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A

Welcome to the Huberman Lab podcast, where we discuss science and science based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is doctor Michael Eisenberg. Doctor Michael Eisenberg is a medical doctor specializing in urology and an expert in male sexual function and fertility. He is both a clinician who sees patients as well as a research scientist, having published over 300 peer reviewed articles on male sexual function, urology and fertility. And he is considered one of the worlds foremost experts in male sexual health. Today we discuss a broad range of topics important to all men, including erectile dysfunction and function. We also discuss prostate health and urinary health. We discuss fertility and sperm count. We discuss even topics seemingly esoteric, such as why penile lengths are actually increasing over time while sperm count seem to be decreasing today. You'll also learn some very interesting surprises, such as the fact that a very, very small percentage of erectile dysfunction actually stems from hormone dysfunction. Rather, the vast majority of erectile dysfunction stems from issues that are either vascular, that is related to blood flow, or neural. And today you'll learn about a large variety of treatments for erectile dysfunction. Doctor Eisenberg also dispels a lot of common myths that you hear out there, both on the Internet and in popular culture, that relate to male sexual health and function. By the end of today's episode, I assure you that you will have a thorough understanding of what male sexual health is, how it relates to other aspects of health, and how to think about treating, maintaining and improving aspects of male sexual health, fertility and function. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is element. Element is an electrolyte drink with everything you need and nothing you don't. That means plenty of salt, magnesium and potassium, the so called electrolytes, and no sugar. Salt, magnesium and potassium are critical to the function of all the cells in your body, in particular to the function of your nerve cells, also called neurons. In fact, in order for your neurons to function properly, all three electrolytes need to be present in the proper ratios. And we now know that even slight reductions in electrolyte concentrations or dehydration of the body can lead to deficits in cognitive and physical performance. Element contains a science back to electrolyte ratio of 1000 milligrams. That's 1 gram of sodium, 200 milligrams of potassium, and 60 milligrams of magnesium. I typically drink element first thing in the morning when I wake up in order to hydrate my body and make sure I have enough electrolytes. And while I do any kind of physical training and after physical training as well, especially if I've been sweating a lot, if you'd like to try element, you can go to drink element. That's lMnt.com Huberman to claim a free element sample pack with your purchase. Again, that's drinkelement lmnt.com Huberman Today's episode is also brought to us by waking up. Waking up is a meditation app that includes hundreds of meditation programs, mindfulness trainings, yoga, Nidra sessions, and NSDR non sleep deep rest protocols. I started using the Waking up app a few years ago because even though I've been doing regular meditation since my teens and I started doing yoga Nidra about a decade ago, my dad mentioned to me that he had found an app turned out to be the waking up app, which could teach you meditations of different durations and that had a lot of different types of meditations to place the brain and body into different states and that he liked it very much. So I gave the waking up app a try and I too found it to be extremely useful because sometimes I only have a few minutes to meditate, other times I have longer to meditate. And indeed, I love the fact that I can explore different types of meditation to bring about different levels of understanding about consciousness, but also to place my brain and body into lots of different kinds of states depending on the which meditation I do. I also love that the waking up app has lots of different types of yoga nidra sessions. For those of you who don't know, Yoga Nidra is a process of lying very still but keeping an active mind. It's very different than most meditations, and there's excellent scientific data to show that yoga Nidra, and something similar to it called non sleep deep rest, or NSDR, can greatly restore levels of cognitive and physical energy, even with just a short ten minute session. If you'd like to try the waking up app, you can go to wakingup.com huberman and access a free 30 day trial. Again, that's wakingup.com huberman to access a free 30 day trial. And now for my discussion with Doctor Michael Eisenberg. Doctor Eisenberg welcome.

B

Thank you. Good to be here.

A

I've been looking forward to talking to you for a long time, because these days, we hear a lot about the diminishing quality of sperm, which in some way seems to be tacked to the conversation about diminishing quality of environment, people intelligence. There's a lot woven into this statement that sperm quality is declining. And some of it, I think, people assume, is related to environmental changes. Some of it, I think people assume it, are related to changes in behaviors. So maybe less exercise, less sunlight. Who knows? Hopefully, you'll tell us what's really going on. But the first question I have is, is sperm quality actually declining? And regardless, what is sperm quality?

B

Yeah, great question. So I think it's very controversial, I think, as your question alludes to. So I think we'll start by just talking about what sperm quality is and why it's important. So, for reproduction, as you've covered on the podcast before, a man makes semen and that has sperm in it. And so when we're talking clinically about a semen analysis, there's a few things we look at. We look at the amount of ejaculate semen that comes out. We look at the sperm, how many there are. We look at their motility or movement. We look at their morphology or shape. There's some more advanced testing that's done, in rare cases, looking at fragmentation of DNA, for example. Or there's some newer tests looking at epigenetic profiles of sperm. But essentially, these are all markers of fertility. Fertility in itself is a team sport. It's hard to label a man as fertile or not fertile without knowing about his partner. But nevertheless, based on these different parameters, we try and quantify how likely a man is to be able to achieve a pregnancy. The World Health Organization, every decade or so, looks over the existing literature and defines these different cut points of what's normal or what's subfertile for those levels. So that's sort of the backdrop of what Siemen is and how these tests are done or what these tests represent. Now, the question of whether they've declined over time has been a question for a number of years. There was a landmark paper in the early nineties by Carlson in a group in Denmark that showed this temporal decline over the last 50 years from that time point. And so what the investigators had done is looked over the literature for studies that reported semen quality around the world and noted that the quality in the earliest studies, like in kind of the mid 20th century, were here and then over time they had sort of declined the more recent studies. Now, that study was very controversial. There was questions about waiting from different studies putting, because you can imagine there's not a lot of early studies, so putting a lot more importance on those rather than some of the later ones. And so since then, there's been many other studies that have come out in time, and even today it remains very controversial. I think if I were to say that I believe there's a decline, some of my colleagues and friends would be very upset with me. If I say I don't believe it, some of my colleagues and friends would be very upset with me. So I would say that my opinion really varies based on whose paper I've read. And there's some very convincing studies on each side of it. Most recently, just in the last year or so, there was a meta analysis of tens of thousands of men where they looked at, again, a host of these studies over the last number of decades all around the globe. Prior studies have really just focused on the western hemisphere, western countries, because there was more data from that. But more recently, we've gotten a lot of data from Africa, from asian countries as well. And those also support this decline. So one of the counter arguments to why we're seeing that is just sort of an evolution of techniques over time. So that's one of the sort of the popular questions about whether there's really a true decline. You know, I think, as you're alluding to, why there would be a client is also, you know, unknown. And but you've sort of labeled perfectly the most common hypotheses. So whether some environmental exposures, a lot of things have changed over the last 50 years. And I think chemical exposure is certainly one of those. And there have been some fairly convincing preclinical studies, so mostly done in animals, that show that exposure to different chemicals, phthalates, BPA, other things, may actually harm reproductive function for men and for women as well. It may be that these chemicals that we're being exposed to as kids and adults, or even probably more sinisterly, when we're developing in utero, that may be the most harmful exposure. But there's also been an obesity epidemic as well. And there's a strong link between man's reproductive function and body weight. And so that's also thought to play a role in some of this, too. So I think there are convincing studies. But the other, I guess, aspect to this is that there's variations in semen quality around the country and around the world. There's geographic variation. And so that's also sort of an unknown explanation. There could be different genetic compositions of men, and so there's different reproductive potential in that source. There could be different environmental exposures, diet, exercise, lifestyle. There's a famous study done a number of years ago where they looked at semen quality among fathers. So these are men that had achieved a pregnancy. And at the first prenatal visit, they had the fathers give a semen sample. And so this was done four centers around the country. I think one in California, there was one in the midwest, there was one in New York. So they basically found that semen quality was sort of highest in the urban centers in New York, tended to be the highest numbers where it was lower in the midwest. And so the hypothesis was potentially because it was a more rural setting, maybe there was pesticide exposure, and that had led to these lower numbers. But another equally plausible explanation may be that sort of a different population and maybe that could explain these differences. So I think it's very important, and I think one of the sort of lacking things in this is there's not really longitudinal data. One of the greatest things would be if we just started tracking semen quality around the country, just like we do obesity, like NHANEs, CDC's survey of health in the US. If we added semen quality onto that, that way you could really see how it varies around the country and sort of compare. Like to. Like to see over time if there's really this progression. You know, one of the only studies to do that in Denmark that started around, you know, around 2000 and tracked semen quality among volunteers that came in when they were conscripted for military service in Denmark. They were offered the opportunity to participate in this study. And so some men did. And what they found is actually the semen equality was fairly uniform over about 20 years where they had data. But sort of another very interesting part of that study is that only about a quarter of those men had normal semen quality. So sort of very concerning. You know, it was, I guess, reassuring that it wasn't further declining, but very concerning that only a quarter of danish men had normal semen quality. And they're one of the, I think, thought leaders in this field, just because sort of a reproductive crisis there.

