The Peter Attia Drive - #351 ‒ Male fertility： optimizing reproductive health, diagnosing and treating infertility, and navigating testosterone replacement therapy

00:00:00.000 Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Atiyah. This podcast,

00:00:16.540 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

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00:00:53.200 of the subscription. If you want to learn more about the benefits of our premium membership,

00:00:58.000 head over to peteratiyahmd.com forward slash subscribe. My guest this week is Dr. Paul

00:01:06.260 Turek. Paul is a world-renowned expert in male fertility and reproductive health, and you can

00:01:12.160 think of this as part one of a two-part mini-series we're doing on fertility and reproductive health,

00:01:17.840 with this one of course being on the male system. Next week, we'll feature Dr. Paula Amato, who is

00:01:24.460 going to be the female expert on this topic. Paul is the founder and medical director of the Turek

00:01:30.740 Clinic, specializing in cutting-edge treatments for infertility and men's health, and a pioneer

00:01:35.100 in advancing research on sperm biology, genetics, and reproductive longevity. He's also the host of

00:01:41.660 the Talk with Turek podcast. In this episode with Paul, we explore the intricate and highly evolved

00:01:48.580 process of conception, discussing the challenges sperm face on their journey to fertilization.

00:01:54.500 This, of course, is important to understand all the places where it can go wrong. So it's not just

00:01:58.420 an interesting story, it also explains how challenging it actually is. Paul shares insights

00:02:03.200 into male fertility, including how sperm function in coordination to navigate the female reproductive

00:02:09.000 track. We discuss how various factors such as heat exposure, stress, and environmental toxins

00:02:14.040 impact sperm quality. We talk about what men can do to optimize their reproductive health. Paul

00:02:19.620 explains the effects of testosterone replacement therapy on fertility, debunking many myths and

00:02:24.500 offering strategies for men looking to preserve their ability to conceive while being on hormone

00:02:29.060 replacement therapy. Talk about the emerging fertility technologies, including advanced sperm sorting

00:02:34.340 techniques, genetic testing, and innovative treatments that could redefine

00:02:38.760 reproductive medicine. We also talk about the differences between the risk in the aging male

00:02:44.300 and the aging female. And this was actually one of the most interesting things I learned about in

00:02:48.160 this podcast. So without further delay, please enjoy the first of two parts on a discussion

00:02:53.020 of fertility and reproductive health. This one with Dr. Paul Turek.

00:02:57.860 Hey, Paul, thank you so much for coming out to Austin.

00:03:05.740 Peter Attia, the man, the myth, the legend. I am so excited to be here.

00:03:09.500 This is in many ways, I guess, what's going to be part one of a two-part series I hope to do on

00:03:13.660 fertility. And given the complexity of it, I think the most logical way to do it would be to break it

00:03:18.860 down into male fertility, female fertility. And there's obviously going to be things we talk about

00:03:23.060 that will overlap. But I was trying to think about the best way to start this. The first thing that came

00:03:27.100 to my mind was, can we just explain what's involved in conception? And maybe do it through the lens

00:03:33.160 of the sperm. But how much of a challenge is this? I mean, obviously, there's an enormous

00:03:37.060 evolutionary pressure for this to go as easily as possible. But what is actually involved? So what

00:03:43.300 happens for a sperm to fuse with an egg? What are all the things that are standing in its way,

00:03:49.560 so to speak? So reproduction is an incredibly highly evolved million-year process and remarkably

00:03:55.400 conserved among mammalian species, even among land species and water species of animals,

00:04:01.660 vaginas, cervixes, uteruses. And the question is, why is it so much work for a sperm to get into the

00:04:08.220 vagina, especially in, say, water, and then have to go through a cervix? And then the immune system

00:04:13.140 in the uterus is very active because there's a hole in the woman to the peritoneum, to the abdomen.

00:04:18.460 So it has to be highly protected. And then you have to go through the uterus. So there's a

00:04:23.900 10-inch, 12-inch swim, which is equivalent to about a 20-mile swim for a human.

00:04:30.280 Based on the size of the sperm.

00:04:31.060 After ejaculation and how much distance they have to go. And they do that in minutes,

00:04:35.100 which is crazy. So it's an interesting challenge that nature has kept in place for a million years.

00:04:41.100 And I really respect evolution. And it is why we're here for, you know, eat, sleep, reproduce. So

00:04:46.480 basically with ejaculation, the penis is shaped to fit into the cervix. Everyone wonders,

00:04:51.920 is it getting to the right spot? It's also interesting that the semen is coagulated and

00:04:56.700 then it liquefies. And that's because there's a lot of species of lower phyla that they have to

00:05:03.480 leave as soon as they have sex. Otherwise they'll get killed like praying mantises and black widow

00:05:07.220 spiders. So you got to get out of there as a guy. So our ejaculates and humans are sticky.

00:05:12.600 By the way, is there an evolutionary explanation for that phenomenon?

00:05:15.540 I have no idea, Peter. I have no idea why you would do that.

00:05:19.060 I don't know why one queen bee and the bees in the hive die after mating. I have no idea why

00:05:25.040 that's an advantage, but I guess females are prioritized in evolution. And that makes sense.

00:05:29.880 The anatomy is perfectly defined. So a lot of men think they're having trouble placing things.

00:05:35.280 I usually don't worry about it because the cervix and the penis expands, it forms a seal.

00:05:39.500 Then there's a crypt. Sperm have to go through a crypt, a channel, which is only a few sperm

00:05:44.440 make it. So a hundred million sperm may start out. Maybe five million make it through the first

00:05:48.840 barrier, which is the cervical barrier. The vaginal fluid is acidic.

00:05:53.060 How acidic?

00:05:54.060 Five, pH of five. And the semen is a pH of seven. It's all buffered as a hostile environment. So it

00:05:59.640 has to get out of there quickly. As soon as it liquefies, there's sugars in there and then

00:06:03.340 they go through the cervical path. So five million will make it. One out of 20 makes it through

00:06:07.760 the cervix. Then a hundred make it to the fallopian tube and then one will make it to the egg.

00:06:12.700 Literally only a hundred?

00:06:14.500 Right. And the Settlage studies in the fifties had women have sex before hysterectomies. And

00:06:20.460 then he swabbed different parts of the reproductive tract. These are young women for different reasons,

00:06:25.380 not infertility, and found these numbers. And that's the basis for our move to technology from

00:06:31.100 five million moving sperm is when we start doing inseminations versus sex, et cetera. So

00:06:37.460 those are based on numbers of sperm that reach the uterus and reach the thing. What's really

00:06:43.140 interesting is there's some fascinating research. Everyone thought the vanguard sperm wins.

00:06:48.200 Yeah.

00:06:48.600 Right. So it's the Phelps sperm that's going to make it.

00:06:50.540 Right.

00:06:50.940 And there's a company out of Boston called Eric's Biosciences, and I'm consulting with

00:06:55.660 them, disclosure. But they've discovered that sperm work in phalanxes. So because the

00:07:01.280 immune system is so vibrant in the uterus, the first round of sperm gets through the cervix

00:07:06.380 and typically absorbs the immune system, secretes FCR receptor.

00:07:11.300 And by the way, we've referred to the immune system a couple of times now. What is it? Is it

00:07:15.480 just a bunch of antibodies? Are they B cells? What is the barrier?

00:07:19.080 There. There's T cells, B cells, and antibodies.

00:07:21.900 It's a full immune response.

00:07:22.980 Absolutely.

00:07:23.460 So it's a specific immune response.

00:07:25.660 Anything foreign.

00:07:26.820 Wow.

00:07:27.240 And there's also a mucus plug that exists for 28 days a month to prevent anything from going

00:07:32.660 through because it's a hole into the woman's body and peritonitis is severe, right? And the

00:07:37.040 cervical mucus thins, and that's to let sperm through for two days a month. It's incredibly

00:07:41.360 detailed, perfectly orchestrated system. So it looks like the first round of sperm get through

00:07:48.140 the cervix, get into the uterus, and they get demolished, like a phalanx, like a Roman

00:07:52.320 phalanx. And maybe a second round goes through and they get demolished and they're secreting

00:07:56.340 the FCR receptor on the immunoglobulin because that's what antibodies bind to. So the female

00:08:02.860 antibodies bind to that. And we don't know how many phalanxes go through, but then it's like

00:08:06.740 a run up the middle. And then eventually a couple of sperm or fourth make it and the immune

00:08:12.400 system's deactivated and they get there. It's wild.

00:08:15.560 And that can be measured now. And there's actually going to be an assay available to

00:08:20.080 look at whether you're doing this. They're calling it a sperm cycle, almost like ovulation,

00:08:25.560 spermulation. But it's an hour and a half cycle when the phalanx is working, sperm are deactivating

00:08:32.260 the immune system, and then maybe they don't. So there are jaculates, which is a group of sperm,

00:08:37.880 some of which do this well and some of which don't. And that can be a whole reason for infertility.

00:08:43.340 If you're not able to deactivate the system, you're not going to be able to get through

00:08:47.120 because the immune system is active.

00:08:48.860 Let's go through those numbers one more time. About 100 million ejaculated.

00:08:52.240 At the cervix.

00:08:53.320 5 million get through.

00:08:54.720 To cervix into the uterus.

00:08:56.020 Yep.

00:08:56.440 100 to 500 get to the fallopian tube and one gets to the egg.

00:09:01.460 Wow.

00:09:02.140 Why do you need so many sperm? The classic answer used to give is they don't like to ask for directions.

