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BackTable / Urology / Podcast / Transcript #167
Podcast Transcript: Solving Semen Analysis Barriers: Innovation & Accessibility
with Dr. James Smith
In this episode of Backtable Urology, Dr. James Smith, Director of Male Reproductive Health at UC San Francisco and CMO of Fellow, discusses advancements in semen analysis and fertility testing with Dr. Jose Silva. You can read the full transcript below and listen to this episode here on BackTable.com.
Table of Contents
(1) Understanding Male Factor Infertility
(2) Barriers to Semen Analysis Access
(3) Expanding Access Through Innovation
(4) Addressing Leukocytospermia
(5) Semen Quality: Evaluation & Impact on Fertility
(6) Testing Guidelines & Strategies for Early Intervention
(7) Advances in Post-Vasectomy Semen Analysis
(8) Redefining Standards in Semen Diagnostics
(9) Key Features of the Fellow Kit
(10) Population Trends in Semen Quality
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[Dr. Jose Silva]
I'm happy to introduce our guest, Dr. James Smith. Dr. Smith earned both his medical degree and master's degree from UCSF and UC Berkeley. He did his urology residency at University of Utah and he did a fellowship in andrology and fertility at UCSF as well. Until recently, he was the director of male reproductive health at UCSF, and currently he remains clinical professor of UCSF, but he is the chief medical officer and founding physician at Fellow. Jim, welcome to Backtable.
[Dr. James Smith]
Thank you, Jose. I'm thrilled to be here. Thanks for the introduction.
[Dr. Jose Silva]
James, so today we'll be talking about fertility and innovation in semen analysis, but first let's just start talking about your background and just a little bit about yourself.
[Dr. James Smith]
Great. No, thank you. Again, I'm thrilled to be here. My background as an undergrad was in molecular biology. I've always been interested in science and the lab and innovation. As I was thinking about my career, though, I found that in urology, you get that terrific blend of being able to follow your patients for an extended period of time, terrific science underpinning the field, and I really began to grow passionate about ways to help people start families. I realized that as an andrologist and a reproductive urologist that I'd be able to do that.
That fellowship was really impactful for me, and it led to me coming on as an assistant professor, associate, and full professor at UCSF, it really led to a lot of exciting things. Over the course of my time at UCSF, did a lot of basic science research into how sperm work, how sperm stem cells work, also did a lot of larger scale projects looking at access to care and breaking down barriers.
About five or six years ago, I was introduced to the founder of Fellow by my department chair, Peter Carroll, introduced me to the founder of Fellow. In that first conversation, I was asked, "Jim, what are pain points that you face in your practice? For me, the semen analysis as a reproductive urologist was a really big pain point. It's very difficult for patients to get into the clinic.
It's fundamental for everything that we need to do when we're trying to evaluate the fertility of our patients to try to see whether or not a patient's vasectomy worked. Yet, there were just huge logistical barriers in terms of a guy coming in and getting scheduled for the semen analysis. It was hard on my staff, my nursing team, the secretarial team. It was tough on patients, traveling long distances when they had to produce a sample and get it analyzed within an hour. It's a short overview of where I got to.
(1) Understanding Male Factor Infertility
[Dr. Jose Silva]
Good. We'll talk about quality in a while, but let's just start with just general fertility. Usually, do you see men alone or are you seeing couples?
[Dr. James Smith]
It's really a mix. I will see both. I'll see husband and wife or husband or male and partner together and also the man by himself. I'd say that probably more often in my practice, I see just the man by himself.
[Dr. Jose Silva]
In terms of, I know the number have been changed, but usually, I remember it was 1/3 male factor versus 2/3 female factor. is that still true or we have seen some changes?
[Dr. James Smith]
Roughly speaking, we think that within a couple, it's about a 50-50 phenomena. If you look at just isolated male factor, your numbers are pretty right on. It's about 1/3 only isolated male factor, but then an extra 20% of couples have both a male and a female factor. As you would expect, when a couple comes in about half the time, there's at least a contributory part of the male.
[Dr. Jose Silva]
When you see patients in the office, you're just a specialist, so I guess they have already seen a urologist or you've seen some patients that have never been, have had a workup for infertility?
[Dr. James Smith]
I see both. As a subspecialist at an academic institution, I do see many patients who've already been evaluated. They've gone to an OBGYN, they've gone to an REI and they've come to me or they've gone to their general urologist, come to me, they've gone to family practice, gone to semen analysis, and then come to me when there's abnormalities. There's a fair number of men who are just curious about their fertility and so they'll reach out to me as a fertility specialist just to get an evaluation and to see, "Is there anything I need to worry about?" They're getting married and you want to see the problem. They're planning on getting married down the road and they're just trying to get a tune up and a checkup.