A

You mentioned that some of this apparent decline in semen quality might be related to the fact that the tools to measure semen quality are getting better and better. That would make sense if, for instance, one is just looking at total volume morphology, which means shape. I should have clarified that. How many forwardly motile sperm there are. And then also adding in a very sensitive measure, such as DNA fragmentation, essentially, as the instruments get finer and finer, you discover more and more details. And if you are rating quality along a number of different dimensions, then it would make sense that those would tear out into different levels. If one were to simply ask for couples who want to get pregnant. And assuming that egg quality is not the issue, what percentage of failures to achieve successful pregnancy are the consequence of deficient sperm? Deficient in any way? And is that number increasing over time?

B

Yeah, so I think that's really key. I think when couples think about fertility, usually it's thought of as a female problem, and I think there's just historic reasons for that. If you look at data in the US, when couples do seek care for fertility, the man is bypassed probably a third of the time, even though when you look at the reasons for infertility, man contributes probably half of the time to infertility. So I think there's a half. Half? Yeah. So I think there's a huge need just to understand and evaluate the man. And one of the reasons for this, I think, is that one of the main treatments for infertility in the US is IVF, which is very powerful. I think one of the greatest marvels of medicine in probably the last quarter century is our ability to mix a sperm and egg in a dish and create a life. It's really remarkable. But because it now takes just a single sperm through something called intercytoplasmic sperm injection, where you can inject one egg or one sperm into an egg, the bar has gone down dramatically for couples just trying without any assistance. Probably need 20 to 40 million moving sperm. But now, with these remarkable techniques, you just need one sperm. Because of that, I think a lot of our innovation and research on male fertility has probably gone to the wayside, just because clinically we just need a few dozen sperm for most couples.

A

What about testosterone levels? Are those also declining? We hear this, and when I look at the literature, I can find evidence for that. But the question is also whether or not the amount of decline in testosterone levels is significant in a way that impacts, let's say, fertility, but also vitality in other ways, energy, mood, sexual health, et cetera. What's the story with testosterone levels? Are they indeed declining on average across the male population in the US and elsewhere?

B

I think there is pretty convincing evidence that that is happening, and I think the reason for that, again, is probably not certain. But there have been some pretty nicely designed cohort studies where they recruited men in the two thousands, the nineties, the eighties. And you can see that depending on when these men are recruited, just matching age for age, these testosterone levels tend to be lower. And then NHANes, which is, again, this sort of longitudinal study run by the CDC that has also shown, looking at testosterone levels over decades, the testosterone levels have declined over time. Chemical exposure is one possible explanation, again, either an adult or adolescent life or in utero. But obesity, I think, is also a convincing explanation, is we're more sedentary, we get bigger. That's one of the places that testosterone can decline. I think there's different explanations for that. You know, is testosterone produced, it's aromatized in peripheral tissue, you know, in fatty tissue. Fat has a lot of this aromatase. So that converts testosterone to estrogen. So it necessarily, you know, lowers the testosterone level that's circulating in our body. Also, just insulating the testicles or thighs get bigger. Insulating the testes can also sometimes lower the efficiency of production a little bit, too.

A

Because of heat effects.

B

Because of heat effects.

A

I was going to ask about this later, but I'll ask about it now since we're talking about heat effects and sperm and testosterone. The heat, of course, being not good for sperm health and testosterone, which is. I've read a meta analysis. I don't know how high quality it is, but that explained that there is some evidence for either heat effects or possibly non heat related effects of cell phone, smartphone in the pocket, impairing sperm health, maybe even testosterone levels. Now, you hear this more often in biohacky, I don't know, circles, which I'm not a fan of the word biohacking. It's not clear what it means to. It sounds like it means something about taking a shortcut, using one thing for a purpose. It wasn't intended. But it also makes sense to me that a smartphone could generate some heat, some radiation that might impair testicular function and therefore impair sperm quality or testosterone levels. But is there any real solid data that carrying your cell phone in your pocket, let's assume on that the cell phone is on, is bad for sperm health or testosterone levels?

B

Yeah. So I think there's not convincing evidence that it's going to help testosterone levels.

A

I think that it's going to hurt testosterone.

B

It's not going to hurt. Yeah. So I should make clear that I think that in terms of production and heat effects, sperm production is much more sensitive than testosterone production. But there have been some studies looking at cell phone exposure, because, again, you're getting this. Whether it's heat whether it's the radio frequency waves coming in, I think you could posit different explanations of why that may be harmful. There have been some studies that looked, early on, men that used cell phones more or less. They had lower semen quality if they used it more. But you can also imagine there's huge differences in men that do and do not use cell phones. It's a hard experiment to design, but there have been some studies doing this in vitro. So in the laboratories of taking, you know, sperm in a cup, basically, and putting a cell phone next to it or not next to it to try and see if that played a role, there have been studies done where they sort of normalize the heat. You know, they kind of put it on sort of a special stage so that it's not heat necessarily, but maybe it's rf exposure. So those studies, I think, don't show sort of a clinically meaningful change. But there have been some studies that say that maybe DNA fragmentation of sperm can go up a little bit if there's close proximity to a cell phone. So I think when patients ask me that, which is a common question, I get in clinic, obviously, patients are coming in. They want to do whatever they can to try and improve their chances. Generally, I think the data is not convincing. But if it's easy enough, certainly, to be aware of it, I think putting a laptop on a desk rather than in your lap, I think for heat exposure is probably the biggest thing that we want to minimize.

