitting an obstruction on their way from the testicle out of the body. Those can be congenital causes, they can be acquired causes, and there are a lot of different reasons why somebody may have obstructive azoospermia. On the other hand, non-obstructive azoospermia is typically an inherent issue with sperm production inside the testicle.

There's no blockage, but the testicle itself is having trouble producing sperm, which can also come from a lot of different causes. This can be congenital as well. It can be genetic.

It can be due to an exposure, for example, chemotherapy or a medication that may have a negative impact on sperm production. It could be a hormonal issue. Lots of different causes of non-obstructive azoospermia as well.

Can we dig in a little bit more on the obstructive azoospermia causes? You did mention that there are a few things that can potentially result in this. Absolutely. If we think about the genitourinary tract, and specifically the male reproductive tract, we're looking at sperm being made in the testicle, making their way into the epididymis, which is the structure that sits on top of the testicle where sperm are stored and where they're mature.

That epididymis finds its way into the vas deferens, which is a long looping tube that makes its way ultimately to join with the prostate, the seminal vesicles, and ultimately the urethra, where sperm finally make their way out of the body. This is basically a really long pathway and there can be an obstruction or a blockage at any point along the pathway. Some of the more common causes that we tend to see, for example, congenital bilateral absence of the vas deferens, some men are born without that long tube, the vas deferens, that carries sperm from the testicle out of the body.

Oftentimes they can be missing this on both sides. It turns out that that condition actually is associated with being a carrier for cystic fibrosis. Men with that condition typically have normal sperm production in the testicle, but those sperm are not able to make their way out of the body due to the absence of that tube.

On the other hand, we can see blockages or obstruction further downstream in the process, for example, at the level of the prostate where all of these different structures coalesce. You can have ejaculatory duct obstruction due to, for example, a cyst in the prostate or a number of other causes. So really anywhere along that track, there can be a cause of a blockage, which could be congenital, in some cases acquired, infection can sometimes cause scarring, and a number of other conditions can result in blockages anywhere really in the system.

And for non-obstructive azoospermia, are there certain particular etiology that can result in this? Yeah, the causes of non-obstructive azoospermia in some ways are actually a lot more broad. And I mentioned this a little bit earlier, but they fall into a number of different categories and a number of different rubrics we can use to think about stratifying those causes. So we can think about congenital and acquired, we can think about kind of hormonal versus genetic, we can think about exposures, and all of those do factor into play.

There are certainly genetic causes of non-obstructive azoospermia. The most common one is Klinefelter syndrome, or men who have 47 chromosomes and an extra X chromosome. Klinefelter syndrome results in most men in azoospermia.

Very rarely, some men will have a few sperm in the ejaculate, but it is one of the most common causes of testicular dysfunction due to a genetic cause. And that's one of the things that we see quite a bit. There can be hormonal causes for non-obstructive azoospermia.

For example, some men are born with hypogonadotropic hypogonadism, that is the lack of gonadotropin secretion, leading to stimulation of the testicles to make sperm and to make testosterone, and that can be potentially a cause of non-obstructive azoospermia. We also see this, unfortunately, quite a bit in patients who have been treated for various cancers. We know that chemotherapies, radiation, they can impact sperm production, impact the spermatogonial stem cells, and a lot of patients who undergo spermatotoxic chemotherapies will have acquired non-obstructive azoospermia as a function of their treatment.

So that just scratches the surface of some of the causes that we tend to see in men with non-obstructive azoospermia. Now, one of the other common causes of non-obstructive azoospermia that we haven't talked about yet, but is really important, is exogenous testosterone and anabolic steroids. There are a lot of men who are using testosterone, who are using anabolic steroids, sometimes prescribed, sometimes not prescribed, because there are a lot of these direct-to-consumer platforms that are offering these medications or these compounds now.