00:09:07.000 Men don't like to ask for directions, but this is probably why.

00:09:10.100 So let's also define what makes up the ejaculate because we've talked about the sperm. So how are

00:09:16.260 sperm made? Because an important consideration for a sperm is it can only have half the genetic

00:09:20.720 information contained within all the other cells in the man's body. So when does that take place?

00:09:25.560 So the testicle makes sperm. It takes about 60 to 70 days and it's a process called meiosis. So

00:09:32.100 in a car assembly line, the Model T assembly, you know, mass produce, you want it all be the same.

00:09:36.820 In meiosis, which is unlike mitosis, you want things to be different and to be a little

00:09:41.540 easy peasy. So you get what's called recombination. And so that's the source of evolution.

00:09:47.660 So the genes, the chromosomes blend in a different way and separate a different way. And through that

00:09:52.120 process of a couple of those, you get half the number of chromosomes, which is required to join

00:09:56.280 the other half.

00:09:56.860 But it's not always the same half.

00:09:58.720 Correct. It's a loosey goosey. It's not the same as when it started.

00:10:02.280 Yeah. A funny story, which I think I've shared on the podcast before, but if not, I'm sure someone

00:10:06.980 will be amused by my stupidity. I had to take the MCAT before doing any of the pre-med stuff because I

00:10:13.200 had studied engineering and then decided I wanted to do medicine, but didn't want to spend two years

00:10:21.380 preparing one year, taking the post-bac and then the MCAT and then doing it. So I was like, I'm going

00:10:26.560 to just wing it and take this MCAT having never taken a biology class since high school. I took

00:10:32.820 freshman biology. So I am studying my heart out for this little MCAT test and the physics and the

00:10:40.280 chemistry are fine, but this biology thing is killing me. And I bought this cheap study guide.

00:10:47.300 I didn't have the money or I didn't want to splurge for the official study guide. There's an

00:10:51.140 official MCAT study guide, but the thing was like 60 bucks, but there were these knockoff books for

00:10:55.780 10 bucks. I was like, ah, they're just as thick. So I buy one of those. And every time I encounter

00:11:01.280 the word meiosis and mitosis, I assume it's a spelling mistake because I bought the knockoff book.

00:11:07.180 So I'm treating it as the same thing. Every time I see the word meiosis, I'm like, these guys,

00:11:12.060 they just misspelled it, idiots. It's mitosis, mitosis, mitosis. Finally,

00:11:16.660 on the night before the exam, which I still remember, August 17th was the day I took the

00:11:21.820 test. I realized they were two totally different things. Big things. Oh my God. That realization

00:11:28.900 might've got me into med school because I think I barely got a 10 on the biology section, which was,

00:11:35.380 it's hard to get into a good med school if you'd get below that. So anyway, to this day, I get such

00:11:39.740 a chuckle out of the confusion of the nomenclature. But again, just to explain for people, mitosis is what

00:11:46.040 happens when cells are dividing in our body constantly, where they're trying to create a

00:11:49.700 perfect replica of the entire suite of DNA. So really, to my knowledge, the only time we're

00:11:54.120 undergoing meiosis is in the creation of an egg or a sperm. That's right.

00:11:58.200 Okay. Now remind me, are women born with all of their eggs? I feel like that's something I vaguely

00:12:02.500 remember. Five million eggs at conception, one million eggs at birth, and you basically ovulate

00:12:07.240 a thousand in your lifetime. Okay.

00:12:10.160 So by the time you're 45, you're out of eggs, you actually ovulate one a month, but you actually

00:12:14.660 produce 10 a month. So you lose 10.

00:12:18.080 For every one.

00:12:18.660 Right. So a lot of waste, but they're stuck in a stage of perpetual space where they're

00:12:24.620 just, you know, and they get older and they don't evolve really. And then they mature when

00:12:29.500 they're asked to at that time, but sperm are constantly renewed.

00:12:33.140 Is that just a mass space problem? Because the testes, if we did the same thing women did,

00:12:37.580 would we just have to have an enormous set of testes?

00:12:40.080 Why do you think out of the box like that? So, no, I'm not sure. I mean, there's a whole

00:12:44.360 issue of what's the source of human evolution. It's really sperm.

00:12:47.980 Yeah.

00:12:48.280 Because they're constantly dividing. They're constantly influenced by the environment

00:12:51.500 and they're throwing off mutations and epigenetic changes. And what's most interesting for me

00:12:56.460 for this talk is that whatever happens in sperm happens to offspring.

00:13:02.120 That's an interesting point.

00:13:03.200 So it's transgenerational.

00:13:04.840 Does that mean that the father is more likely to pass on environmental stressors than the

00:13:09.900 mother?

00:13:10.820 Probably. Yeah. And that's definitely been shown.

00:13:13.500 Hmm. Okay. So let's go back to it. So the sperm is the actual cell. Where does it get

00:13:18.960 the little tail from? And what is the other part of the cocktail that is-

00:13:21.920 One of the most magnificent transformations of a cell in the body is the making of a sperm.

00:13:25.920 It starts with a spermatogonial stem cell, which looks like other cells. That spermatogonial

00:13:30.300 stem cell is actually the first and the bottom of a tube. There's 12 stages of spermatogenesis.

00:13:35.080 That cell is remarkable. It's actually the human male embryonic stem cell. So I have a patent on

00:13:41.620 that cell because if you take that cell and you put it in a niche environment, like an embryonic stem

00:13:46.720 cell, it'll become embryonic, almost like it can become multipotent.

00:13:50.240 It's pluripotent?

00:13:51.440 Multipotent. We don't know about pluripotent, but you can form tumors and you can form bone,

00:13:55.620 mesoderm, ectoderm, and endoderm. You can do all three layers of the body with that adult

00:14:01.060 spermatogonial stem cell.

00:14:03.060 Is there any other cell in the body that is capable of that?

00:14:05.480 No. I mean, there are stem cells in the bone marrow. There might be stem cells in fat,

00:14:09.800 but none of this, we showed the capability of the cell is magnificent. I think it's the source.

00:14:15.220 Women have eggs and embryonic stem cells. That's the male embryonic stem cell, in my opinion.

00:14:19.680 It hasn't been taken advantage of yet with cell-based therapy, but it is

00:14:23.060 really incredible what this cell can do.

00:14:26.180 And a man potentially has access to this cell his entire life?

00:14:30.020 Yep. As long as he's making sperm. So that starts out and it usually

00:14:34.020 reproduces mitotically and then in puberty, it'll go down the path of meiosis,

00:14:39.120 which is a couple steps more than meiosis. Is mitosis involved with meiosis? But it's the

00:14:43.180 halving and the mixing up of the chromosomes and the newness of the genome introduces mutations

00:14:50.000 and stuff. And most mutations are bad and some are good. You don't really think about that.

00:14:54.360 But we could have a long talk about genetics versus epigenetics.

00:14:56.780 Actually, let's focus on that for a second. I hadn't considered that. So when the cell that

00:15:01.580 is becoming a sperm undergoes meiosis and it divides, what's the fraction of times when this

00:15:07.900 becomes an aneuploidic sperm and explain maybe to people what aneuploidy is and what's the process

00:15:14.460 by which that thing gets discarded?

00:15:16.700 So if you look at healthy human sperm for chromosomal content and what's correct and

00:15:23.100 what's incorrect, probably 2% of them are off. They're still being made. They're just off because

00:15:28.480 it doesn't really click the system to negate it. We don't know at what level of chromosomal abnormalities

00:15:33.920 the system will say this is a bad product. But I would say if you look at making of sperm,

00:15:41.100 it's very logarithmic. You're probably looking at one out of four that are being made go through

00:15:46.700 the epididymis, which is the next 10 days, which is a collecting duck after the testicle where it

00:15:52.000 matures, gets epigenetically modified, and you'll see these zones, different epididymosomes and things

00:15:58.160 like that happening. And there's a lot of post-production modification, not of DNA essentially,

00:16:02.900 but I think there's a filter going on where a lot of the bad aneuploidy comes out. Because

00:16:06.540 if you look at the chromosomal abnormality rate in testicular sperm before it goes through the rest

00:16:11.340 of the system and compared to ejaculate, it's higher. It's two to three fold higher.

00:16:15.280 So something is getting filtered.

00:16:16.300 So there's a filter.

00:16:16.900 Yeah. And just so folks know, when we say aneuploidy, we mean you don't have one copy of

00:16:21.180 each chromosome. You either have none or you have two or anything that's not one is bad.

00:16:25.840 Right.

00:16:26.100 Right. When aneuploidy occurs in the fusion of the sperm and the egg, do we know, I guess we can

00:16:33.200 figure out pretty easily if it's maternal or paternal in origin?

00:16:36.160 If you look at the embryo, it's kind of hard to tell. There are some markers of paternal and

00:16:39.460 maternal origin. It depends on where you're going back in mitosis and meiosis. So they can sort of

00:16:45.020 ascribe it in the embryo. In the sperm, you're really going to have to look at the sperm. And if you see

00:16:49.380 a translocation, some characteristic change in sperm, and you see it in the embryo,

00:16:53.840 then you know it's paternal, but not usually. And 98% of sperm are typically normal. And a guy

00:16:59.560 with infertility, it might be 95%. Here's an example. If you have a patient with

00:17:05.700 Kleinfelter syndrome, a male with an extra X chromosome in every cell in their body,

00:17:10.720 or a transgenic model with that feature.

00:17:14.680 So this is a man who's XXY instead of XY.