A

About a year and a half ago, I did an episode about testosterone and estrogen, where it's manufactured in the male and female body, et cetera. And I found a very interesting graph in a textbook on behavioral endocrinology by a guy named Randy Nelson, who I happen to know through the field of behavioral endocrinology as it's typically studied in animals. So most of that book centers on animal studies, but there's a fraction of the studies that center on human data. And there was a very interesting graph that showed testosterone levels as a function of age in males. And as one might expect, testosterone levels were, on average, much higher in late teens, early twenties, thirties, and there was a progressive decline. But what was remarkable to me about that graph is that even when exploring the scatter plots, because they showed individual points, they didn't just show the averages of testosterone levels in men in their fifties, sixties, seventies, eighties, even nineties. There were these outliers, these guys who had testosterone levels that were on par with testosterone levels of men in their thirties, but these guys were in their fifties, sixties, seventies, eighties, even nineties. Do you observe this clinically? Do you observe that men are coming in who are older than 40 and have testosterone levels and presumably free testosterone levels as well, that are still very high? The reason I ask is, I think we've all been told, and we presume that testosterone levels decline with age, and one would expect some outliers. We don't know whether or not those guys in their nineties who have the testosterone levels that match the averages of men in their thirties didn't have even greater testosterone levels in their thirties. But given that they were ceilinged out around 900 nanograms per deciliter toward the high end normal, depending on the scale already at age 90, it's kind of hard to imagine that earlier they were walking around with 2000 nanogram per deciliter testosterone. Do you see this? Is there just a lot of natural variation in testosterone levels of men who walk into the clinic at any age? And, of course, what is special about these individuals that are maintaining high normal testosterone levels into their later years?

B

Yeah, that's a great question. I think this is such a common question. Anytime we talk about testosterone, I think anytime we talk about most clinical tests that we do, what is average, what is normal? So we do see great variation, just like you're saying. I usually let everybody know that usually testosterone peaks kind of early twenties, and it tends to go down probably 1% a year forever. But there are people that have very, very high levels. Just mirroring that graph that you describe. I certainly have patients, we screen for testosterone levels when patients come in with complaints or we're worried about that low energy level, low libido, some of the symptoms of low testosterone sexual dysfunction. And, you know, to my surprise, sometimes these men, you know, I've seen 80 year olds that certainly have the highest testosterone level. I'll see, you know, for six months. You know, why that is, I think is not certain. Maybe it has to do with, you know, I would think with everything. There's probably sort of a bell shaped curve and everybody's a little bit different. But androgen sensitivity, you know, sensitivity of the receptor, you know, they make it more efficiently. But I have not really noticed, again, because at least in clinical practice, when patients come in, they come in with a complaint. And so even men with very high levels, they may have some of the same dysfunction, men with low levels. So I think with low levels, you can try and treat that, and that may be the solution. But for men with these, what we would consider high levels, there may be other issues. Going on?

A

Let me frame the question I was going to ask a little bit differently. When someone comes into your clinic and you measure their testosterone levels, as you mentioned, they're likely coming in because they have some issue, prostate issue, sexual function issue, et cetera. But you do get a read on their crude morphology of their body, you could visibly determine whether or not they're likely to be obese or not, regardless of age. Earlier, you mentioned obesity as a risk factor for lowering testosterone and sperm quality. You mentioned that fat aromatizes testosterone into estrogen. So that's at least one mechanism by which that could happen. But if you were to just step back and say, okay, if somebody who walks into my clinic tends to be, let's say, healthier looking, not obese, let's just put the cut off at what you would presume is obese, is there a higher probability that their testosterone levels are going to be within normal range? Conversely, when somebody walks in and they're obese, do you fully expect their testosterone levels to be subnormal, or are you sometimes seeing obese people walking in with high testosterone? And the reason I'm asking this is not to create confusion, is that I think that everybody out there who's thinking about sperm quality and testosterone levels and this apparent decline, trying to figure out, okay, what can we do in order to maintain the health metrics that are going to, of course, increase fertility? But for those that don't want to have kids or who already have kids, are going to at least maintain or improve vitality? Is obesity really the thing to avoid? So is there not one for one, but is there a tight correlation between obesity and testosterone levels?

B

I would say that you cannot predict. I think that sort of would be the take home. And so I think that more information is always better. When I see patients in clinic. Some patients are walking around with, everything is totally normal, and they're very healthy. All the numbers come in at the normal range. But sometimes when men look totally normal, they talked about taking care of their life. They exercise five, seven days a week. Their testosterone levels can be very low. So even despite having what we would consider should really give them symptoms, they're able to compensate. Maybe they've lived their whole life and that they don't know what normal is. Now we get them to sort of normal levels. A lot of times they feel better again because they had no idea how they should feel. But I think that that's just sort of important, that everybody should be screened. I think that testosterone semen quality there have been shown to even be barometers of health. So men with lower testosterone levels have higher risk of heart disease, diabetes, mortality. The same studies exist for semen quality as well. Again, they may have sort of a similar relationship and explanation why that may be. But I think it's hard to just predict, based on appearance what testosterone will be, what semen quality will be, what testicular function will be, without actually getting some objective data. Actually, if you look at the trend of semen quality decline over time, getting back to some of those earlier points you're making, if you were to overlay that on the known association between obesity, its effects on semen quality, that actually doesn't explain the whole decline. The purported decline in semen quality is about 50%. But if you were to say, well, what would we expect? If we look at. Because we were able to track exactly how much fatter we are now than we used to be, that actually only explains about a 10% decline. So I think there is, to your point, something more, and it is not something that you can just identify by high.

A

What are the do's and don'ts as it relates to? I don't want to use the word optimizing. It's gotten me into trouble before, because the word optimize or optimal suggests that there's a perfect number that one should all attain if possible. But in reality, optimal is a day to day thing at least. But what should people avoid in order to get their sperm quality as high as possible, their testosterone level? Again, here I have to be careful. I don't want to say as high as possible, because some people might not want excessive androgen. But at the high end of normal, perhaps would be the ideal for many people. What should people do? What should they avoid? And here I'm setting aside any prescription clinical treatments such as testosterone injections or things like human chorionic gonadotropin, things that we can talk about a little bit later. But what should every male be doing in order to optimize these health parameters?

B

Yeah, so I think that there are some risk factors that we do. Like, we'll start with semen quality. So we talked about heat. I think that's a big one. So, like hot tub saunas, try and avoid those. Some light data on sea warmers. Anytime we kind of get this external heat source to the scrotum, you know, the testicles are outside the body because they need to be a little cooler. So anything that warms them up can certainly be a problem.

A

Could I just briefly interrupt there to ask? We've done episodes on sauna and some of the health benefits of sauna. Is it sufficient for somebody to bring in a cold pack to the sauna and put that in their groin? I actually have suggested that that's actually what I do when I go into the sauna, and I have suggested this on podcasts, not just for people who are trying to conceive, because it seems like heat, as you mentioned, is bad for sperm, not quite as bad for testosterone levels. But is it also true that heating the testicle too much is generally bad for endocrine function in males? And therefore, if one is going to go into a hot sauna for 20 minutes or more to essentially cool the scrotal area.

B

Yeah, I mean, I think the spermatogenesis or sperm production is certainly a lot more sensitive. Whether you can thwart the effects of external heat with a cooling pack, I think it makes sense. There are studies that have looked at different ways to cool the scrotum and have compared, you know, semen quality before and after. And there's some data that may help. It gets depends how long you're gonna spend in the sauna and how cold, you know, that pack is gonna remain.