There are a lot of guys who can get this from their local gym, etc., but sometimes these men are being prescribed medications by their primary care physician, endocrinologist, even their urologist, and these medications can be useful in a lot of ways, but they can be very, very dangerous and very, very impactful in a negative way when it comes to fertility. In fact, a lot of men who go on these medications will have an impaired sperm production to the point of having azoospermia or no sperm at all. They're ejaculate, as we've been talking about, and the reason for that is that taking exogenous testosterone, taking anabolic steroids, really shuts down the body's own production of the hormones that are necessary to promote sperm production and to promote its own testosterone production inside the testicle.

In fact, testosterone inside the testicle is about 100 times the levels of those in the bloodstream, and so you really do need that endogenous intratesticular testosterone production in order to support good sperm production, and when men are on testosterone, their pituitary gland shuts down production of LH and FSH, those two hormones that are really important when it comes to testosterone and sperm production, and so we, in many, many cases, see azoospermia, and that's becoming increasingly prevalent in my practice, in the United States, according to some data, and it's something that we're seeing more and more in the clinic on a daily basis. When we do see those men, we really have to start peeling back those layers, taking them off of the medications that are causing the suppression of their sperm production and of their hormone production endogenously, and put them on other medications that can support those activities when it comes to spermatogenesis, testosterone production inside the testicle, and that's things like selective estrogen receptor modulators, or CIRMs, one of the most common ones in our practice being clomiphene citrate, gonadotropins, things like HCG that can really kind of wake up the system, promote LH and FSH production, and over time, return sperm to the ejaculate, but sometimes that does take a while. The majority of men who go on a regimen like that will see sperm back in the ejaculate within about six months or so, but a substantial proportion of men will continue to have azoospermia for a period of time after that, and in some cases, there are men who don't recover sperm production at all, and so this is something that we're seeing as a huge problem with men not understanding the potential implications of these medications when it comes to their fertility.

So it certainly sounds like there are a myriad of things that can kind of come together to result in azoospermia. For folks who are affected, are there signs or symptoms that they may notice throughout their life that might tip them off that something might be going on? You know, it really depends on the cause. So for some of these causes, there are some signs and symptoms that might be a tip-off, so to speak.

For example, we talked about congenital bilateral absence of a vas deferens. Those patients actually also tend to have some abnormalities in their seminal vesicles, leading them to have very low ejaculate volume most of the time, and so these are men that may have a clue to some extent that for as long as they can remember, their ejaculate volume has been very low. Sometimes I had patients telling me they always suspected something was maybe a little bit off, but on the other hand, you know, it's very hard to compare one's ejaculate volume to what they think it should be.

We don't really necessarily have a rubric for something like that, and so a lot of men actually don't notice this. The same goes for, for example, testicular resides. We do see that in some of these conditions, Klinefelter syndrome, for example, men will have very small testicles.

Oftentimes men will look around in the locker room and say, you know what, things are a little bit different for me compared to a lot of my buddies, but other times some men may not have that context. So those are certainly some circumstances where there may be a sign or a symptom, but whether or not a man notices that is not necessarily the case. Now in other conditions, there may be no sign at all of azoospermia or specifically, for example, non-obstructive azoospermia in the setting of certain genetic conditions or even acquired conditions.

A lot of men will have normal sized testicles. They will have normal ejaculate volume. There's just no sperm in the ejaculate, and it turns out that sperm only make up about five, maybe maximum 10% of the ejaculate volume.

So if ejaculation is normal, but sperm are absent from the ejaculate, it's really not going to impress upon most patients as far as what the volume of their ejaculate looks like, and they really won't notice a difference. This is why, for example, when men get a vasectomy and they have essentially iatrogenic azoospermia for the purpose of contraception, there is the proverbial kind of saying or concept that these men are shooting blanks because they actually don't see a change in their ejaculate volume, but there's no sperm in the ejaculate, and so we see that in non-obstructive azoospermia as well. For example, in genetic conditions such as Y chromosome microdeletions, those men oftentimes have totally normal testicular size.

They have totally normal ejaculation, and they have no other health conditions associated with that genetic abnormality, and really the only manifestation of their abnormality is the lack of sperm in their ejaculate, which they tend not to notice until they start trying to conceive. So this really sounds like it could be something that's somewhat insidious in nature and that folks don't necessarily even know is happening. That's exactly right.