[Dr. Jose Silva]
Let's just talk about those patients that they don't know, they haven't had any issues. What do you order for them? What is a general checkup in terms of fertility?
[Dr. James Smith]
Yes, so the answer for me as a subspecialist is a little bit different than what I would teach my residents, for example, or more I would say on [unintelligible 00:06:57]. In general, the minimum evaluation would entail a history, physical exam and from a lab standpoint, at least one semen analysis, but often two semen analyses and at a minimum, a testosterone and FSH.
I typically will expand that list to have a more full picture of the pituitary and often patients are waiting a long time to get into the subspecialist. I'll often expand that panel of testing, but at a minimum, semen analysis or two, FSH and testosterone, history and physical.
(2) Barriers to Semen Analysis Access
[Dr. Jose Silva]
You mentioned already the semen analysis and what were some of the barriers of people doing a semen analysis and I'll talk as a general urologist and I see a difference between a patient going to just the lab in the corner versus I try going to a fertility clinic. I guess now with Fellow, it's different, but in the past, that patient that just wants to do a general checkup, do you always tell them to go to a specific lab or what do you do in the past?
[Dr. James Smith]
It gets to be the convenience as well as things like, "Does your insurance cover?" For Northern California, patients who are coming from hours away to relatively close by in San Francisco and so it really depends. Some of my patients are in the East Bay of San Francisco or in the South Bay of the Bay Area and so we'll look for places that they can get their semen analysis done.
That's one of the significant barriers, is actually trying to find a lab that offers a semen analysis, finding a lab that does a post-vasectomy semen analysis. That's pretty tricky. There are quite a few labs that have stopped offering the semen analysis. In many of the far-flung areas, they may not have a lab to do the semen analysis. Those are challenges and those were really some of the main pain points that got me really interested in the concept behind Fellow in the beginning.
[Dr. Jose Silva]
You mentioned the accessibility, and traditionally it's 45 minutes that you need to process the sample, right? Or–
[Dr. James Smith]
An hour.
[Dr. Jose Silva]
-was it a little bit or an hour?
[Dr. James Smith]
One hour.
[Dr. Jose Silva]
You mentioned access before. Is there literature around this, around semen analysis and access to that semen analysis?
[Dr. James Smith]
It depends on what you talk about. There's literature around things like compliance with testing, for example, as terms of one metric of access. The AUA guidelines recommend that all men get a semen analysis after they get their vasectomy done, usually around 12 weeks or so after the vasectomy. The studies typically are around 25% to 50% compliance with that. That's impartial due to the kind of barriers and access one way or the other.
Like many conditions, we suspect that race, education, income are all potential barriers. The occupation that a person has, the ability to take time off of work and drop everything that they're doing and go to a place, produce a sample in a lab in the middle of the day. There are lots of logistics barriers, there can be cost barriers, the cost for semen analysis ranges quite widely and can range from $150 up to $500 for a semen analysis and insurance often doesn't cover very well.
(3) Expanding Access Through Innovation
[Dr. Jose Silva]
When the founder of Fellow approached you and he told you that, "Hey, there might be a solution." How do you approach this? You will fall in with a suggestion or what happened at that point?
[Dr. James Smith]
For me, this was really at the time was very much just one of many projects that I had going on. We were doing interesting work in sperm physiology and putting electrodes into individual sperm and watching how ions flowed across individual sperm cells. This idea was something that in the beginning wasn't too much and I was only spending about an hour a month even doing this. As time went on, I got more and more involved and eventually led the scientific team in developing the Fellow kit.
We had to test a range of conditions. We had to figure out why it was that the WHO requires a one-hour time to get the sample in. In large part, it's due to the inaccuracy of cell death, of the loss of motility. Motility in a semen analysis is a marker for the cells just died. If the sample is produced and then analyzed after an hour, you really can't give an accurate result because the cells have died at inconsistent rates.
What we had to do in the lab in the beginning was really to figure out what drives that. We found that temperature was important, the kind of sperm media that you use was important, bacterial overgrowth was important. These were all factors that we were testing extensively and with thousands of semen analyses and many different permutations of these parameters. Eventually, we were able to design a kit and that's led to the clinical validation paper that we published in Fertility and Sterility a couple of years ago, where we were able to show that with the kit, you can see a linear decline in motility.
Now, when a sample shows up in the Fellow lab, we're able to correct for a known decline in motility over time. If a sample shows up anywhere up to 52 hours after production, we can give a highly accurate semen analysis reading. That's really is a game changer because then my patients who live three hours away can produce a semen sample and those are shipped overnight back to the Fellow lab. It comes, say, 35 hours later. That patient doesn't have to take a long trip, a three-hour trip here and a three-hour trip back. He's able to get a CLIA-accredited semen analysis from the comfort of their own home.