A

So ice pack and in the sauna for 20 to 45 minutes.

B

And is the ice pack still cold afterwards?

A

Yeah, yeah, they actually sell. And by the way, I have no relationship to any of these companies, but they actually sell cold packs that are designed to be worn in your shorts. So if you go to a. You know, I'll go to a russian banya every once in a while now, I guess I'm outing myself. Yes, I have a. Yes, I have a cold pack in my shorts when I go to the russian banya. But they have sort of an insulation so that the very cold surface is cold enough, but it's not right up in contact with the scrotal skin, because that could get. I want to make a bad joke and say it could get sticky, that situation. You don't want it being so cold that it actually would stick to the skin, and then it could potentially damage the skin when you're trying to remove the cold pack. So it has a thin, insulating layer, and. Yeah, that's essentially what it is.

B

Yeah. I mean, frostbite to the scrotum is not theoretical. It could certainly happen. So you do want to be careful. So, I mean, in theory, that should be adequate to sort of, you know, to decrease the risk of that particular effect. You know, I keep coming back to health, how important that is to maintain, you know, adequate sperm production, because I think these two are very linked. You know, there have been studies that show that men with more comorbid conditions, so obesity, hypertension, hyperlipidemia, as these sort of stack up, we see a decline in testicular function. So lower testosterone levels and lower sperm quality. So I think taking ownership of your health, I think, is important as well. A lot of times, fertility tends to be one of the first touch points that some men have with healthcare, because generally, what brings men to the doctor, it's usually pain or kind of a problem. So if men are in their twenties and thirties, getting ready to start a family or forties, and in some cases, sometimes they haven't seen a primary care doctor. So some of these things, some of this relationship has not been established yet. So I think thinking about ways to start that I think would be important, too. And then I know you don't want to talk about testosterone, but testosterone is actually a fairly common problem that we see in fertility clinics. I would say that estimates say maybe about one in 20 infertile men are that way because of testosterone. So I think when people get testosterone from different places, and hopefully whatever provider you're getting it from tells you that one of the side effects of this is lower sperm production, it's actually been tested as a contraceptive and with some other agents, it can actually be fairly effective. We just want to make sure that if men are starting testosterone, they're doing it for the right reasons and they're doing it safely.

A

I think about testosterone replacement therapy, although, as we were talking about before we started recording, I am really on a push now to rename what people call TRT, testosterone replacement therapy, because indeed, some people have low testosterone and need it replaced, the R and TRT. But I think what you're referring to, if I'm not mistaken, is that there are probably millions of young men and older men taking exogenous testosterone injections, creams, pills, pellets, any number of nasal sprays, now, any number of different routes of delivery of exogenous testosterone. And that dramatically reduces one's endogenous testosterone production and dramatically reduces one's sperm count and maybe even quality. We'll maybe talk about this a little bit later, but maybe even I've been told that it can perhaps introduce a DNA fragmentation within the remaining viable sperm as well. Do I have that? Craig? You're saying that you see one in 20 men have issues with fertility because they are taking testosterone, so their testosterone levels presumably are going to be high end normal or more, but they are doing presumably not testosterone replacement therapy, but they're doing what I call testosterone augmentation therapy, meaning they were somewhere in the 300 to 900 nanograms per deciliter range, but decided to start taking testosterone anyway, and then their sperm count essentially diminishes to nil or close to it in some cases.

B

Yeah. So, I mean, I think there's various reasons that you would take testosterone. I think some people have been treated years ago, and so they do need to replace testosterone, but some people do it for augmentation. I just usually say testosterone therapy just so it's correct.

A

You kill the r. I like that. That's better than the t at, which doesn't sound very good. Just testosterone therapy.

B

Yeah.

A

Okay.

B

But if you had, you know, for example, if we take 100 of my infertile patients that come in to see me in clinic, at least five of those men will be infertile because they're on testosterone therapy. And some of them do have that suspicion. They say, I'm going to level with you. This is why my levels are probably low. But a lot of men were not told that when they started therapy. So I think certainly for reproductive aged men, that's a very important conversation to have because there can be some other ways that we maintain sperm production. I think sperm cryopreservation is a good option for these men as well. Or there may be other therapies they can think about just because of reproductive toxicity.

A

What about hcg? Human chorionic gonadotrope? I hear about a lot of people who go on testosterone therapy who take hcg every other day or so. Typically the dosages that I hear about, because people write to me about this stuff all the time.

B

Really.

A

It's one of the most commonly asked questions. I get many questions about many topics, but I would say a full ten to 20% of them are about penises or testosterone. Those are perfect then, right? Exactly. A number of those guys who are taking testosterone will be prescribed hcg to stimulate sperm production, endogenous sperm production to maintain healthy sperm, presumably because they either want to conceive or intending to conceive in the future. Is that the best line of treatment for maintaining fertility while people are taking testosterone therapy?

B

Yeah, that's one of the therapies that we use and I think it can work well. You know, just a low dose usually. Again, for those that know, 500 to 1000 units every other day is usually adequate.

A

I'd like to take a quick break and acknowledge one of our sponsors, athletic greens. Athletic greens, now called ag. One is a vitamin, mineral probiotic drink that covers all of your foundational nutritional needs. I've been taking athletic greens since 2012, so I'm delighted that they're sponsoring the podcast. The reason I started taking athletic greens, and the reason I still take athletic greens once or usually twice a day is that it gets me the probiotics that I need for gut health. Our gut is very important. It's populated by gut microbiota that communicate with the brain, the immune system, and basically all the biological systems of our body to strongly impact our immediate and long term health. And those probiotics and athletic greens are optimal and vital for microbiotic health. In addition, athletic greens contains a number of adaptogens, vitamins and minerals that make sure that all of my foundational nutritional needs are met. And it tastes great. If you'd like to try athletic greens, you can go to athleticgreens.com huberman and they'll give you five free travel packs that make it really easy to mix up athletic greenshouse while you're on the road, in the car, on the plane, et cetera. And they'll give you a year's supply of vitamin D, three, k, two. Again, that's athleticgreens.com huberman to get the five free travel packs and the year's supply of vitamin D, three k, two. So if somebody is not taking testosterone exogenously, they gotten their body fat level down to a point where they're not considered obese. So they're hopefully doing some cardiovascular exercise each week, maybe doing some sport or some resistance training too, with the intention of maintaining all around good health, stave off cerebrovascular cardiovascular issues. What are some of the other don'ts? I'm going to assume that smoking cigarettes or vaping cigarettes is bad. Are there any studies that have looked specifically at vaping and sperm quality or testosterone levels? And is there any evidence that smoking cigarettes is good for testosterone levels or sperm production? Because I'm guessing the answer is no. I feel like nowadays we just say don't smoke, but the data are the data. Who knows? Maybe nicotine can help sperm. I have no idea.

B

Right. It's possible. I don't think we have the data on that yet. But yeah, I mean, I think to your point, I think lifestyle factors are certainly a big one and some of these potentially kind of unhealthy habits. So smoking is certainly something you should not do. There have been lots of studies that do link that to lower quality. Again, all the different measures that we look at. Also looking at fertility, these men tend to have a longer time to get pregnant. Alcohol, I think, is another very common question we get asked as well. And I think for that, there's, I think, less of a strong association that we've seen. So there have been some studies that show that very high levels of alcohol. And I guess that's sort of subjective, what some would consider higher or not. But when you get above maybe 20 drinks a week, there have been some effects.