And what recommendations would you give regarding when patients should really seek attention, seek evaluation? Well, certainly anybody who feels as though they may be having a particular symptom related to sexual function, infertility in general, anybody who has the suspicion of low ejaculate volume that may be associated with one of the conditions that we mentioned is somebody that should be looking for an evaluation with a reproductive urologist. But again, most of the time, or certainly a lot of the time, azoospermia is going to present not with signs or symptoms, but predominantly with infertility and a semen analysis that ultimately leads to azoospermia. Again, azoospermia is not really a symptom.

It is a finding on a semen analysis. So most of the time we're going to be seeing couples who are presenting with infertility. They're getting a semen analysis.

It's showing that there's no sperm, and they're going to be referred to a reproductive urologist to begin that evaluation for trying to discern whether it's obstructive azoospermia, non-obstructive azoospermia, and starting to think about treatment paradigms. Excellent. And so, you know, one of the things that I typically hear as a reproductive endocrinologist from patients is, oh, a male partner in a couple has had a child previously, several years ago in a previous relationship.

Is that something that you would think is necessarily protective, or is it a guarantee that sexual function and reproductive function is going to be normal now just because they had a child previously? So the answer to that is no. There is no assurance based on prior pregnancies that somebody couldn't develop azoospermia. We actually do see secondary azoospermia quite a bit, and that would be the progression of somebody from having a normal semen test or a slightly abnormal semen test, some established prior paternity, and subsequently presenting with azoospermia.

And sometimes the cause of that is very apparent. As I've mentioned a couple times now, chemotherapy is something that could potentially cause azoospermia, and so somebody who has had a child and then has been exposed to some sort of spermatotoxic chemotherapy, typically that's a pretty clear inciting event that might lead to secondary azoospermia. But we do see plenty of men who present with azoospermia without a clear inciting event, or at least not something that they can really put their finger on, whether it's an exposure, change in their health, or otherwise.

And we certainly do see men have a negative downward progression in their fertility to the point of azoospermia for all sorts of reasons. Wow. So I think that really highlights the importance of making sure that all partners in a particular couple or relationship are tested to make sure that nothing's being missed.

Yeah, absolutely. And I think, you know, one of the messages is that early semen testing to try to detect azoospermia, particularly when couples have been trying to conceive for a reasonable amount of time, is really critical because azoospermia is something that may not present, as we've talked about, with a particular sign or symptom, and only a semen test is really going to lead us down the pathway of diagnosis and treatment. So what type of workup is typically employed to first see if this is an issue, and then if it is, figure out what the cause of it is? Yeah, so the critical components of the evaluation for azoospermia beyond the semen analysis, and of course, repeating the semen analysis to ensure that azoospermia is confirmed, really involves a good physical exam, some detailed analysis of the semen test, and laboratory evaluation.

Typically, the physical exam can tell us a lot about the potential cause of azoospermia. I've mentioned absence of the vas deferens. That is a clinical diagnosis that we make on physical exam, and something that we can detect within just a minute or so of examination of the patient.

I've talked about testicular size. There can be other indicators of obstruction, such as epididymal dilation. There are a number of things on the physical exam that we would be looking for as a clue, but perhaps one of the most critical data points is the follicle stimulating hormone, or FSH, and what we've known for a long time now is that men with non-obstructive azoospermia tend to have a highly elevated, or at least somewhat elevated, FSH, which according to prior studies is probably around 7.6 or above.

It's a very specific number, probably not a hard and fast rule. There are certain exceptions to it, but typically men with non-obstructive azoospermia will have a high FSH, whereas men with obstructive azoospermia will typically have a normal FSH, and so it's usually a combination of the semen parameters, certain elements of that, such as the semen volume, the pH, along with the physical exam, and that blood work is going to give us most of the diagnosis, and then there are some specific genetic tests that are indicated as well. I've mentioned things like Klinefelter syndrome, like chromosome microdeletion testing.

Those are both appropriate when non-obstructive azoospermia is suspected, and then when obstructive azoospermia is suspected, particularly congenital bilateral absence of the VAS, CFTR testing, if it hasn't been done already, is also indicated. Excellent. And is this something that can be treated or cured? Well fortunately the answer to that is yes, and again it really does depend on this distinction between obstructive azoospermia and non-obstructive azoospermia.