00:17:17.980 Right. So 47 chromosomes, not 46.

00:17:19.860 Yep. And phenotypically, he kind of has a distinctive look.

00:17:23.840 Right. 10% of the time.

00:17:25.700 Oh, really? 90% of the time, a man with Kleinfelters, you'd never know.

00:17:29.100 Yeah.

00:17:29.640 Okay.

00:17:30.140 So that's the board question.

00:17:31.500 That's the board question, right?

00:17:32.460 That's the MCAT question.

00:17:33.820 Yep. Yep.

00:17:34.820 All right. So in these men, if you look at their sperm aneuploidy, right? So every cell in their

00:17:39.300 body and in the mice, in the transgenic mice, all have an extra X chromosome. Only about 10%

00:17:44.500 will have it in the sperm.

00:17:46.040 Meaning they will produce an X or a Y sperm.

00:17:49.060 Just like everyone else.

00:17:49.840 The only difference is they have a two thirds chance of producing an X and a one third chance

00:17:54.100 of producing a Y, I'm assuming, instead of 50-50.

00:17:56.160 Don't think we know that.

00:17:57.740 That's math.

00:17:58.700 Yeah.

00:17:58.960 That's math.

00:17:59.520 Yeah.

00:18:00.220 Biology is not math, remember?

00:18:02.560 And I had two Kleinfelters patients yesterday that I operated on, and they're not doing

00:18:06.360 pre-implantation genetic diagnosis of the embryos that they're going to create from their sperm

00:18:10.340 because the chance is not that high. So it goes from, in mice, 0.1% chance of normal men having

00:18:18.520 an X, X, Y sperm or an aneuploid sperm, an abnormal sperm to 1%. In humans, it goes from 1% or so to

00:18:26.780 10%. But 90%, that's remarkable.

00:18:29.720 That's amazing.

00:18:30.400 It's remarkable how efficient this is.

00:18:32.440 I interrupted you. You were in the process of explaining how we actually make the sperm,

00:18:35.820 where the tail comes from, and the whole process.

00:18:37.720 It's all done in the testicle.

00:18:38.920 Yep.

00:18:39.500 It's an amazing machine. Weird question we should maybe get to is, why is it out in the

00:18:43.100 breeze like that?

00:18:44.140 I assumed it was temperature-related.

00:18:46.020 Why?

00:18:46.800 Why? Does it need to be a little cooler?

00:18:48.680 Yeah. Why?

00:18:50.280 I would guess, because I like to mix things up, that it's so energetically demanding that it's

00:18:54.980 giving off more heat in the process of creating something that is going to be so efficient to be

00:19:00.080 able to swim 20 miles effectively. And that's very glycolytic, I'm assuming. The amount of ATP

00:19:05.380 that must be generated. 75 mitochondria for sperm. That's like, it's an electric motor on each wheel.

00:19:11.240 Yeah. So that would be my guess, is it's an overheating problem if you tried to keep those

00:19:15.620 guys inside.

00:19:16.480 And I think overheating could be translated to oxidative stress, which is a cause of a lot

00:19:19.860 of infertility.

00:19:20.660 We don't know is the answer.

00:19:21.760 Right. And it's interesting that ovaries are inside, so men get in hot baths and they're cooked.

00:19:26.800 Women can get in hot baths and they're okay.

00:19:28.780 It's funny. I had a buddy over who shall remain nameless. He does not have kids,

00:19:32.360 but he would like to have kids. And we sauna'd the other day. He went up to my freezer beforehand.

00:19:36.600 I didn't really know what he was doing in there. I thought he was getting a drink or something.

00:19:39.040 And he came down with ice packs. We were sitting in the sauna and he was in the sauna,

00:19:42.760 but he's got ice packs all over his groin. Immediately understood why he was doing that.

00:19:46.780 But yeah. We'll come back to whether or not that's an important strategy for men in saunas who want to

00:19:52.260 have kids.

00:19:53.300 So the complete sperm, spermatogenesis is the whole process. Spermiogenesis is when you go from the

00:19:58.600 round cell stage and you get half the number of chromosomes, and then you have to make a tail

00:20:03.480 and then hold motor assembly. And that is the most profound transformation of a cell in the body.

00:20:08.520 It takes about three weeks to go from that stage. And we're learning now it's a lot of it's vitamin

00:20:13.880 A driven.

00:20:14.720 Three weeks?

00:20:16.020 Of the six or seven to make a sperm. Then it's complete and non-modal and it's packaged.

00:20:22.180 Give us some size comparison. Before the tail is on, what is the size of that cell?

00:20:26.940 Probably similar to a lymphocyte, half the size of a lymphocyte or half the size of a red blood

00:20:32.380 cell, a couple of microns.

00:20:33.760 And then the tail makes it now.

00:20:35.080 35 micron tail. Yeah. So really magnificent engineering feat. It's got microtubules in

00:20:40.600 the middle and there's these links to the tail. It's like a kite and the engine runs it and the

00:20:45.380 tail wags. Remarkable. 300 genes control movement of sperm alone. There's mitochondrial DNA in there,

00:20:52.920 all that stuff. It's just wildly compact. 10 times more compact than any other cell in the body.

00:20:57.960 From a mitochondrial density standpoint?

00:20:59.760 From a cytoplasmic standpoint and nuclear standpoint, it goes from histones to protamines.

00:21:05.020 The DNA is condensed a lot more because it's got to go on the road. So it's got to be packaged

00:21:08.540 really well to survive outside the body and be in good shape because it's transgenerational.

00:21:14.500 So a lot of energy in that. And then during the epididymis, which is a collecting duct.

00:21:20.220 Sorry, one other question. Where is the ATP or carbohydrates, whatever the glucose stored in the

00:21:25.960 sperm?

00:21:26.460 Stored probably in the cytoplasm and in the tail.

00:21:29.140 Okay. And it's interesting. You know, when you think about a rocket ship with its payload,

00:21:32.580 it uses a solid fuel, obviously, as opposed to a liquid fuel. It's packaged for that one shot.

00:21:37.900 I assume it's the same here. There's no transporters to bring glucose in or anything.

00:21:41.480 It has its solid fuel, one shot, go for broke.

00:21:45.720 That's right.

00:21:46.720 Yeah. It is a lot like a rocket, isn't it?

00:21:48.260 It is a lot. So that's going to bring the physics in. So then there's two week period

00:21:53.980 where it stays in the epididymis, which is a 35 foot tubule with estrogen and there's a lot of

00:21:59.760 post-modification of the sperm.

00:22:01.760 The epididymis is 35 feet if you stretched it out.

00:22:04.220 Roughly, yeah.

00:22:05.080 And just for folks listening-

00:22:05.980 700 feet of tubules in the testes.

00:22:08.000 The epididymis is on the back of the testes.

00:22:10.160 It's a comma-shaped organ in the back, yeah.

00:22:11.840 Yeah. And we'll come to this, I'm sure, later. This is prone to infection and that'll probably

00:22:16.520 factor into maybe some of the issues that deal with fertility.

00:22:19.260 Infertility, right.

00:22:19.680 Yeah.

00:22:20.460 Epididymis has been relatively understudied, but it has actually become very important. Epididymisomes.

00:22:25.840 And there's a lot of modifications we don't really understand. I wrote the chapter for our

00:22:29.380 textbook on reproductive physiology and it really is a lot of work in the 50s and 60s, but

00:22:34.120 now we're beginning to understand DNA fragmentation and the quality of sperm is driven by the epididymis.

00:22:40.700 A lot of the quality of sperm, not the shape and stuff like that.

00:22:43.900 Meaning based on its residence time within the epididymis?

00:22:46.340 And what other environmental influences that occur there? Because the epididymis is not as

00:22:50.820 walled off from the body as the testes is immunologically and otherwise. It's more susceptible

00:22:55.720 to drugs, exposures, heat, et cetera. Testes is very walled off. Very little happens in the

00:23:03.560 testes because the sertola cells that line the tubules have a blood-brain barrier, a blood

00:23:08.100 testes barrier. Same as the brain. It's highly protective.

00:23:10.620 It's as protective?

00:23:11.720 Yes. Harvey Cushing at Yale did that in the late 18th century, took brain dead patients,

00:23:16.100 injected them with dye, methylene blue, I think. The blood-brain barrier came about when

00:23:21.180 nothing went into the brain and nothing went into the testicle. Two areas of the body that were

00:23:25.640 completely immune from normal transport processes.

00:23:29.320 Wow.

00:23:30.120 Blood testes barrier. So the two things that we know happen in the epididymis after production

00:23:36.140 of sperm are motility improves. So sperm begin to learn progressive motility. So they start

00:23:41.380 moving forward as opposed to not moving or moving in circles, which is important. And the

00:23:46.100 most curious thing is they learn how to smell.

00:23:49.700 Meaning there's basically a chemical signal that they need to be able to track to, which I'm

00:23:53.240 assuming is the egg?

00:23:54.000 Mm-hmm. So the follicular fluid. So they actually detect follicular fluid. So if you take

00:23:58.280 testicular sperm and inseminate it into a uterus with insemination technology, it'll just be

00:24:03.940 killed. If you take an epididymal sperm and you do that from the top of the epididymis,

00:24:09.160 it'll maybe run in circles and it'll be killed by the immune system of the female.

00:24:13.300 It has to go through that whole epididymal cycle.

00:24:15.220 Once it's at the end of the epididymis where it's stored.

00:24:17.680 And that's how many weeks?