A

But usually a lot of drinking, I.

B

Would think that's a lot. Yeah, but some people don't.

A

But, yeah, I did an episode on alcohol. I think anything more than two, I know people are going to balk at this, but I think any more than two drinks per week is where you start to see some negative effects on some health parameters. But I'm not a teetotaler.

B

Yeah, but when you get to this 20 drink, that's when we started to see some effects on semen quality. But the thing about that is that usually if these men are drinking 20, they're doing other things, too. Smoking. There can be other drug use as well. So it's hard to tease that out. But in general, that's, you know, I think certainly anything in moderation is probably, you know, it's probably better. And so that's how I counsel patients. I think, again, it's very rare that I see men that are at that level, but I certainly let them know when I do. There's some new data coming out of that we've started to work on looking at if there are different sensitivities to alcohol. So some East Asians have a mutation that leads to flushing. And so that may put those men at higher risk when they mix alcohol. We may see some slightly lower sperm parameters.

A

You mean skin flushing because they don't make alcohol dehydrogenase is the idea. Yeah, I've heard about that in asian cultures. Is there an asian population? Excuse me, but is there any evidence that other populations might have slight variance on alcohol dehydrogenase? That perhaps, maybe they don't lack it altogether, but they have. I don't know. They're hypomorphs for whatever gene makes alcohol dehydrogenase, and therefore they don't metabolize it as well. And therefore the toxic form of alcohol is active in their system longer. Is there any evidence for that?

B

No, I think you're exactly right. I mean, I think the one that we think about is east asian cultures where it can be depending on the region, like chinese, taiwanese. Probably about 40% to 50% of the population has mutation in the ALDH two gene, but other populations in people with african ancestry, there's a rate of mutation, I think. I'm not going to remember the exact percentage, but I think a few percentage points. Some individual with hispanic ancestry, ashkenazi jewish ancestry. In this particular gene, there's a mutation, not the same one that East Asians have. But again, I think it gets to why a mutation where we see negative effects would persist, and the hypothesis that millennia ago potentially gave some benefit for maybe an infectious disease or something similar to cystic fibrosis. Why again, this mutation would persist in our population if there's not some advantage to those carrying it. But we do see in other men as well. So I think if it's a simple question, do you flush? If you flush, then maybe alcohol may have more of a harm than someone else. And then getting along the lines, I think drug use is also something that we should try and we do counsel patients about because that can also negatively affect semen quality.

A

Do you think it's fair to say that, okay, moderation is best, but if somebody had the option to either not drink or drink in moderation that they should not drink, would that be even better? Is there any evidence for that? I mean, it seems like nowadays we take the stance that not smoking at all is better than smoking a little bit, actually. When I was a postdoc at Stanford from 2005. Yes, 2005 to end of 2010, you could still smoke on the Stanford campus. I'm not a smoker, but there was this collection of. I have to be careful what I say here. There was a particular group on campus of postdocs and graduate students that would, you know, that would colonize this little area outside the hospital and smoke, because that's where you could smoke. That was eventually eliminated as a possibility. You can't smoke on Stanford campus, as far as I know. But they would smoke right outside the hospital. Actually, a lot of the hospital workers would take a cigarette on their break. This is very common irony.

B

Yeah, exactly.

A

Yeah. And this was common all over the country.

B

Right.

A

This isn't unique to Stanford, but nowadays you just don't see that because it's not allowed. And we hear don't smoke. It's terrible for Xyz and every other letter of the Alphabet. With alcohol, we tend to hear that if you're going to drink, drink in moderation. It's not clear exactly what number that is. But is it possible that zero alcohol is better for sperm and endocrine health than any alcohol? Or is that not a fair assumption?

B

I mean, I think that's a good question. I think your point about tobacco is an excellent one, because I think any smoking is bad, but alcohol, I think we don't have that data for yet. And so I think it's harder for me to make that recommendation to patients, especially because people do it for different reasons, and if it's not necessarily gonna help them, it'll harm them in social situations or other things. Yeah, I usually give the. The moderation one. Unless, again, for the very high drinkers. I definitely talk about that.

A

You mentioned other drug use. I'm going to assume that unless prescribed for post surgical pain or something like that, that benzodiazepines, heroin, opioids of any kind, are just bad for sperm and testosterone. I think that we could probably make that a short discussion. Yeah, I can't imagine any of that would be good for reproductive health.

B

Yeah, that's true. I mean, there's. Again, you'd imagine, or maybe not, but there's not a lot of data on it. It'd be difficult to enroll or maybe easy to enroll, but a lot of those studies have not been done, but there's limited ones of people in rehab where they have shown these associations with addicts or users and lower quality. So, yeah, that's how we talk to patients.

A

What about cannabis? I did an episode of this podcast about cannabis, and I did highlight some of the medical applications of cannabis. I also highlighted that very high THC cannabis may predispose, especially young males, to later psychotic episodes. There are more and more data coming out about that all the time. I got a lot of flack for saying that, but that's my take on the data. And I know a lot of people use cannabis recreationally and in a kind of pseudo therapeutic way. I say pseudo therapeutic because I think a lot of people use cannabis to manage their anxiety and as an alternative to alcohol for a number of reasons. What is the relationship between cannabis use and testosterone and sperm production? Or I should say sperm quality? Excuse me.

B

Yeah, so this is also a very common question. Again, with this wave of legalization across the country, I think more and more men and women are exposed to it. So again, there's data that the more men are exposed to it, it can lead to some harm in terms of sperm morphology and sperm numbers as well. One of the landmark studies was about 1200 men, and it found that men that use cannabis daily had significantly lower concentration, motility, morphology compared to those that didn't use it. So I think that's generally how men are counseled. But there's also other data that shows really a null effect. It goes into probably the composition, how men are taking it, the frequency, because a lot of that data is not well teased out in a lot of these studies. So I think I sometimes struggle with this with patients because some of them are taking it for some, what they consider legitimate reasons, anxiety, sleep, pain. And if there's not very convincing evidence that it's going to help, and they're taking it maybe lower than the threshold, where I know that there's good data that'll cause harm, I guess I'm trying to be sort of honest about where we are, but I think with a lot of things related to sperm, I think our level of evidence is not great.

A

Are there any common over the counter medications that can negatively impact sperm quality and or testosterone, things like nonsteroid anti inflammatory drugs, tylenol, advil type stuff, ibuprofen, acetaminophenous, things of that sort that I and others might not be aware of? I'm not probing for anything in particular here. I just. I know that a lot of over the counter drugs have effects that we're just simply not aware of.

B

Yeah, I mean, I think we probably need more data, but I think currently we think all those are safe.

A

I'm curious about the pituitary. Pituitary gland, as many listeners of this podcast already know, is a gland that receives signals from the brain. The gland sits near the roof of the mouth. I think that's fair. And releases critical hormones into the bloodstream that control the output of testosterone from the testes, as well as output of hormones from other glands. I know a number of people end up playing sports, like football or rugby, or even lacrosse, or even soccer. I've readdeveloped. There are data on this. You know, they're heading the soccer ball quite a lot, or martial arts, or they get a head injury at some point. And I certainly hear a lot from people who played these high contact sports, and then to their surprise, later, they have diminished testosterone levels. I also work with a number of military groups that talk about this. You know, that they leave, and maybe it's from combat related stress, et cetera, but they wonder whether or not there's any traumatic head injury or maybe pituitary injury related impairment to the reproductive axis that includes brain, pituitary, and the testes. Do you see that? And if somebody played a contact sport, in particular, a contact sport where the head was hit, or they were hitting things with their head often, or if they have a TBI or had a TBI that their reproductive health can be impaired.