[Dr. Jose Silva]
You mentioned in the past, in terms of insurance, patients maybe they don't want to pay out of pocket. What do you tell the patient? Maybe at the end of the day, they're actually saving money by just going straight to this more specific or easier test to be done in their house. How do you word the patient or how do you talk to the patient about this?
[Dr. James Smith]
Yes, patients often ask me that question. Often when they're thinking about their diagnostic testing, they're wanting to use their insurances as best they can. I tell them that they can submit the receipt for their semen analysis, whether it's Fellow or the in-person semen analysis, and submit that. It's usually is reimbursed by their FSA or HSA accounts,Carrot, and Progeny. Some of the insurance benefit managers, they will often reimburse the semen analysis.
I think you're right. I think that that's the calculation that the patients are thinking through. The Fellow semen analysis costs $189 for the semen analysis, $139 for the vasectomy semen analysis. They're thinking, "How much is the hassle factor, taking time off work, going in?" It's grown increasingly popular all around the country.
[Dr. Jose Silva]
Is there a patient that is not a candidate to using this type of technology? You will say, "Hey, just go to the fertility clinic," for example.
[Dr. James Smith]
Yes. I think the Fellow semen analysis is a terrific screening test. I think it's great for figuring out if a man has normal parameters, abnormal parameters, azoospermia. For patients who have very low ejaculate volume, the Fellow does not do a post-ejaculate urine analysis test. We don't currently do leukocyte staining. If someone was concerned about infection that way, there's not a culture of the semen or looking for leukocytes. Those are a couple of situations that would not be a good fit for Fellow. For example, if the semen volume was low and I got it from Fellow, I would often send a second semen analysis at UCSF and I would get a post-ejaculate urine analysis to look for a retrograde ejaculation in that patient.
[Dr. Jose Silva]
Also not many labs are doing the post-micturition test. It's not like it's going to be easy to find one.
[Dr. James Smith]
No, that's exactly right. For this kind of specialty situations, often men are coming to a reproductive urologist to exactly– to sort that out. For reproductive urologists, we have partnerships with high-quality labs that can do that advanced testing. Going down the road of Fellow, that's some of the things that I get excited about is to be able to add that on to the offering at Fellow, so that eventually, there would be a whole host of andrology tests that could come out of the semen analysis.
(4) Addressing Leukocytospermia
[Dr. Jose Silva]
Jim, you mentioned leukocytes, the preferred lab to use from my institution. I will say 100% of the patients have leukocytes and it says that it has bacteria and even patients that are asymptomatic. You talk about quality, how confident are those labs that every time they have leukocytes, they have bacteria, most likely it's contamination, right?
[Dr. James Smith]
Yes, that's right. I don't generally make too much out of leukocytes. The first finding that shows up in the semen analysis are round cells. What we'll do at UCSF is if there's more than a million round cells per milliliter, well, we'll reflexively stain those for leukocytes. If there's still a high fraction of leukocytes in the sample, then I'll think that it's possible there's an infection.
In a man who's asymptomatic though, this could very well just be contamination. He's producing samples through masturbation and he has bacteria perhaps on his hands or on his genitalia. Most times, I don't find that the leukocytospermia, the white cells in the semen are terribly informative. It is an area of concern for REI and there's the concern that these elevated white blood cells are going to impair the in vitro fertilization cycle.
The data on this is very mixed, as is treatment with antibiotics for this situation. Often if you culture semen in this situation, you'll often see a mix of flora. Treat with antibiotics, you'll see a new mix of flora and often grow yeast or something else and not necessarily change your IVF outcomes. This is a tricky area, but I've grown to think that it's not a terribly helpful metric on the semen analysis.
[Dr. Jose Silva]
The patients that come with that type of situation, that they probably have done already a sperm test, a semen analysis with the primary, they come to the office thinking that they're infertile because there's a bacteria there. How do you approach that patient to change the way they're thinking or just to try to, "Hey, that's nothing. Don't worry, let's do some tests."?
[Dr. James Smith]
I think that's a great question, Jose. I think for me, the number one metric is the total motile count. When I look at the semen analysis, the first thing that I'm doing is if it's not already calculated for me, I'm looking at the semen volume, the sperm concentration, and the percent motility, and I'm multiplying those to look at the total number of moving sperm in the sample.