00:24:18.420 Two, 10 to 14 days. 600 million sperm live in a bucket, a pot of soup to cauda epididymis.

00:24:25.220 And you ejaculate from that pot, which tells you a lot about sperm quality because it can get old.

00:24:30.700 But that sperm, if you put it in, it will know exactly where to go and it'll move forward.

00:24:35.260 Because it's like a shark sensing blood in the water. One part per billion of follicular fluid

00:24:40.480 can be sensed by a sperm. That's incredible. It's literally an olfactory sense. It's a smell

00:24:46.000 sense that sperm have for follicular fluid. So they know exactly where to go.

00:24:51.240 Again, it's, um, you have to wonder how many years it took to perfect this system, right?

00:24:56.540 You do have to wonder.

00:24:57.880 Do we know what the chemoreceptor is?

00:25:01.700 It was published in Nature recently and stuff like that. So it's really interesting.

00:25:05.060 It's an olfactory type receptor. Yeah.

00:25:07.120 Do we have anything else that we can...

00:25:09.260 It's very smell, Peter.

00:25:10.400 Yeah. Is there anything, like, what is the most noxious thing that we can smell with our

00:25:15.200 nose and at what concentration can we detect it?

00:25:18.720 I have no idea.

00:25:19.440 Yeah. Because I wonder, just for comparison...

00:25:21.380 Give me a minute.

00:25:22.020 Yeah, yeah, yeah. No, I've always thought about this. I like to hunt. So anyone who's ever

00:25:26.660 bow hunted, especially, knows that animals can smell at a level that we can't even fathom.

00:25:32.960 They can smell us literally a mile away if the wind is just blowing their direction.

00:25:36.860 And so it's always seemed to me like we have really, really insufficient noses. We were given

00:25:42.800 lots of superpowers in many ways, but smell wasn't really one of them.

00:25:46.200 I think I would agree with that. And it also say that if you block a sensory bank of the five,

00:25:51.680 others increase remarkably, like braille. I'm a microsurgeon. This stuff matters a lot,

00:25:56.840 but I can't do braille or hearing. I think you can crank it up if you lose a sense. And you see

00:26:02.360 that with people who are deaf from you. Your ability to see, and I don't think seeing better

00:26:06.740 is really the issue, but hearing and smell, I think it can crank up.

00:26:10.380 So one part per billion, this is remarkable. So you mentioned that at the base of the epididymis

00:26:16.340 is basically the launch pad. How many are stored in that?

00:26:20.080 Half a billion.

00:26:21.080 Half a billion. So five ejaculations.

00:26:25.240 Yep.

00:26:25.840 Okay.

00:26:26.440 That's a pot.

00:26:27.560 And what's the time to rebuild that? What's the rate at which you fill?

00:26:31.300 Oh, I don't know.

00:26:32.660 We're going to come to this, I'm sure. But is there a frequency of ejaculation that is too much

00:26:36.960 that if a guy is say, ejaculating every single day, is that insufficient to get a complete

00:26:43.000 replenishment where if he's having infertility, you would say, you got to move it to every other

00:26:47.140 day or whatever the number is.

00:26:48.540 So that's a great extrapolation of the pot of soup idea. And so on that note, I would say,

00:26:53.340 typically we recommend two days of abstinence, sex every other day.

00:26:58.020 To optimize.

00:26:58.780 Right. But not for the semen analysis. That's for conception.

00:27:01.380 Depends how old you are in your biology, but most men need a day or two to recharge

00:27:06.420 completely. A day or two. That's why we recommend that. That's sort of a generalization. Some men

00:27:11.140 are fine every day. I had a guy once who had to bank sperm for hepatitis treatment.

00:27:15.780 And he was like Mickey Rourke. He had a wooden leg and he's about 50. And I said, you're going to need

00:27:22.840 to abstain for a couple, three days to do this semen analysis. So we get a good stamp. I want it

00:27:26.840 to be optimized one. He looked at his partner and she looked at me and she grabs him and says,

00:27:31.700 you can't do that. He's every day. He can't do that. I don't know what he's going to do. So he's

00:27:35.480 like, he was panicking that he had to hold off. I said, often do you have sex? He said, twice a day,

00:27:40.220 every day. I'm like, okay, that was great. Then I had one man, wonderful orthopedic surgeon at

00:27:45.600 Stanford. And I asked him on my questionnaire, I said, how often do you have sex? And he wrote

00:27:49.100 0.00001356. He divided once a year, 0.00 weekly, 0.0015 Avogadro's number, right? Which meant he was

00:27:59.760 so frustrated. A beautiful way to say that was the 0.001355. So anyway, for a semen analysis,

00:28:08.960 for diagnostics for infertility, when you abstain longer, your sperm count will rise,

00:28:14.800 but your motility will fall because it's older.

00:28:17.860 There's a min-max curve that you're optimizing for, which you would say is...

00:28:21.960 Three days would be about right. When you're not going to gain that much, you're not going to lose

00:28:25.320 that much motility after that. So there's biological variability, which we try to minimize when we do the

00:28:31.440 semen analysis. So two to four days of abstinence. That's a different period than what we're

00:28:36.900 recommending for sex, which is every other day. And that's based on a New England Journal paper,

00:28:41.500 where they looked at, I think, 700 couples and they had them keep diaries. It was a Boston-based

00:28:47.340 paper, keep diaries of how they had sex, when they ovulated and when they got pregnant. And then they

00:28:52.900 said, do what you normally do and then give us the diaries. And then they evaluated them and they

00:28:57.460 found that having sex, say ovulation is day 15 of the cycle. When they started having sex on 9,

00:29:03.700 11, 13, there were significant pregnancy rates and every other day was the optimal interval.

00:29:08.920 But even five days before and three days before, there were substantial pregnancy rates before

00:29:13.840 ovulation. But if you waited to ovulation and then had sex, that's about 20% of conception. So

00:29:20.060 when you get the kit, don't react to it, predict in front of it. So front load the sex, very important.

00:29:26.860 And why is that? Is that because...

00:29:29.100 There's a reservoir effect in this uterus. It's managed. Sperm will survive for a day or two.

00:29:34.120 If ovulation is day 15, how could a day 11 sperm survive four days?

00:29:41.520 It's nurtured once it's past the vagina.

00:29:43.860 But how many of them are surviving? Is it literally the lone wolf or is it the last hundred?

00:29:48.740 Maybe.

00:29:49.580 Some of the sperm bind to the oviduct and wait.

00:29:52.280 Remind me where the oviduct is?

00:29:53.340 So there's the uterus and the fallopian tubes.

00:29:55.420 Fallopian tubes.

00:29:56.060 And that's the oviduct.

00:29:56.880 The oviduct is right below where the ovaries sit.

00:29:58.920 The scorpion tube essentially.

00:29:59.860 Yeah.

00:29:59.960 They bind to the endothelium and just park as if there's no egg. They'll just sit there.

00:30:05.020 So again, going back to our moon analogy, this is after you've done stage one, stage two,

00:30:09.680 stage three, you're now out of gravity, right? Like it's actually not an energetics problem anymore.

00:30:14.980 Right.

00:30:15.360 Or death's dog problem, right?

00:30:16.580 That's right. You've escaped the hostile environment in this case of gravity.

00:30:19.800 So now it's a fun place. It's the right pH. It's warm.

00:30:22.260 So do we have a sense, this would be a very interesting experiment, of what is the longest

00:30:28.360 duration that a sperm could survive for conception? In other words, to do the experiment, let's just

00:30:35.060 make it as a thought experiment. You had a large number of women that you knew were going to ovulate

00:30:39.320 on day 15, and then you would have them have intercourse on day 7, 8, 9, 10, and you create

00:30:47.900 a histoplot or a distribution of what's the frequency of pregnancy across those things and

00:30:52.540 ask what's the bottom fifth percentile, which is the theoretical possibility.

00:30:56.540 Yeah, that's a good one.

00:30:57.420 And then the same thing after. You want to develop the bell curve of the whole thing.

00:31:01.380 Well, we know that once the egg is ovulated about eight hours and then it's over.

00:31:04.560 This is a very important point. It really needs to be front. If it's only eight hours of survival.

00:31:10.660 After ovulation, about eight hours, it's dead. If it's not.

00:31:12.760 This is a very, very left tail curve.

00:31:15.220 Correct.

00:31:16.560 Ah, I did not know that.

00:31:18.180 So you want the sperm there ahead of time. 80% of conceptions naturally or at home occur

00:31:23.500 when sex is front loaded as opposed to reacting to ovulation. And most of the apps that are available

00:31:28.600 nowadays will tell you that. Peter, you're drawing a graph.

00:31:31.880 I am. I have to draw.

00:31:33.320 And it looks like it's algebraic.

00:31:36.720 This is incredible. It's easier for me to think about these things graphically

00:31:40.040 than to think that it basically shuts off at about eight hours.

00:31:43.280 So I give some more physiology. There was a study that showed how long it took to make a sperm.

00:31:48.120 And it was published in Science, I think, in the 60s. And they gave men trudiated water.

00:31:53.700 They gave men radioactive hydrogen. And then they biopsied their testicles,

00:31:58.300 which would never be done nowadays. But I did a little different. I gave deuterated water

00:32:02.080 with a group at Berkeley. And we gave healthy men deuterated water for a week. And then we

00:32:07.240 checked the first...

00:32:08.800 Sorry, dumb question. Why didn't they just measure the ejaculate? Why did they have to biopsy

00:32:14.240 the testes?