B

That's fascinating. I have not. I mean, I think it's interesting, I guess, what the pituitary does, you've obviously covered this before, but it does go to a lot of our therapies for your listeners. That pituitary produces two hormones, LH luteinizing hormone and FSH, follicle stimulating hormone, which then stimulates the testicle. So the luteinizing hormone stimulates the leydig cells to make testosterone, and then the follicle stimulating hormone, or fsH, stimulates sperm production. So both of those are very key in terms of production. And interestingly, when exogenous testosterone is used, it shuts down that axis, as you know. So we get less of these gonadotropins, this LHFSH, to stimulate the testicle. And the other sort of reason that sperm production is lost with exogenous testosterone use is actually the intertesticular testosterone is much higher than serum levels. So, you know, our serum levels are between 309 hundred nanograms per deciliter on average. But in the testicle are probably tenfold higher, at least. So when men are given exogenous testosterone and they're not producing their own, the levels of testosterone in the testicle, which are necessary for sperm production are much, much lower. But it's interesting because I think I'm not aware of sort of how traumatic injuries would, would do that.

A

Okay, that's good to know. I'm curious about the non endocrine, non chemical effects on sperm quality and testosterone levels. So here I'm thinking about a bunch of news stories we heard a few years ago about how bicycle seat pressure on the prostate, or maybe it was other, other portions of the. Maybe it was the nerves running to the penis itself or surrounding areas. Maybe it was pelvic floor related. And somehow you'll tell us, I'm sure, was impairing sexual function. Was it impairing sexual function in any way by impairing testosterone levels, cutting off blood flow to the testes here. Perhaps the most important thing to ask straight off is riding a bicycle bad for male reproductive health and sexual health?

B

Yeah, these are great questions. Again, living in the Bay Area, working in the Bay Area, cycling is very, very popular. So these are questions that I get a lot. So I think in general, like we talked about before, anything that's good for your heart, it's going to be good for fertility, so good diet and exercise, maintaining good body weight. And so I always try and encourage physical fitness. I think that's important. But, you know, may be possible that some particular activities may put men at more risk. So I think cycling could be one of them, but it would sort of depend on exactly why we think that may be a problem. So I guess the theory is heat. If you're in the saddle for a long time for these prolonged rides that men take on weekends, hours, that may be, if there's too much heat exposure, that may be the mechanism where sperm production would decline. So there have been some studies say maybe 5 hours a week would be, you know, that may be too much. So if you're above that level, the sperm counts have shown to be lower. If you're less than that, that may be okay. So when I talk to patients about it, I try and just encourage them to stand up in the saddle to try and again, sort of air things out, to try and dissipate heat. If that's the mechanism we're going to think regarding sexual dysfunction, that is thought to be pressure you're alluding to. So the way that the saddle is configured, ideally all the pressure is put on our ischial tuberosities or our sit bones. That's what I'm sitting on now. But on the saddle, there's obviously the rigid nose, and if there's too much pressure on that, that actually squeezes between the ischial tuberosities where the main blood flow to the penis goes and the main nerve supply is too. And so if there's compression on this, you get this sort of lack of blood flow or ischemia, and you can get a neuroprexia as well if you crush these nerves. And so that over time can lead to problems. So some patients will say that after I cycle, things are numb down there for 30 minutes or a day, or I don't get erections for that sort of same amount of time. Or sometimes men just sort of ride through it and hopefully things come back in a day or two. That could be the mechanism. There are some saddles that hopefully will be a little safer. And I think that this first was noted probably around 2000 or so, and there is a big redesign in terms of saddles to try and make them a little bit more anatomically correct, to try and minimize some of this. And there's cycle fit that can be done, or saddle fit, rather, that can be done at some of the cycling shops to try and look at your body position, look your size, and try and find a saddle that's safer. This doesn't happen to everybody. I would say maybe if you were to survey cyclists maybe 20% to 30% of men and women tend to be susceptible to this. So I think if you are having discomfort when you cycle, whether it be pain, numbness, or you notice dysfunction, I think certainly you should think about changing saddles or think about changing riding style. There's other strategies that are sometimes used, but it's absolutely something that everybody should be aware of.

A

I meant to ask this earlier, but I seem to recall a study that drew a correlation between amount of walking and maybe it was sperm quality, but I think it was testosterone levels, maybe some other metrics of male sexual health. Forgive me, I'm not recalling the details now. Is there any evidence that walking more, standing more, maybe even using a standing desk, is beneficial for pelvic floor health, blood flow, prostate health, who knows? Could be any and all of those things in some way that is beneficial for sperm quality, testosterone level, and or overall male sexual health?

B

Yeah, I think one of the ways that we can characterize activity is step count. I think I have a watch that tells me that it's something that I look at every day and kind of strive for, and it turns out that the more active you are, it's been shown, looking at large national data pools across different age ranges, that it is associated with testosterone levels. So being more active, I think, is very important. And that's another thing that everybody can do to try and improve testicular function broadly. But testosterone specifically.

A

And do you know whether or not that can be separated out from the relationship between being more active and less obese? Is this something that's independent of obesity? In other words, can we incentivize people to walk more simply on the promise of improved sexual health?

B

Well, I don't know. Sexual health will be a different one, but we can. I think there is associations between testosterone levels and step count across different bmi strata. So I think whether you have the ideal body weight, whether you have a few pounds to lose, perhaps if you walk more, you will see higher levels of testosterone.

A

Okay. And another question I meant to ask earlier, and then we can close the hatch on exogenous testosterone therapy, at least for the time being. Maybe we'll come back to it. Is assuming that somebody can maintain adequate sperm production through the use of HCG or some other therapy, or perhaps they don't care if they're still making sperm because they've already had children, or they don't care to have children, maybe they've bank sperm. In any event, assuming that somebody takes testosterone therapy because they were prescribed that, let's say in your clinic. Let's just use you and your clinic as an example. And they are happy with the psychological and physical consequences of that, and they are comfortable with the trade offs. Is there any increased risk of, say, prostate cancer or other forms of cancer? And here I'm going to assume that this person is keeping their lipid levels in check because you hear about some hyperlipidemia with testosterone therapies. Let's assume that they're either taking a statin or they're not taking a statin, they're getting enough cardiovascular exercise, that things are in check in terms of LDL, HDL, APOB and all of that. And their testosterone levels are now high normal and they're feeling better, and they don't have to worry about sperm production because they're either maintaining it or it's been banked or they don't care about that. Is there an increased risk of prostate cancer? My understanding is the answer is no. But what's the real deal? Does taking testosterone therapy, assuming all other things are being held in check, in a healthy check, does it increase the risk of any kind of cancer?