If a man had 100 million moving sperm and he had some white blood cells, I'd do everything that I could to reassure him. If I did a rectal exam and he's got a very tender prostate or he has significant LUTs, then I'd be treating him for prostatitis. From a fertility standpoint, I'm looking at the total number of moving sperm in the sample and if there's lots of sperm, and he has some white blood cells, I'm usually telling him that this is something you don't need to worry too much about, other than if he had symptoms and maybe think he had prostatitis.
(5) Semen Quality: Evaluation & Impact on Fertility
[Dr. Jose Silva]
What about progression? The classic semen analysis parameters, there's a progression one, two, three, four. How does that impact you in the decision-making?
[Dr. James Smith]
Yes. When you look at this from zero, no motility at all, one twitching cells, two and three starting to move, and four just having linear progression across your microscope slide, generally, the higher the progressive motility, the more success you'd have with IUI. In general, the semen analysis, I think, gives you a pretty good idea of what's going on. Is the man likely to conceive with timing sex? Is he going to need something like intrauterine insemination or is in vitro fertilization more likely way to go?
I think of the semen analysis in that big bucket. Generally, I'm thinking if a man's total motile count is less than about 5 million sperm or so, this is my IVF bucket. Is he between 5 million and 20, 30 million, 40 million total moving sperm? That's my IUI range, at least assuming that they haven't conceived for a year. For that man who has more than 30 or 40 million moving sperm, then they're likely to conceive on their own if given enough time and they're timing sex with ovulation.
As a reproductive urologist, I'm always thinking, "What can I do to shift men among those three categories?" If he has 3 million moving sperm, is there something about his lifestyle or his diet, or his exposures in his environment? Does he have a varicocele? Does he have a pituitary dysfunction? Is he hypogonadal? Does he smoke? Does he use marijuana? As part of the history, the exam, his lab testing, I'm trying to figure this out. Is there anything that I can modify to try to shift him from being in that IVF range to being in the IUI range? If he's in the IUI range, is there something I can do to shift them into the just having sex at home range.
[Dr. Jose Silva]
For example, vitamins like CoQ10, is that something that you tell the patient that they might help?
[Dr. James Smith]
I think this is a really interesting area. There has been growing interest in antioxidants of one sort or the other. These are certainly very important in semen as far as capacitation and other parameters for sperm. The data is more than a little bit mixed in this area. Some studies have shown significant benefit from CoQ10 and L-Carnitine and many others.
The largest randomized control trial was one that I was pleased to be part of, and it was with about eight or nine different academic centers. This was called the Moxie Trial. This NIH-supported study randomized men with low numbers of total motile count to see whether or not antioxidants would improve. Overall, it did not lead to improvement. I generally try to focus on a holistic approach for patients. I talk about diet, and exercise, and weight, and removing toxic exposures. I'll tell them if you take supplements, it certainly may benefit you, but sometimes they can be quite expensive. I've gotten away from routinely advising them for patients, but I don't think they cause any harm other than sometimes to your pocket.
[Dr. James Smith]
How long do you wait? Like six month trying to do this diet, exercise, all the holistic method, six months? How long do you wait to tell them to come back with a new semen analysis?
[Dr. Jose Silva]
Each patient is very different. It depends on the circumstances. Some people have been trying for two years already, and I probably wouldn't wait very long at all. If a patient saw me in the very beginning of their journey, which I think is the place where urologists can really do the most good if a patient had not even started trying yet or was two months into their journey, then I certainly would wait three months. Three months is that minimum time for sperm production to happen. That takes roughly two months, and then for another couple of weeks for that sperm to make its way from the testicle through the ductwork and then out the penis with ejaculation.
I'd wait a minimum of three months before rechecking a semen analysis. One of the things I think that's tricky is to be scientific about this. Is it the diet or is it antioxidants or is it the varicocele or is it the obesity or is it the tobacco or a whole host of things. Typically, I try to fix them all at once and talk about the whole range of potential ways that man could improve his semen quality, and then I'll recheck him again three months later.
(6) Testing Guidelines & Strategies for Early Intervention
[Dr. James Smith]
You mentioned already that if a patient comes to the office and wants to be tested, you're doing the testing. How important is that one year mark of trying and not able to conceive?
[Dr. Jose Silva]
Yes. I think that the guideline's currently, I think, conflate too much testing for men and for women. Currently, the guidelines state that a couple should be trying for a year if they're 35 years old or younger, if the woman is 35 years old or younger, or 36 or older, that they could wait six months. That doesn't make a whole lot of sense to me from a urology standpoint. A semen analysis, a history, physical exam, these are pretty low lift, inexpensive tests.
From my perspective, I advocate on an earlier testing. I think that if a man knows that he has azoospermia, there's no sperm there, well, might as well know early so he can see if he can fix something. He's got a million moving sperm and he's got a giant grade three varicocele, would rather fix that early in his journey as it can take three months, six months, or longer to see benefit from that.