00:32:15.240 They just wanted to know about spermatogenesis. But we didn't want to biopsy testes.

00:32:18.720 They actually wanted to torture the guys, but...

00:32:20.160 That's wild. But that was the best data. And we did deuterated water, which is not radioactive.

00:32:24.200 And we could measure that. So we gave them a dose. And then we watched their ejaculates weekly.

00:32:29.100 And we looked for when deuterated, the hydrogen showed up in the DNA. And it was an average of 74

00:32:34.700 days. So normally, say, three months to make a sperm. So someone were 42 days. And that's going

00:32:40.960 through the epididymis and getting ejaculated. We talked about maybe two months in the testes and

00:32:45.840 two weeks, a week or two in the epididymis, and then maybe a couple of weeks to ejaculate.

00:32:50.460 And this was all the average 74 days. So it actually changed the timeline enormously to a

00:32:55.780 much faster one. So 74 days. So when you do anything to a man fertility-wise, you're not going

00:33:01.620 to expect to see anything change for at least two and a half months. And when you talk about full

00:33:06.860 replacement of that semen, it's probably end up being 90 days when it's all replaced. The pot is

00:33:11.480 replaced. That's a limitation of what we do. 42-year-old women want now. And we have three

00:33:17.340 to six months. When I did a study on fixing varicoceles, which is an infertility problem

00:33:22.180 in men, it's surgery. And I looked at the mean time to conception. It was about seven months after

00:33:26.900 repair, which is two cycles of sperm production.

00:33:29.840 So let's now define infertility. We've been using this term quite a bit. I suspect it actually has a

00:33:36.020 formal definition. It's one year of inability to conceive after sex, using sex.

00:33:40.560 Okay. Doesn't have to be timed intercourse, just has to be whatever the couple does when they think

00:33:44.180 they're trying to conceive. When someone shows up in your office, is it usually after they've

00:33:50.800 gone down the rabbit hole of troubleshooting the female partner? Or are people doing this in

00:33:57.660 parallel? There's a large bias in Western worlds about how infertility is evaluated. The reasons are

00:34:03.540 complex. But I would say my practice is not typical. So most of my patients have been through

00:34:09.560 a lot before they come to me. And typically, I think Keith Jarvie's data was good at about 23%

00:34:16.140 of men get a formal evaluation for infertility before couples go through IVF in North America.

00:34:23.480 And how does that differ from the rest of the world?

00:34:25.380 I don't think it's been studied in the rest of the world. But there are countries like Germany and

00:34:29.080 Spain with single insurers and government pays. And it's also recommended by society guidelines like

00:34:35.800 American Society of Reproductive Medicine, WHO, et cetera, that both partners get evaluated

00:34:41.260 simultaneously. But the bias is female gets very evaluated for lots of money. And the men typically

00:34:49.600 may get a semen analysis, but may not. And it's very complex reasoning there. It's a different beast.

00:34:54.340 They're not part of the problem. They refuse to do it. There's a lot of denial. It does get at your

00:34:59.840 masculinity a little bit to get checked out and things. So it does go deep for men. It can be a

00:35:05.420 little bit of a problem. So I would say that lately with large insurers coming in, progeny, maven,

00:35:14.460 and things like that, you're seeing a lot more men up front, which is fabulous. And we can have long

00:35:18.640 discussions about the biomarker concept, why that's good for the field and good for men's health and good

00:35:23.340 for longevity. Okay. Let's talk about your workup. What do you do when a guy comes in and what are

00:35:29.760 the things you want to know about him? So getting a guy in is great. Usually they're dragged in by

00:35:35.240 their partners. Usually the partners come along to make sure they show up. For me, it's one visit.

00:35:40.480 So we do one visit and I do everything else where they are, where they are. I don't ask them to come

00:35:44.700 in a million times anymore. So it's a very different kind of practice. But I try to get everything done

00:35:49.020 in one visit because when you get them there, it's rare to get them there. And the physical

00:35:52.600 exam, so you do a history, a very thorough history, which is usually preceded by a questionnaire. I give

00:35:57.440 200 questions and that has all the hot bath stuff and all the exposures they have. And they have to

00:36:03.640 do that before they see me. That's a really important part of it. If you could pick one in a

00:36:08.180 multiple choice question, what matters the most is probably the history. History of paternity matters,

00:36:12.860 a history of exposures matters, et cetera. Physical exam, very important. One to 5% of male

00:36:18.360 infertility can be due to a major medical issue, testis cancer, diabetes, things like that. So

00:36:23.720 physical exam, varicocele is very important. You could be missing a vas deferens. One in 500 men

00:36:29.240 have perfectly normal testicles, but they have a natural vasectomy. It's congenital absence of the

00:36:34.300 vas. They're going to be sterile or infertile. Can you explain what that, we haven't talked about

00:36:38.720 how a vasectomy works and why a guy still ejaculates but is infertile. Explain what the vas deferens,

00:36:43.960 how the whole thing works in the plumbing. Right. So we didn't answer that question,

00:36:47.200 which was what's the semen consist of. It's about 10% vasal fluid with sperm. It's about 80%

00:36:54.460 seminal vesicle fluid, which is an accessory sex gland in the back of the prostate and about 10%

00:36:59.160 prostate. So typically during ejaculation, prostatic fluid, which is clear and sticky,

00:37:05.660 will grease the barrel of the urethra pre-cum. Then during the ejaculation process, the pellet of

00:37:12.220 sperm gets pumped from the vas deferens into a chamber called the ejectory duct. And this happens

00:37:16.700 quickly. And then the semenal vesicle, which is like a bladder, contracts, sends it into the

00:37:21.000 prostatic urethra between the bladder and the outside world. There's two valves. One is the

00:37:26.120 bladder neck. It closes. And one is the urethral sphincter that we pee through. And that opens and

00:37:31.660 it gets forced out with muscular contractions in seconds.

00:37:34.580 Yeah. So therefore, if the vas deferens is clipped, you're getting essentially 90% of

00:37:40.120 the volume. You're just missing the 10% of the volume that contains the payload.

00:37:43.920 So in 3,000 men I've done vasectomies on in 30 years, two men have said, my volume went down.

00:37:48.940 And I said, really? One of them banked sperm and he had a semen analysis before and after,

00:37:53.860 and he did go down by 15%. And he noticed it. And I said, good for you. What do you want to do now?

00:37:59.500 So it can be noticeable, but not usually. And so the color is the same. The opacity is the same.

00:38:05.920 The whole process of liquefaction is the same. Viscosity, et cetera.

00:38:09.820 So physical exam, do you need an ultrasound? How are you able to detect if a person is

00:38:14.780 congenitally missing a vas deferens?

00:38:16.900 Pure physical exam.

00:38:18.000 What, you feel it? Interesting.

00:38:19.920 So my fingers can feel two and a half millimeters. The vas deferens is like a piano wire. I mean,

00:38:24.940 it is different than anything else in the cord. I did a study, a third of my men,

00:38:29.500 with abs and vas. We're only found out having procedures until I saw them. I usually just do

00:38:34.920 the exam, but it is an expertise thing. Yeah. It's not like the PCP can figure this out. You

00:38:39.700 have to be doing this all day, every day. Yeah. I think you need to be trained on that. But if

00:38:43.160 you're well-trained, it should be purely a physical exam. What percentage of men are congenitally

00:38:47.520 missing their vas? One in 500. One in 500. Okay.

00:38:49.960 The most common gen X's in America is cystic fibrosis. So the big implication is these men can't

00:38:56.340 conceive naturally. They have a natural vasectomy. We use sperm

00:38:59.320 retrieval techniques and IVF, but they definitely have the chance of passing on cystic fibrosis to

00:39:05.300 a child. Why is that? It's a very interesting biology, but men with cystic fibrosis, the most

00:39:11.140 common gen X's in America, have no vas deferens. Okay. So what's the Venn diagram of cystic fibrosis

00:39:17.280 and congenital lacking vas deferens? The genes for that were discovered. It's a chromosome 7.

00:39:22.600 Then there's 1,700, 1,800 mutations, maybe 2,000. So they cloned the genes and got the

00:39:27.580 variants in the late 80s. And then they found that there's another group of men who are perfectly

00:39:32.360 healthy, do not have cystic fibrosis, which is a major metabolic disease with a short life

00:39:36.560 expectancy, better now. Those men had absent vas deferens in the absence of disease. They took

00:39:42.480 the gene sets and looked at them and they were the same. There's not as many. So you have

00:39:46.700 homozygous or heterozygous. So you have a carrier for cystic fibrosis will have an absent vas,

00:39:52.720 but a full-blown CF patient, cystic fibrosis patient, will have no vas deferens too. So it's

00:39:57.960 a form-fruist of cystic fibrosis, but it doesn't have all the chemical and metabolic side effects.

00:40:03.280 So in other words, when you identify a man who does not have CF with a congenitally absent vas,

00:40:09.060 there's a very good probability he's a carrier of CF.

00:40:11.940 Yes. And you can usually define it.

00:40:13.360 Which we can genetically test easily.

00:40:14.960 Yeah. And then you have to worry if there's a 4% chance in America anyway,

00:40:18.560 that a partner might carry it. There are two carriers. You have a one in four chance

00:40:21.840 of having a very affected child. So that's the big concern in my practice. And I'm proud to say

00:40:27.620 in 30 years, we have no CF children. It's all about good engineering and doing it right. So

00:40:32.640 that's the vast deference part.

00:40:34.780 What else on physical exam are you looking for?