B

Yeah, I mean, this is another great question because I think there's a lot of myths around testosterone, and that's one of them. The origin is that prostate cancer is thought to be, or is sort of androgen mediated. One of the Nobel Prize, again, decades ago, was awarded because it was found that when we lowered man's testosterone, the prostate cancer would regress dramatically. So that put that association between testosterone and prostate cancer. So then the concern began, if we were to either replace testosterone or augment testosterone, give a man testosterone, is that going to alter his risk or increase his risk? So I think we have pretty convincing data that that's not the case. Lots of longitudinal data spanning decades where if man is given testosterone, it doesn't change its risk. The reason for that, in a sort of seeming contradiction, this contradiction between prostate cancer, a therapy where we lower testosterone, where if you give a man testosterone, it doesn't change, as prostate cancer risk is not certain. But there's this popular model called the saturation model, so that once there's enough testosterone in the body, and it tends to be a fairly low level, that all the sort of the prostate testosterone receptors you can kind of think of as have been filled. So if you were to give man more testosterone, it doesn't change anything regarding the prostate cancer, prostate growth, any of that. So it is safe when we're looking at prostate cancer as an outcome, getting.

A

Back to prostate health and neural innervation of the penis and blood flow to the penis. You mentioned the bike seat related issues. Are there other things that men should do in order to maintain prostate health, stave off prostate diseases, and to maintain healthy blood flow and neural innervation of the penis? For obvious reasons, and we'll get into the specifics of those reasons in our later discussion.

B

Yeah, I mean, I think that I always kind of think of the penis as a user, to lose an organ. So that doesn't mean necessarily you have to have sex. But normally we get erections every night, so that should be maintained. And if there's any reason to sort of suspect that that may not be going on, usually in my practice that would be from some pelvic surgical intervention or something like that, sometimes we can intervene to try and maintain that.

A

You're talking about spontaneous erections during sleep, and short of assigning one's partner to check frequency and tumescence, what is the way that men would know that that's happening? Are you talking about waking up with an erection? Is that requisite for knowing that nocturnal erections are occurring?

B

Well, yeah, I think you kind of caught me. I think that's a good question. So I think a lot of times you won't know, but I think if you have sort of normal response when either by yourself with a partner, I think that generally means that you are going to get normal erections. So I think, I guess when I say use it or lose it, it doesn't mean necessarily that the man has to stimulate himself or kind of make sure that he does have adequate function, because usually most of that normal function just occurs with his nocturnal penile tumescence, which we all get. I think sometimes men do notice when they wake up at night. Sometimes in the morning, you wake up with an erection and men notice that. But the absence of that doesn't mean it's not happening. It likely is. Most people sleep through it, which is normal. Otherwise men would never get any sleep because it happens many, many times a night. So I think, again, if you're not having normal function, I think that's something you should probably see a physician about. And then same for urinary function, I think if it bothers you, if you're waking up at night, if you have to go to the bathroom often, if your stream is getting weaker, those are all complaints that we hear about what is often.

A

My understanding is that it's normal to wake up perhaps once during the night to urinate. And this is, of course, assuming, and again, forgive me for all the caveats but I've done this long enough that if I don't get really granular about some of this, then people say, well, what if I drank 32oz of fluid right before sleep and I'm urinating three times per night? Well, we're assuming that people are tapering their liquid intake as they approach bedtime and that waking up once, maybe twice, but once in the middle of the night to urinate is normal for somebody, let's say age, I don't know, 18 to 40, and maybe from 40 to 100, that number might be in the one to two times per night. Is that about right?

B

Yeah, I mean, I think once a night. Yeah. Is normal for most men. And then I think if things start to bother you, I think you could certainly see somebody. But it's hard to get better than once or twice a night. Yeah. For most men.

A

My understanding is that there's a pretty good relationship between the nocturnal erection and the amount of REM sleep, rapid eye movement sleep that one is getting, that this tends to be more frequent toward morning as the proportion of rapid eye movement sleep increases. I don't know if that's true or not, but I found a couple of studies that at least point in that direction, no pun intended, that raises a bigger issue that we haven't talked about yet, which is getting adequate amounts of quality sleep each night. And I think for most people, that's seven to 9 hours ideally, which means getting sufficient slow wave, deep sleep as well as rapid eye movement sleep. But nowadays, a lot of people, including young people who are not working excessive hours, are getting four, five, 6 hours of sleep per night. Is there a direct relationship between getting less than sufficient amounts of sleep and sperm quality, testosterone levels and sexual health?

B

Yeah, I mean, I think certainly there's reasonable data for semen quality, and there tends to be, you know, we call, like in science, sort of a u shaped relationship so that it's not sort of linear. So as you get more sleep, things are better. There's sort of. There's this concept of too much sleep and not enough sleep. So the ideal, I think, as you pointed out, is seven to 9 hours. And for men that are not getting that, semen quality tends to be lower. And then for men getting too much, we also see a decline. And why that is, is not certain. Again, if you're able to get that much sleep, maybe there's other things as well that we should look at. But so I think kind of getting in that ideal sleep amount is best for semen quality and probably for broad testicular function as well.

A

You keep bringing up semen quality in a way that makes me wonder whether or not is semen quality a proxy for overall vitality and health, or is testosterone level a proxy for overall vitality and health? It sounds like semen quality is the metric that you keep coming back to in a way that I have to assume reflects your clinical experience and the many papers that you've authored in this area. I think for people that hear semen quality and who are not interested in conceiving children now, or who are, which, of course, could include people who've already had children or who don't want children, semen quality sounds like something that relates to fertility. But is semen quality something that is a good goal for those who are interested in overall male vitality and health? Is it one of the better metrics of overall male vitality and health?

B

Well, I think, you know, I think it's an excellent marker for overall health. I think there are studies that support it can be a measure of how healthy you are. You know, if you look at men with more health problems, they tend to have lower semen quality. But also, if you look at semen quality just by itself, and then you look into the future, how these men tend to do. If they have higher semen quality, they tend to live longer, need to go to the doctor less, lower rates of cancer. So I think there's a lot of different ways that semen quality may be a good barometer of health. Why that link exists, I think, is not known, but there's lots of theories. One is that probably about 10% of the male genome is devoted to reproduction. It makes sense, given that we only have about 24,000 genes in the body, that there's a lot of overlap. So one gene that plays a role in reproduction may play a role in the cardiovascular system or the neurological system. And so if we get the first sign that reproduction is not perfect, there may be some other health consequences down the line. Another sort of hypothesis is that, again, going along this line, that reproduction is one of the first things that we see is that gestation is very critical to our existence. Perturbations to that system have prolonged effects, the so called developmental origin of adult disease, or the Barker hypothesis. We know that premature children have higher risk of cardiovascular disease. There have been studies to show that. But we also know that these gestational effects can also play out on reproductive function, too. So that also may be kind of a link, early seeding of reproductive function. And then that's maybe the first marker that we're going to have for other health effects later on. There are also just sort of inherent similarities between reproduction and some other sort of social effects. So kind of one confounding factor when we're looking at some of these studies I talked about looking at mortality, for example, and semen quality is that there's sort of factors that necessarily involve reproduction. So your children and having a partner, and having a partner prolongs life. Having kids prolong life even though it feels like kids are killing you. If you look at studies, men with kids tend to live longer. So that's another possible explanation. But I think really sort of this health, you know, link between fertility, I think, is sort of a powerful one. So I do think it should be a barometer. I think that, you know, it should be sort of, when I've given lectures on this, I call it the six vital sign. I think it's something that we should probably check because if there is, you know, sort of lower levels, that may tell us about something else going on. You know, when, when men come in for infertility evaluations, a lot of times we do diagnose, you know, these new medical problems. Sometimes we diagnose cancer, sort of alluding to some of the questions you've asked, diabetes and some other very significant genetic conditions as well. And the first way that we would identify it is reproductive failure because their sperm counts are low and other things. So it is something, I think, that it's very important, I think, for people to realize, and it would be great, I think another advantage to the Centers for Disease Control, for example, to start tracking it.