I think more often what happens is that couple tries for a year, they get frustrated, they go see their OB who sends them to their REI. The REI starts them on the path of IUI and IVF, and then they send them to a reproductive urologist and say, "We're going to start IVF or IUI in two weeks. Dr. Smith, what can you do for us?" Then I say, 'Well, nothing that we do could actually improve things too much in two weeks." Those are some of the challenges we face. I think that moving the diagnosis up sooner in a couple's journey, in a man's journey is more beneficial then and more likely to let us do less expensive interventions, less invasive interventions to help them.
[Dr. James Smith]
In terms of repeat testing, are you still doing two full semen analysis or with new technology like Fellow, do you need only with one you're good enough?
[Dr. Jose Silva]
If a man has a really normal semen analysis, then I'm often content with just one. If there's anything that's borderline about that test, his motility is a bit low, his morphology is a little bit low, his concentration is low, and then I'll often repeat them. There's a great deal of variability from one semen analysis to the next. It's common to see a 25% to 50% variation from the same man separated by a couple of weeks.
I'm trying to get roughly where is this individual? Is he in the IUI range on a couple of semen analyses? Is he consistently in the IVF range or is he consistently in the normal range? For pretty much most abnormalities, I'm going to get at least two. Sometimes I'll see very different numbers. I'll see one with very good, one relatively poor, and I'll get a third as a way of trying to break the tie.
(7) Advances in Post-Vasectomy Semen Analysis
[Dr. James Smith]
Out of curiosity, that patient goes to the office just for a regular checkup, oligospermia. How do you tell the patient the news?
[Dr. Jose Silva]
I think in a compassionate, straightforward way. I let him know that his sperm concentration is a little lower, that he still may be able to conceive. I've seen men over the years conceive even with thousands of sperm. It doesn't mean that they can't. It only takes one sperm for a man to conceive, but I tell that man with, say, 10 million cells that it may take him longer and that there may be things that we can do to try to improve that, whether it's diet or exercise or stopping a medication that may be hurting his fertility or fixing that varicocele. Those are all things that I think are opportunities for us to try to improve his chances of trying to conceive.
[Dr. James Smith]
Then you mentioned it's about chances, and that's what I tell the patients. I don't see that many, but the ones that I do get, it's probably the-- so don't try not to get frustrated, and then I send it to somebody like you in the area. You mentioned the vasectomy testing before with Fellow. Do you do a lot of vasectomies?
[Dr. Jose Silva]
Yes, I do. That's been a very big part of my practice over the years.
[Dr. James Smith]
In the past, how's your testing rate post-vasectomy?
[Dr. James Smith]
This again was one of those pain points when I met Will Matthews, the CEO, and we were talking about pain points. I tell each of my patients, "Look, there's a chance, perhaps 1 in 1000, that the two ends of the vas deferens are going to grow back together. You never know if you're in that group. It can take a while for all the sperm to clear out of that sample. You don't want to inadvertently get your partner pregnant. Get a semen analysis. Every time I'm doing a vasectomy.
I would say that despite that, the rate of getting it done was about 25% to 30% of men actually getting it done. That's been one of the big parts in this new role. A year ago, I became chief medical officer at Fellow and in large part, because I'm excited about being able to try to help men and improve access to care at the national level and at a much bigger scale than I was able to do only at UCSF. A good example of this is that we are about to present at AUA and have data under review now, but the compliance is 85% in 10,000 plus men who we followed over greater than six months.
The compliance, and this we looked at whether it was a large urology group, a small urology group, an academic center, and it really was basically about the same. It was all really good and, in the '80s or higher in some locations. That's been pretty impressive. It's certainly, it's been a game changer in my own practice. My secretary would spend hours a day scheduling semen analyses and now she spends basically none. My nurses would struggle to find reports. Now it's the easiest thing to do by just popping into the portal and getting results. That has been really, really terrific.
[Dr. James Smith]
We've been using Fellow in our practice for a few months already. What we've been doing is that prior to the vasectomy, we're already giving the kit to the patient. I think that's been the most helpful part of this because like you mentioned, most people don't do it afterwards. They just, maybe they call you two years after, "Hey, I just want to do it. I broke up with my wife or with my girlfriend. I just want to know," then they do it.
Definitely, for you guys out there that don't know about this, they will get the full report at congratulations, the assert certification that there's no sperm. Also let's say they do it three or four months later and there's still some sperm. The next one is also free. I think there's two that are free and, it definitely, it takes away from the office that awkwardness [unintelligible 00:29:31] "Hey, you need to do it again."