00:40:37.040 Cancers, infections, epididymitis.

00:40:40.360 Yeah. Tell me about epididymitis. Obviously anything that interferes with that

00:40:43.800 section of the journey is going to be critical. Remind me, is it EBV that we typically are measles,

00:40:48.880 mumps? What's the infection?

00:40:50.340 Mumps. Yeah. So among viruses in the world, there aren't many that get into the testicle

00:40:55.660 like other things. Very little gets into the testicle, similar to the brain. But the mumps

00:40:59.600 virus does it about a third of the time when you're a child with mumps, the parotid gland infection.

00:41:05.380 It's a glandular disease. So it really only matters when you're pubertal and you get mumps.

00:41:13.280 Then it goes to lots of glands. It can go to your pancreas, cause diabetes. It can go to the

00:41:17.040 salivary glands. It can go to the testicles. It's some kind of, there's an open time.

00:41:21.740 So just one more reason why everyone should really get the MMR vaccine when they're a child,

00:41:26.300 notwithstanding the tragedy of children dying from preventable diseases. But this is another

00:41:31.860 non-lethal, but significant complication of the mumps. Absolutely. And it will cause viral

00:41:37.120 necrosis and edema of the testis. And similar to a brain, it's in a calvarium, right? The brain is in

00:41:43.160 a fixed space. So when it swells, you got to do something because it can die. If it swells too

00:41:48.420 much, testicle is a fixed cavity with the tunic albiginia. And so if it swells too much, it necrosis

00:41:53.500 and then you get fibrosis and then you get sterility. I've got techniques where I can find sperm in lots

00:41:58.440 of these men, very little pockets, but most of it, you're ablating the testis. It's going to scar

00:42:03.020 and die from ischemic necrosis. Zika, Ebola. I mean, the CDC called me when these were coming

00:42:09.300 around. Zika has been transmitted through semen. It causes the anastephaly issues. When these pandemics

00:42:14.560 were occurring, Ebola too. I got a call that there was an Ebola patient who survived, went to the

00:42:19.840 Institute, survived hemorrhagic fever. And then a year later, transmitted Ebola to a partner who

00:42:27.480 transmitted to six other men. And it was another outbreak in South Africa.

00:42:32.920 Meaning the patient that survived Ebola, the virus managed to survive in the testes?

00:42:40.240 Somewhere, but it was transmitted sexually a year later when he was well.

00:42:44.380 When he was asymptomatic. He had already developed immunity.

00:42:46.480 Right. We don't know about testis, but we know that mumps will do that to the testis,

00:42:50.220 but there are Zika is also persistent in the semen.

00:42:52.700 But in that case, you have to think wherever the virus hung out, it had to be very, very

00:42:57.900 immune privileged.

00:42:59.020 Yep. Or at low levels, like low viral loads where there's no disease. I'm not sure. But

00:43:03.840 these are concerning cases.

00:43:05.540 But then it was transmitted at a low viral load, an even lower viral load.

00:43:09.180 Right. So it's tricky. There may be bulboidurethral glands. Maybe it's somnolvescal. It's hard

00:43:13.920 to know, but yeah, it's getting away. But most viruses don't go there. So the big one would

00:43:18.820 be COVID. What did COVID, there was a big deal about the AC receptor being in the lung and

00:43:23.420 being in the testicle. And maybe COVID infection would make you sterile. There was one Zika paper

00:43:27.960 in Nature that looked at if you infect mice or was it rats with Zika, the testicles shrivel

00:43:33.580 up and they get infertile. And that caused a huge scare in the field, but we really didn't

00:43:38.680 see it. Maybe see it and see if we don't see it in fertility.

00:43:42.200 And what is it about the Zika virus that does this?

00:43:44.200 We're not sure. Why did it in rats? It's a blood testis barrier thing. It's an amazing

00:43:49.340 barrier and nothing really gets through, including viruses. But mumps does, only at

00:43:53.440 puberty.

00:43:54.220 And Zika does.

00:43:55.220 Zika does in animals, but we didn't see it in humans.

00:43:57.520 But I thought you said that Zika was leading to anencephaly in cases.

00:44:00.420 Yeah, but that could be seminal. That could be just in the semen itself, not in the sperm.

00:44:04.000 Like Ebola is probably seminal, not testicular. It's not on sperm. It's around sperm or in the

00:44:09.520 fluid. That's the conclusion so far. So COVID, the big worry was when this Chinese paper came

00:44:15.660 out, like, oh my God, it's going to the lung, buying to the AC receptor. It's testicle has

00:44:19.340 it too. It's going to make men sterile forever. And there were cases of infertility with bad

00:44:24.240 infections. Was that just the fever, which typically does it even after a flu, or was that COVID

00:44:29.760 specific? And we didn't know. A couple of colleagues did some papers. One, which impressed

00:44:33.980 me, was out of Cedars, was a bunch of men, maybe not reproductive age, died with florid COVID. So

00:44:40.980 they got autopsies and they looked for virus in different locations in the body. And I think out

00:44:46.200 of 10 men or seven men, one had it in the testicle. So these are the men with the highest viral load

00:44:51.720 you can imagine, and only one of them had it. So I believe that there is a risk of it. But I'd say

00:44:57.500 in the thousand men I've seen since COVID, I think there were two cases that I would say were

00:45:03.000 unexplained, where men were either fertile or had normal semen quality, had a bad COVID infection,

00:45:08.400 maybe hospitalized, and three months later, sterile. So I think there's a low perfusion

00:45:14.540 rate there. What is the phenotype of their sterility? Aside from the presentation that says

00:45:19.700 I can't get someone pregnant. So sterility means no sperm in the semen. And typically if you measured

00:45:24.020 the signals to the testicle. Oh, that's literally what it means. I'm sorry. Okay. So literally no

00:45:27.960 sperm in semen. They stopped. Understood. It's a primary problem. So the third thing we do,

00:45:32.560 history, physical semen analysis is a third. Fourth would be hormones. And that's what we check

00:45:37.260 in men too, because production of sperm is driven by the brain. So nothing happens to sperm being made

00:45:44.980 without the brain telling it what to do. Similarly with eggs and controlling, it's all a homeostatic

00:45:49.260 mechanism with negative feedback. Classically anabolic steroid users. Yeah. Which I want to talk

00:45:54.380 about in detail. Can we go back to semen analysis? You're looking for obviously the count and the

00:46:00.360 motility. What else do you look for? So in the semen analysis, there's several features. I

00:46:04.060 consider it sort of a poker hand. There's a volume, how much of the semen volume. There's a count,

00:46:09.080 concentration of sperm. That's numbers per mil. And then there's motility, which is percent motion.

00:46:14.280 You do a forward progression. So how good is the quality of motion? And typically some measure of

00:46:18.940 shape called morphology. There's three liquid issues, liquefaction, agglutination, and viscosity.

00:46:25.380 And then you look for other cells that aren't sperm. They're called round cells. And either

00:46:30.260 they're going to be pus cells or immature germ cells that are ejaculated early.

00:46:34.340 And presumably you want to see fewer of those?

00:46:36.460 There's a number of like less than a million is normal.

00:46:38.500 Okay.

00:46:39.180 So if you ask me, well, how do I look at a semen analysis? That's a little different. I look at

00:46:43.020 that as a poker hand with each card has a meaning, but they have a look. So if you said, what do you

00:46:47.760 mean by that? So if the volume is low, it's one of five things. You're always going to find

00:46:52.900 something. It's at the collection error. I call it first sample syndrome. Guy's not good

00:46:56.760 at it. You know, it's like, okay, you got to put it in the cup and I got to stop doing

00:46:59.600 what I'm doing. So you do a second sample. And then there's low testosterone can cause

00:47:04.240 it. There's an absent vas deferens, which means you have an absent seminal vesicle. There's

00:47:07.740 ejaculatory.

00:47:08.300 And by the way, do you ever have that on one side and not the other?

00:47:10.700 No, no, it's very variable. It's segmental. So there's five real issues. So when I see a

00:47:14.960 low volume semen as a surgeon, I'm going to find something. So that's really good. Other

00:47:19.840 than that, the semen analysis, I think I've been published as saying it's a

00:47:22.800 blunt instrument for fertility. Unless it's zero, you can't really say much about their

00:47:26.940 fertility because people conceive at all levels.

00:47:29.920 Obviously you rattled off a whole bunch of parameters that you can access there, but are

00:47:34.220 there certain null states that don't exist where everything is amazing, but this one

00:47:38.100 thing is horrible? Like, do you see scenarios where everything is remarkable? Perfect motility,

00:47:42.960 but bad morphology or perfect morphology.

00:47:46.100 Isolated.

00:47:46.880 You do see isolated things.

00:47:48.100 Right. So one of them is called, I call it syndromic sperm shape problem. So you can have

00:47:52.440 a perfectly normal semen analysis, count, motility, volume, progression, and the sperm

00:47:57.380 look terrible. And so there are rare conditions, one in 5,000, where you might have globosospermia

00:48:04.580 or two-tailed sperm or pinhead sperm. So if you look at shape, 4% should look normal, just

00:48:10.380 terrible. We can have a whole discussion about why 4% of human sperm being normal is normal

00:48:14.380 when 99% of animal species in the wild have normal looking sperm. But it's all a construct.

00:48:19.980 It's all a construct of someone decided what normal is. But in men who have large abnormal

00:48:25.920 forms, like 4% is normal, if they're 1% normal, and you look at the abnormalities.