A

Would it be a good idea for males in their twenties and thirties to get a sperm analysis, just to have a baseline? I confess I'm 47 now. One thing I wish I had done in my twenties was to get my blood hormone profiles and lipid profiles done when I was in my teens and twenties because I'd have something to compare to. I started doing that in my mid thirties, and I'm so glad I did because I can now compare to my mid thirties levels. I started including sperm analysis about eight years ago with the intention of freezing sperm and did that because I was also reading at that time about the increased risk of autism in offspring of males older than 40. Something that I really would like your take on, but it seems like it's inexpensive enough to do a sperm analysis. I think now people can get it done at home. They have mail kits, although I don't understand how the motility could be maintained. If you're mailing your sperm back at room temperature, or it's heading through the post office now everyone's imagining all these sperm traveling through the postal service. They're out there, folks. Yeah. What are your thoughts? Should people invest the. I think it was a couple hundred dollars to get a sperm analysis. More costly to get the DNA fragmentation than you get up into the low thousands. But if people have the disposable income, is it a good idea for them to do?

B

I mean, I think it's a worthwhile test. I think more information is always good. I think sort of one of the same reasons that you're talking about checking, like, lipid levels or we tell men and women to get blood pressure checked. I think getting that sort of early health indicator, I think, can be important. I think going back to not knowing exactly why semen quality is telling us about health, what the exact link may be, you know, means that if somebody is coming in with a low sperm count or completely absent sperm count, it's hard to know exactly how to counsel that that person, other than there may be reproductive difficulties. But I think just as sort of a marker for reproductive potential, I think it's useful. And like you said, I think it's become a lot easier. One of the innovations in the space, and, you know, somebody that is in the reproductive world, I think it's just really great to see this influx in capital and new companies coming in that try to just decrease the barrier to getting a semen test. It used to be you have to go to a lab, schedule an appointment. Sometimes they would send you to a bathroom, which can be uncomfortable because people are doing, you know, what people do in a bathroom just next to you while you're trying to collect.

A

Oh, they would send them into a common space.

B

Common space, bathroom.

A

They wouldn't even give them the quiet room with the red light, which is what I hear they do now.

B

Yeah, some of them do have videos, so there are some higher level.

A

Oh, I didn't even mean videos. I just. I think that. Okay, yes, I've done this. I'll just say, I mean, I've been trying to normalize things related to all aspects of mental health, physical health. So, yeah, I decided to free sperm. And basically they sent me to a room. I went to a university based clinic. It actually wasn't Stanford, but different university. And, yeah, they put the cup through the window. They give you the cup, they close the door, and they tell you that as long as that red light is on over the door, no one's going to walk in and then they leave. And I think the assumption now is that you figure it out one way or another how to provide the sample, and then you put the sample back through the thing. And then one thing these clinics really need to work out is that anytime you're walking out, you see the people processing your sample as you walk out. So there's all this. This feigning of anonymity, but really it isn't there because they're like, see you later, and you're like, great. They rarely ask you questions on the way out. But it's a pretty simple process overall. And I must say that the data are informative. You get the volume number, motile, forwardedly motile. I did opt for the DNA fragmentation data. I just love data. So I think it's really interesting. But again, maybe this is a good time to flag this set of findings. I believe that there seems to be a small but statistically significant increase in the number of autistic births due to pregnancies where the male was over 40 at the time of conception. So I figured, why not freeze some sperm? And it's relatively inexpensive. Yeah.

B

Yeah. So I think paternal age is also, you know, something that's increasing in this country. So over the last 40 years or so, we've seen that the average paternal age has increased from about 27 and a half to about 31. And I should say that this is all fathers. So birth certificate data or birth data is collected at maternal level. So, you know, when a child is born, somebody comes in to collect data on the birth. So they ask, you know, all the characteristics of the mother. And they also asked characteristics of the father, you know, age, education, obviously, region of the country the child was born. So we don't know what number child that was for the father. We know it for the mother. They do ask, is this your 1st, 2nd, 3rd, etcetera child? So the father, unfortunately, we just have data that sort of all lumped together. But over the last, again, 40 years, we've seen that increase. Interesting. Over the last 40 years, the youngest father was eleven and the oldest was 80.

A

811.

B

Quite a span. Yeah.

A

88. Goodness. Unrelated.

B

I don't know. I assume. I assume.

A

Goodness.

B

It's anonymized data.

A

Eleven. I have to ask this. Sorry to take us on a slight tangent, but what is the average age of puberty in males in the United States now?

B

Yeah. So you're asking about, I guess, sort of spermarki when like, sperm production begins? Yeah.

A

There are a lot of markers of puberty, secondary sexual characteristic beard growth, deepening of voice, et cetera. They happen at different rates in different people, but, yeah. Thank you. At what point are males undergoing puberty at the level that we're talking about here?

B

Yeah, so there has been data that we're going through puberty a little bit earlier now than we used to, but it really varies. So I think it's nothing. Just like testosterone ranges between 309 hundred. That's a wide range for anybody. I think for most individuals, puberty is probably twelve to 1516. In general, I just give a very wide range when we're going to say, that's okay. Some of the data I'm basing it on is when sperm production begins in boys. It's actually not that simple to be able to figure that out because we don't generally talk to young boys about how to masturbate, how to collect, and then check on that. But there's something called first morning voided urine where we can actually look at that. And there have been some studies done and they see if there are sort of nocturnal emissions, whether there's sperm in there. And so generally it probably starts around the earliest would be kind of 1112 13, but usually most is probably a little later. So maybe I'll refine that puberty and move it a little bit later. Probably 14 to 16 is when probably about 70, 80% of boys are going to have produced, started producing sperm.

A

My understanding is that in females, puberty is also shifting earlier, perhaps at a more dramatic rate than appears to be the case for males.

B

Well, I think there is some data for males, too, I think. But again, for your listeners, I don't want to have this onslaught of, you know, pediatricians seeing kids that haven't, you know, when boys haven't gone through puberty by a certain age. So I think it's still fairly wide.

A

Let's get back to age of the father and issues like autism. What are the data there? And this, to me is a practical issue because I think if there's one obvious takeaway from our discussion today, it's that males should probably not wait until they're trying to conceive in order to assess their reproductive health at the level of sperm quality. Testosterone levels, perhaps, but at least sperm quality. But perhaps men should also be freezing their sperm if, in fact, conceiving children after 40 places their children at far greater risk for autism. My understanding is that the rates of autism are somewhere between one and 80. You'll hear as high as one in 50 male births. But I think it's probably more like one in 60 to 80. Is that about right? And that the age of the father is a risk factor?

B

Yeah. I think that this gets into the larger issue of how men perceive fertility. So we know that as women age, fertility declines. But the oldest father ever is 96, so the biologic potential certainly persists.

A

Wait, I want to know how long he lived to see how long his child grow up. He conceived at 96, supposedly.

B

Supposedly, yeah.