Actually, we'll keep testing for free until it's zero. We're committed to just getting that patient down to zero. We centrifuge every sample that comes into the lab. We're committed to getting to zero. It's just an automated part of our process that there's any cells on that semen analysis, the patient just automatically gets another kit for free. It didn't matter the number, whether it's two or three or whatever.
[Dr. Jose Silva]
Jim, do you usually wait three months or are you doing just by number of ejaculations? What are you doing?
[Dr. James Smith] I think that's an interesting question, Jose. We're in the midst of trying to analyze that now. Stan Honig from Yale and I and some other colleagues are trying to look at this and sort of figure this out. We're not completely sure that the ejaculation frequency is the thing. That's what I have always thought, but we're not seeing that as much in our data. You certainly need to.
I think three months for the guidelines is a very reasonable time and the vast majority of men will have cleared their ejaculates by three months, but this is an analysis we're looking on now and tens of thousands of post-dissecting samples to try to come up with some better data for the field.
[Dr. Jose Silva]
Because I have patients that they do it after three month but they haven't had ejaculations or anything. My wife has been in bed for two months and she had a surgery, haven't done anything, and then it's lower, but still not zero. Definitely, I guess telling the patient more clear instructions will be much better in the future. That data you're going to have in the future will be great.
(8) Redefining Standards in Semen Diagnostics
[Dr. Jose Silva]
Jim, in terms of down the road, you mentioned the different types of molecules that you used to test when you were a student. How do you see the future?
[Dr. James Smith]
I think this for me is one of the most exciting things that we can do. I'll back up a little bit. Fellow really began in this teeny little lab space. It was a startup of startups outside of UCSF. It was in this little incubator space. As we did these thousands of semen analyses, we're building the kit. Eventually we took that technology that we developed through this R&D process and transferred it to a CLIA lab. The first CLIA inspector told us that we had at a 50 square foot little bench that we had the smallest CLIA lab that he'd ever certified.
[Dr. Jose Silva]
Back when you met the founder, there was no CLIA, there was no company yet?
[Dr. James Smith]
There was nothing. No. When I met the founder, I met him outside of UCSF in a cafe. There was just an idea. He's a really bright guy, had been investigating the space, and wanted to do something in male reproductive health. It really came directly from doctors and patients and what are some of the needs that we have as urologists caring for our patients.
[Dr. Jose Silva]
Awesome, and then you went to work?
[Dr. James Smith]
Also that as a team. There were some terrific engineers and terrific folks who really did a lot of the hard work to get this done. It was a pretty expensive process to develop the Fellow kit. I remember back in the beginning, there were exciting ones that did turn into a company, was CLIA-accredited, where Will would tell me and he'd say, "Jim, there were 10 semen analyses this week." That just kept ramping up. Two weeks ago, there were about 450 semen analyses in one day. It's been a really exciting ride.
Where that leads to your question is that what we're able to do really well now is to get a semen sample from any place in the country to one really high quality lab in the Bay Area, in San Leandro, near the Oakland airport. There is a lot of information in a semen sample that we just don't currently have the capability to test at scale. There are certainly molecular markers. Some colleagues have looked for epigenetic markers in semen that perhaps could predict fertility outcomes. Perhaps there are environmental markers, whether it's environmental toxicants or other markers in semen that we could learn about. That's one of the things that I'm excited to do, down the road as the company continues to grow, is to try and develop brand new tests that can actually move the needle for our patients.
[Dr. Jose Silva]
Just like genomics for high-risk versus low-risk, just go straight to this. That would be awesome.
[Dr. James Smith]
That's right. The semen analysis is really helpful to put men into these groups, is this, "Things look generally pretty great. You're low, but okay, you may be able to conceive, get enough time to really low," like IVF may be the right thing, but can we do better than that? Can we do develop better biomarkers that are helping to predict who's going to succeed with your varicocele surgery? We still don't know that terribly well. Going down the road, could we predict something about BPH or other aspects of a man's reproductive health?
I'll circle back around to one of the things that I'm also excited about. When I think about breaking down barriers and access to care, one of my colleagues was very curious about whether or not Fellow would break down barriers and access from an education, income, and race standpoint. This is a colleague of mine named Alicia Tolani. Dr. Tolani is an REI Fellow at UCSF. We have a fertility clinic at our San Francisco General Hospital or County Hospital. She was finding that it was really often very difficult for these patients to get a semen analysis. They couldn't proceed with their REI care until they had a basic semen analysis.