00:48:30.660 I'm sorry, I'm still confused on that point. Are you saying that you would consider it perfectly

00:48:34.940 normal if only 4% of the sperm are morphologically perfect and 96% are not? And that means the 96%

00:48:43.200 that are not could be pinhead, could be double-tail, amorphous or tapering. As a mathematician,

00:48:50.020 that's not a great number, is it?

00:48:51.140 No.

00:48:51.480 If you look at marine species, 99.9 look perfect in the wild.

00:48:55.740 Yeah. And presumably that's because their environment is so much more hostile. They're

00:48:59.200 doing this all in the ocean.

00:49:00.620 I don't know, but it's amazing that we're that good with the sperm. But again, it's a construct.

00:49:05.340 It's like putting stars, ordering stars in the universe, Cassiopeia. Someone named Kruger

00:49:09.700 said, this is what a normal sperm looks like. But we know that two-tailed sperm have double-

00:49:14.100 Yeah. I mean, it might be the two-tail might not be the worst thing in the world. It's just

00:49:17.320 extra rocket boosters. But what about the pinhead? What does the pinhead imply?

00:49:20.640 Pinhead means there's no nucleus. It's a tail with a motor.

00:49:22.440 So that's a true problem.

00:49:23.500 Yeah. It's like a little tiny head and moving along.

00:49:26.340 So if you give somebody credit for their two tails, what does your normal go up to from 4%?

00:49:31.220 Oh, it depends. But maybe 20. But most of them are going to be amorphous. Head's a little

00:49:36.680 rounder, head's a little narrower. Those are called stress patterns. And things

00:49:39.580 like hot baths and varicoceles and smoking will do that, which isn't that bad. In the

00:49:43.800 case of 1% normal, you've got to look at the 99% because that's not the story. The story's

00:49:49.440 in the other chunk. And if they're all looking the same, then it's syndromic. And then you

00:49:54.620 have a problem.

00:49:55.360 I see. So the more homogeneous the failures are, the more likely that you have a clear

00:50:02.580 etiology.

00:50:03.780 And that's hard to fix. I mean, they'll fail with sex. They'll fail with inseminations.

00:50:07.600 They'll fail with IVF.

00:50:08.560 They'll fail with IVF.

00:50:09.600 Yeah, they'll fail with IVF and ICSI. Sometimes with globosuspermia, where they're called lollipop

00:50:14.100 sperm, they just have a big round head with no acrosome. There's all nucleus and there's

00:50:18.320 some of the components. They'll just bounce off an egg. They'll never work. They'll never

00:50:22.700 do work naturally. And to get them to work with IVF, you have to single sperm inject them

00:50:27.060 into the egg and then shock the egg with calcium. Do a calcium or piezoelectrics to get it to

00:50:31.900 start to actually fertilize. Because the sperm is important with fertilization. Not only has

00:50:36.860 the bind, but the calcium channels are regulated by sperm. And what shuts the doors to polyspermia

00:50:42.640 in an egg is calcium activation.

00:50:44.440 This is the reason why even if you launch a hundred sperm at an egg, it's only one that can

00:50:50.820 get in. Because the first guy that breaches sets off the calcium channel that shuts the...

00:50:56.760 I mean, the Star Wars space analogies here are just phenomenal.

00:51:00.820 A million years. Yeah, yeah, yeah. A million years.

00:51:03.700 No more breaches in the hull.

00:51:05.320 So morphology can matter a lot, but it's very rare. So I'd say twice a year in my practice,

00:51:09.560 I'll see this because everything's failing and everything looks normal. And they ask me

00:51:14.140 what's going on and I'll look at it really closely and say, you have this issue and there's

00:51:18.580 not much we can do to treat it. Now we're going to try sperm sorting technologies, which

00:51:22.060 are out new in the market, microfluidics and things like that. And I've been throwing that

00:51:24.980 at them. Sometimes it works, sometimes it doesn't.

00:51:27.160 Is that something that we know the genetic underpinning of?

00:51:32.160 We're getting there. PLZ-zeta deficiency is one of them, recently discovered, that runs

00:51:36.320 the calcium channel, which tends to be associated with a certain look like globals of spermia.

00:51:40.360 So it's coming around.

00:51:41.380 Think about that for a second from an evolutionary perspective.

00:51:44.600 That's a problem.

00:51:45.120 That is the single least desirable genetic mutation you could acquire.

00:51:51.000 Yeah, unless you're not making sperm.

00:51:52.700 Yeah, but this is a dead end to the genome.

00:51:55.100 Right, right.

00:51:55.880 So does that mean it is only an acquired mutation, never inherited? I mean, it can't

00:52:01.840 be inherited, presumably, unless it's homozygous, but even still.

00:52:05.040 That's one of the 50 we throw off each generation, 50 mutations.

00:52:09.380 God, that's just incredible.

00:52:10.300 I think what I would like to emphasize in this podcast is how fluid evolution actually is.

00:52:16.920 And it's sperm-driven, and it's transgenerational.

00:52:20.880 So if you ask me, what's the theme for today? It's a sperm matter a lot. A lot. A lot more than

00:52:28.280 we've given them credit for.

00:52:29.760 All right. So basically, just rounding out the semen analysis.

00:52:32.620 History, physical semen analysis.

00:52:33.580 On the semen analysis, what if motility is the problem?

00:52:37.240 So I look at, in my poker analogy of the hand, if everything looks good, but the motility's low,

00:52:43.420 I think of short-term toxins. Severity. So things like exposures. So medications. I think about

00:52:51.200 habits, pot, smoking, hot baths. I think about behaviors, lifestyle. So I look for an exposure in

00:52:58.340 that individual. Basically picked up on the history. Varicocele is an exposure, things like

00:53:03.240 that. And if the count's down and the motility's down, I think of a more severe exposure. There's

00:53:10.340 royal flushes and there's four of a kind. My goal when I see that semen analysis and see that patient

00:53:14.660 is to figure out if he's not normal, why? By the way, do you get that analysis the day he's in the

00:53:21.100 clinic with you, or is that something you follow up on an appointment with?

00:53:23.820 Pretty much have it in my hand when I see them. Either they give it to me or I get one.

00:53:27.380 I want that there because that's, when I look at them, I'd like to have that in front of me to say,

00:53:31.880 what kind of poker hand are you playing? And this is something that's standardized

00:53:35.220 and automated through microfluidics? How is the assay actually done? So the guy ejaculates in a

00:53:40.440 cup, takes it to a lab. Oh, I mean, used to be done manually. Okay.

00:53:43.600 And now it's done with the hemocytometers. It's done with machines. Computer-assisted semen

00:53:48.580 analysis does most of them in IVF groups. It's really standardized. Oh yeah. I like the bespoke suit.

00:53:54.160 So when I have mine repeated, I usually have someone do it by hand because

00:53:58.480 there's observations I like, which is, Hey, you know what? 1% morphology, but all the others look

00:54:03.300 like this. Those comments are incredibly valuable that you don't really get from a computer-assisted

00:54:09.260 semen analysis, but it's faster and you don't have a lot of human effort involved with the computer.

00:54:14.680 Are they using AI for this yet?

00:54:16.400 Yeah. I mean, some people are for sperm selection a little bit, but yeah, there's a lot of stuff to

00:54:20.940 help out. And now it'll be really helpful for morphology to standardize it because one man

00:54:25.280 named Kruger in South Africa correlated bad sperm shape with IVF outcomes and did not find that they

00:54:30.880 were good when the sperm looked bad. That's where the 4% came from. But it's really hard to do that

00:54:36.260 every time and do it well because it's so hard to do. Hoping AI and machine learning can help

00:54:41.440 standardize the look because sperm is hard.

00:54:44.760 Given how good AI is at image recognition, this should be a one foot putt. Yeah. Okay. You

00:54:51.040 mentioned hormones. You were obviously alluding to LH and FSH. What else are you looking at?

00:54:56.080 Testosterone?

00:54:56.640 Right. So to make normal amounts of sperm, you need a proper amounts of testosterone and FSH. Think of

00:55:01.640 it as flowering a plant. You need the water and you need the sunlight. So testosterone and FSH are key.

00:55:06.480 To get normal amounts of T, testosterone, you're going to need LH, which drives it. Same in women.

00:55:10.680 These are all named in women and females. So that signaling is really important. So there are

00:55:16.800 cases of genetic infertility like Kalman syndrome where men aren't making any sperm, but they're just

00:55:21.880 not sending the signals down and you can just give them the signals with injections.

00:55:26.000 Sorry. These men are not making FSH and LH. No.

00:55:28.500 So they have virtually no testosterone. Right. Nor sperm, but you can give them

00:55:33.180 those signals. Yeah. So HCG, FSH injections, and they will be fertile.

00:55:37.860 So is the problem in the pituitary not the hypothalamus?

00:55:40.480 No, it's the olfactory node in the hypothalamus. So they don't smell either.

00:55:44.740 So could you give them Clomid and would they make...

00:55:47.360 No.

00:55:47.940 No.

00:55:48.660 Pituitary is not working. Yeah. The GnRH is...

00:55:51.580 The GnRH is not...

00:55:52.360 Pituitary.

00:55:52.900 Okay. Got it. What about estradiol? Does it play a role?

00:55:55.440 Yeah. So estradiol is sort of a mild poison for male infertility. So everyone needs estradiol level,

00:56:01.260 female hormone levels. Testosterone gets converted to estradiol. So that's a byproduct of it along with DHT.