So for men with obstructive azoospermia, the question is really where is the location of that obstruction or of that blockage. For somebody missing a VAS deference, we really don't have a mechanism to substitute that tube for reconstruction of the reproductive tract, and so for those men the treatment pathway is really one of sperm extraction, taking sperm from the testicle, from the epididymis, using that for IVF, but typically that is quite straightforward because most of the time those patients have really normal sperm production, and that is a very minimally invasive procedure, and those couples do really well. In other cases, the obstruction may be something that could be treatable without IVF and perhaps with relief of that obstruction.

For example, when ejaculatory duct obstruction is secondary to a cyst in the prostate, for example, we actually have the ability to resect that cyst, something called a transurethral resection of the ejaculatory duct, which is a cystoscopic intervention, camera goes into the urethra, we identify that area in the prostate and kind of scrape away the lesion that is blocking the ejaculatory duct, and that can actually sometimes restore continuity to the reproductive tract, and those men might be able to achieve a pregnancy naturally if they have a good outcome from that procedure. So obstructive vazoospermia, really multiple options on the table depending on where the blockage may be. Some men, for example, may also have obstruction at the level of the epididymis and could undergo epididymal reconstruction with a vasoepididemosomy.

So there's a lot of different permutations for obstructive vazoospermia, but IVF with sperm extraction is almost always going to be an option for those couples. Non-obstructive azoospermia is a little bit trickier in the sense that there's an inherent issue with sperm production in these men, but what we found is that even in men who don't have sperm in the ejaculate due to a sperm production issue, they may be harboring sperm within the testicle, and that is really the underlying premise of what has come to be the standard of care for men with non-obstructive azoospermia, which is the microtestic procedure or the microdissection testicular sperm extraction procedure. So men with non-obstructive azoospermia typically will be prepared for that procedure, which is one that is more invasive than classic sperm extraction procedures insofar as it involves opening the testicle and really bivalving the testicle.

So dividing the testicle in two and using a microscope under very high power magnification to go searching for areas within the testicle that might harbor sperm, and there's some visual clues and visual cues underneath that surgical microscope that help us to try to identify the seminiferous tubules that are most likely to harbor those sperm, and if we are able to find sperm using that microtestic procedure, those sperm can be used for ICSI and has been done quite successfully in many, many cases over the years. But success rates with the microTese procedure in men with non-obstructive azoospermia is certainly not nearly as high as the success rates we would expect in somebody with obstruction who has plenty of sperm in the testicle and has a very clear pathway towards IVF. Excellent.

Well, do you have anything else that you'd like to add for the listeners today, anything that you think that would be important for them to hear as they are either going through this process themselves or managing patients that potentially have this issue? Yeah, I think really one of my take-home messages, number one is early testing is really going to help us to detect azoospermia earlier in the process and get couples on the right pathway earlier than they may otherwise have done. If we know 1-2% of all couples have azoospermia and 10% of infertile couples on the male side are going to have azoospermia, it's something that we want to detect sooner than later. The last thing we want is for somebody who has a physical impossibility of achieving a pregnancy on the male side to try for a year or two before actually having this diagnosis made.

So early testing really might help us to expedite couples to getting the care that they need. And then in the event that somebody is diagnosed with azoospermia or a patient out there is diagnosed with azoospermia, really critical to see a reproductive urologist, somebody who has true expertise in this condition. It's quite nuanced.

There are a lot of variables that come into play and you really want somebody who sees a lot of these patients who is really facile in managing these different conditions and identifying the underlying causes and shepherding you as a couple on your way to getting the appropriate treatment. Well, excellent. Well, thank you very much for your time and thank you for joining us today.

Thanks so much for having me. This concludes this session of the SART Fertility Experts podcast. Please join us again next time.

The information and opinions expressed in this podcast do not necessarily reflect those of ASRM and its affiliates. These are provided as a source of general information and are not a substitute for consultation with a physician.