She and I began collaborating and wanted to look to see whether or not there'd be differences in men turning in their kits based on race, education, income. We hypothesized that there would be really big differences. Alicia presented these data at Pacific Coast Reproductive Society just the other day down in Palm Springs and found that Fellow appears to really break down those barriers. That the rates of getting the kit back were 90% or better. It didn't matter whether a person was Black, white, rich, or poor. That really was an exciting finding for us. That's the kind of thing that's really exciting and motivating for me in this new role to be able to try to help our patients that way.
(9) Key Features of the Fellow Kit
[Dr. Jose Silva]
Jim, in terms of the kit per se, can you go through for the others that have never seen the kit? Does it have any ice packs? What does it entail?
[Dr. James Smith] Right. The semen is actually best around room temperature. If it gets too hot or if it gets too cold, then the cells will die at less predictable rates. The kit itself, the full semen analysis kit, is shipped back overnight. This is in contrast to the post-vasectomy sample that is shipped just by ground shipping. You take three to five days for the sample to come back.
The main fertility full semen analysis, that has a gel buffer that's built into the pack. It's basically designed to buffer that temperature around room temperature, not hot or cold. We found that actually impaired the linearity, that drop in motility over time. Again, the main things were keeping that temperature roughly stable. We've tested this extensively in the lab. In the lab here, we have a fancy oven that allows us to oscillate the temperature to mimic what a sample experiences during shipping. We've looked at over 10,000 samples to get a sense of what that range is, and then we're able to test that range on our samples.
The kit itself has a gel pack to buffer that temperature. It has a proprietary preservative that gives enough sperm nutrients to keep the cells alive. We found that was very important too. If you don't have enough of this media, the cells would die. They'd live for a while and then they would just drop off this curve. Also having an antibiotic was another, among several, this was a really important finding. If bacteria clumps and that man hasn't washed his sample, his hand well, gets bacteria in the sample, if there's lots of bacterial overgrowth, that can because clumping of the cells and you can't get an accurate semen analysis reading.
[Dr. Jose Silva]
Curious about that specificity of the antibiotic. You started seeing some clumping in the specimen. Now let's throw in an antibiotic.
[Dr. James Smith]
What we'll see in the lab, so we'll open up a kit and we'll assess, the first thing that we do when the kit arrives in the lab is we assess how long it's been since the man produced the sample. If it's longer than 52 hours, that sample gets rejected and the man just gets a free kit. There are those kinds of delays. Sometimes if there's a blizzard in the middle of the country and the sample's coming from Florida to California. It doesn't happen too much. UPS does a really good job. That's one of the checks.
Another check is to do a quick look. Every sample that comes in, a slide is made and there's a quick manual check. Is this normal? If it looks roughly there's a lot of cells there, then we have an automated approach, a CASA approach to the analysis. If on the quick look, there's not very many cells, then it's a manual semen analysis that we do. That's also the stage where we could tell if there's a lot of bacteria. You could just see all the cells have clumped up. At that point, the damage is done. We would reject that sample, send another kit, just free another kit, and we'd go back out and make sure to wash your hands and produce the sample as sterile or clean as a way as possible
.
[Dr. Jose Silva]
Just to summarize what we were saying in terms of the high-quality lab that you guys are running this test, there's the temperature control that you do it by the gel, there's the nutrients, antibiotics, and also the data that you collected to know the degrade of the cells.
[Dr. James Smith]
Yes, that's right. It's very different at a lab where we average now more than 300 semen analyses in a day. There's no lab in the country, let alone the world, that one lab is doing hundreds and hundreds of semen analyses. As far as our CLIA lab is concerned, we're making sure that everybody has their training up to date, the machines are calibrated regularly, that QC is happening every single day. This is something that really sets us apart from most labs. We are really the busiest lab. Our team is very, very good at doing semen analyses.
[Dr. Jose Silva]
The 52-hour mark was just based on your data?
[Dr. James Smith]
Correct. We looked at it longer than that. We found that linearity, as time went by, we actually looked out to about four days, and it remained linear a little bit longer than that 52 hours. As time went by, either the nutrients disappeared, and it would die, or we could also find the bacterial blooms also occurred over time, but in that 52 hours, it was highly linear decline. We had highly accurate predictability.
[Dr. Jose Silva]
In terms of the patient per se, how long do you tell the patient to be abstinent?
[Dr. James Smith]
Two days usually. Two to five days, kind of the sweet spot. That's something that we'll track as far as the semen analysis goes. We'll ask them how long had they abstained.
[Dr. Jose Silva]
Does it change your variable? Does it change if it's two days or three days in terms of the report or something?
[Dr. James Smith]
Jose, I think that there's some really interesting insights that are going to come out of our Fellow lab to be able to try to answer that kind of a question. What we've built into the whole Fellow experience is every man is asked if he'd be interested in participating in research. He fills out a long questionnaire if he's willing, and we utilize that data to try to answer many of those questions. We've now have submitted or have accepted many abstracts diving into details of male reproductive health. It's something, again, that I'm really excited about. I'm excited to collaborate with partners around the country to be able to answer questions like that.
(10) Population Trends in Semen Quality
[Dr. Jose Silva]
Jim, so in terms of quality, there's mention that quality has been decreasing in the last couple of years or a long time ago. Is that something that you've been seeing or have you been able to study that in your research?
[Dr. James Smith]
I think it's really an interesting question, Jose, and I hope to be able to answer that question. Research is a big part of what we do at Fellow, and we've built research and these kinds of understanding into everything we do. Men are asked to participate in research. Over time, as the sample grows, I'd like to be able to answer your question well. I haven't looked at that yet in the Fellow data.
In general, COVID and other febrile illnesses are bad for fertility. I definitely advise my patients to try to avoid COVID when they can, particularly in that fertility window, but I would like to study that. There's no current national surveillance system for semen analysis, and that's something that I think Fellow might do a really good job at. Easy to get a semen analysis. Imagine could it be built into something like our NSFG, the National Survey for Family Growth. There's no current system like this to assess whether or not there's an epidemic of fertility problems.
[Dr. Jose Silva]
Fever or illness like COVID, is the damage permanent or is there data about it or there's nothing right now?
[Dr. James Smith]
There is data on this and it does not appear to be permanent. Most men tend to recover in three to six months after their illness has resolved. This is a time where I'd repeat the semen analysis. Sometimes I'll see men with a normal semen analysis, then their quality will fall off the map. I'll talk to them and they'll tell me they had the flu. They had COVID and they recover, we repeat a semen analysis three months later and we see that their numbers are coming up. That happens nearly every time.
[Dr. Jose Silva]
Is it decreasing amount in total sperm? Is it motility? Is it the morphology? What exactly do you see?
[Dr. James Smith]
Yes, it can because abnormalities in all three. It can cause the concentration to go down, it can cause more cells to die and so show poor motility so that it can affect morphology as well.
[Dr. Jose Silva]
Do you think in the future we're going to see a different way that semen analysis is reported? It's not going to be the WHO anymore? It's going to be the Fellow report or something?
[Dr. James Smith]
I don't know about that. I don't think the WHO is going to go away. I think that developing this way has broken down huge barriers. I think it's made it so much easier for us as urologists. It helps our staff in enormous ways. It's vastly better experience for patients. Recently I was talking to a colleague, and we were out at dinner and he said, "Imagine if you were to ask a woman to come into your lab and masturbate and produce a sample." If you think about that, that's what we're asking men to do. We're asking them to come and do something that's so personal and so private and usually not talked about all that much. We're asking them, "Come in and masturbate in your office or in your lab." Just something that a Fellow can make so much nicer and better.
[Dr. Jose Silva]
Do you think at some point insurance will be covering this type of kits?
[Dr. James Smith]
I hope so. I think that would be great for our patients.
[Dr. Jose Silva]
Jim, anything else you want to add?
[Dr. James Smith]
It's been a pleasure to chat with you, Jose. Thank you so much for having me on.
[Dr. Jose Silva]
No, likewise. I definitely learned a lot. I said, I use the kit. I'm not seeing that much fertility patients, but definitely for the semen analysis. It's easier for the patient. That conversation while you're doing the vasectomy, the patient asked, and you tell her, "Hey, you need to wait one week to have sex," blah blah, and then we tell her it's going to be three months of protected sex until you do the sperm count. They always ask, "Where do I do it? Do I have to go to a place to do it?" Definitely, with this, that awkwardness, it's much better.
[Dr. James Smith]
Yes. I think that it also, this really just offloads a bunch of that work from the doctor. For me, it means that Fellow is sending text reminders to patients, they're emailing patients. I don't have to burden my staff who's already overworked with this extra task. I know that the Fellow does a really great job and patient does in the comfort of his home. That's been a real huge win for me in my practice.
[Dr. Jose Silva]
It has. It has. It really has. Jim, thank you for being Backtable.
[Dr. James Smith]
My pleasure, Jose. Thank you so much for having me on.
Podcast Contributors
Dr. James Smith
Dr. Jim Smith is a reproductive urologist and clinical professor at UCSF in San Fransisco and the chief medical officer at Fellow Health.
Dr. Jose Silva
Dr. Jose Silva is a board certified urologist practicing in Central Florida.
Cite This Podcast
BackTable, LLC (Producer). (2024, May 14). Ep. 167 – Solving Semen Analysis Barriers: Innovation & Accessibility [Audio podcast]. Retrieved from https://www.backtable.com
Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.
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