00:56:07.480 And then estradiol goes back to the brain and is a feedback. So if it's there, the brain knows how

00:56:13.200 much testosterone it's making. So if there's too much estradiol, the brain senses it's a negative

00:56:17.840 feedback, senses, hey, there's too much of this. So let's make less testosterone. So it will lower

00:56:22.580 your testosterone to have high estradiol. When estradiol is made, it gets metabolized

00:56:26.620 differently than testosterone. It goes to the liver or to fat. And aromatases convert it to

00:56:31.940 something else or testosterone gets converted to female hormone aromatases. So you can get high

00:56:36.700 levels being obese or having liver dysfunction. So alcohol, alcohol, cirrhosis, hepatitis,

00:56:43.240 it'll rev it up and it'll make a lot more estradiol level. And there's some medications

00:56:46.780 that do it too. And that will act and lower your testosterone, which will lower sperm production

00:56:51.320 because you're not watering the plant. But if you correct for testosterone, so in other words,

00:56:55.520 if a guy has normal FSH, LH, and testosterone, is there an estradiol level by itself that is

00:57:00.660 problematic? Not usually. Okay. So it's really only high estradiol in the context of suppressed

00:57:06.340 testosterone. Right. So that's when you would act on it. If you see that there's a low count and the

00:57:10.320 testosterone's low, and you could say you need to lose a hundred pounds, which is the key secret for

00:57:15.600 everything, right? But you can also give aromatase inhibitors like weightlifters use to keep their

00:57:20.760 levels down. Okay. So those are four big pillars. Anything else besides the history, the exam,

00:57:26.120 the analysis, and the hormones? So you usually do two semen analyses three weeks apart or more

00:57:30.640 to get a sense of things because it varies quite a bit. So a very important point is that the semen

00:57:36.220 analysis, any feature of that semen analysis varied by 50 to a hundred percent. So never make a decision

00:57:41.840 on one semen analysis. It's really hard. Yeah. Especially if it's the first one, as you said,

00:57:45.500 for all the potential. Right. So I do a lot of consulting for the FDA and they do medications and

00:57:50.220 reproductive age men and they're trying to show the semen analysis, they're going to the FDA

00:57:53.340 and they're saying, can you help us interpret this data for the FDA? I said, garbage in, garbage out.

00:57:57.940 I mean, there's so much variability, you really can't say anything. So you have to do at least

00:58:01.240 two samples and it still varies quite a bit. There's inter-observer variability, who does the

00:58:05.620 semen analysis. There's biological variability on what your system's like. So that's the big problem

00:58:10.580 with studies. So what percentage of drugs that are going through an FDA approval process

00:58:15.860 are having a semen analysis as part of the evaluation? I don't think many.

00:58:20.940 Why is that? Because usually the indications aren't reproductive age men or women

00:58:24.360 for some of them. If they do, they'll do animal models. They won't do human studies,

00:58:29.260 do animal models. They'll do beagles, mice and beagles. And if there's no fertility effects,

00:58:33.760 they don't really look at semen analyses in those. They'll look at fertility effects in the animals.

00:58:37.700 If there's nothing there, then they'll probably not require human studies. If there's any suggestion

00:58:43.540 of a problem in the animal models, which is a million dollars of work. So if you ask me why I

00:58:48.960 patented the spermatogenesis stem cell, I want an in vitro test for human infertility that we could

00:58:56.060 use instead of animal models. Save the animals, save a million dollars, do an in vitro spermatogenesis

00:59:01.400 model and see if there's an effect at all. It just seems to me that in this day and age with people

00:59:06.640 reproducing at older and older ages, we shouldn't just assume that because we've developed a drug for

00:59:12.580 blood pressure or diabetes that it's not going to be used by people with fertility. I'll give you a

00:59:18.060 silly example. Have GLP-1 agonists been tested for fertility? No, because it's sort of an off-label

00:59:23.280 use of a diabetic medication. But it's no longer off-label. I know. It's an on-label use today.

00:59:27.720 But it looks like it might be helping with fertility. But even if it was on-label, I mean,

00:59:31.820 I'm just using that as one example of a drug that was initially approved when we thought, ah, this is

00:59:37.100 going to be for people who are not having kids. But the truth of it is you're going to have lots of

00:59:40.920 people that are trying to reproduce on many of these drugs. Absolutely. Absolutely. And, you know,

00:59:44.980 there are 80,000 chemicals out there that are not been studied reproductively that are commonly

00:59:49.040 unused in industry. European commissions are a little better off. They've screened them

00:59:53.280 and they've warned about them. But in America, mm-mm. Why is that? I don't know. It's attention to

00:59:58.820 detail. It's one of those things that just doesn't, I don't know. Is it under the purview of the FDA?

01:00:03.700 Yeah. Or the EPA? Probably a combination or maybe everyone's thinking it's the other person's job.

01:00:08.860 I'm not sure. But they're untested and they're out there.

01:00:12.500 Why don't we just talk about some of those things then now? So this is, I'm sure, a contentious

01:00:17.040 topic. But as you know, lots of discussion around microplastics. So I don't know how far we want to

01:00:22.740 go down that rabbit hole. I recently did a podcast on this topic. I didn't really touch on fertility

01:00:27.400 because I just didn't see any great evidence. I talked more about things where I thought there was

01:00:31.400 a little bit more evidence. Obviously, with the microplastic story, there's quite a bit of smoke,

01:00:35.720 but there's no real fire. My conclusion from the analysis was there is enough smoke that takes

01:00:41.900 steps where they are reasonable and reduce your exposure to these things. So everything from

01:00:46.560 microplastics to PFAS chemicals to phthalates and even the PM 2.5s. There's no reason to expose

01:00:53.300 yourself unnecessarily to this. If you can take relatively straightforward steps, eliminate 60 to

01:00:57.880 80% of it in your life, do it. Tell me what your impression is of the effect of any or all of the

01:01:03.620 above on fertility. So although sperm are made constantly and are susceptible to that, we know

01:01:10.320 the testicles are pretty good place, excuse me, and insulated from exposures. I also think there's

01:01:15.540 a lot of smoke there and it needs to be sorted out. But especially with the 80, 60 to 80,000 chemicals

01:01:20.260 that are being used that aren't really tested at all, I think the only way to know is to do stem cell

01:01:25.020 in vitro testing as much as you can before you put it on at the ID investigational drug stage,

01:01:30.760 not at the final stages for clinical trials, but early on do it. So you're screening them way in

01:01:36.380 advance of getting into clinical trials and when the money gets big. But I think that there are

01:01:41.960 windows of susceptibility in men, unlike maybe with women whose eggs are constantly exposed to toxins.

01:01:50.100 Men have windows, and one of those windows is birth and early development, the first 12 weeks of life.

01:01:55.540 That early. When all organ systems are developing, including testicles,

01:01:58.860 I mean, Shauna Swan did this one, with maternal beef consumption, estrogenized beef consumption,

01:02:05.580 their sons had lower sperm counts when they were 20 years later or something. So I think that's a

01:02:10.920 window of susceptibility. I also think puberty is a window of susceptibility when things turn on.

01:02:16.700 So I think if exposures in those moments are probably going to matter the most to men.

01:02:20.600 I don't know about other times.

01:02:22.480 And what is your advice to a guy when you're giving him counsel on everything he can do? We're

01:02:29.900 going to talk about everything. But on this particular domain, if he says, hey, should I

01:02:34.560 stop drinking Starbucks coffees in those plastic cups with the plastic lids? And should I get a

01:02:40.540 reverse osmosis filter in the house? Like, where are you telling him to draw that line?

01:02:44.320 I'm not great at that because the stress level goes up so much. And I think the stress

01:02:48.280 counterbalances any amount of microplastics you save.

01:02:50.780 I mean, you double the stress in a man and his testosterone level will fall. And then

01:02:54.800 the sperm production falls for a whole different reason.

01:02:56.640 My testosterone level, when I left residency-

01:03:00.320 Oh, I bet.

01:03:01.140 So how old was I? 33. Should have had a pretty good. Total T, 220 nanograms per deciliter.

01:03:07.200 Did you measure LH? That's probably low.

01:03:09.820 Yeah, I'm sure FSH and LH were totally low. I don't remember what they were.

01:03:12.640 Right, because that's secondary.

01:03:13.400 Free testosterone of like three to four.

01:03:15.840 Well, the sleep deprivation, the stress.

01:03:18.480 So what does stress do? Stress is the sympathetic nervous system. It's fight or flight. You're

01:03:22.940 running from a woolly mammoth. It doesn't know what you're running from. It doesn't know whether

01:03:25.800 it's sleep or travel or financial or emotional. It's just the body. We are cats and dogs. We have

01:03:31.800 the same binary nervous system. Either you're on or you're off. And when you're on, do you want

01:03:37.860 testosterone? No, you want cortisol. You're running for your life. And do you want fertility when

01:03:42.840 you're running for your life in any species? No, you're trying to save your life. So cortisol goes

01:03:47.600 on. Testosterone is nowhere to be found. Fertility is nowhere. You turn off all that stuff. Then when

01:03:52.640 you outrun the woolly mammoth and you're behind a rock and you grab the berries and you catch a nap,

01:03:57.300 boom, testosterone shoots up because it's rest and restore and you have to rebuild for the next run.

01:04:01.700 How quickly do you think that occurs in humans? Days, easily. Chronic stress is it. We love acute

01:04:09.160 stress. All species love acute stress. We love that starvation, intermittent fasting. It's really

01:04:14.800 healthy, but not low-level chronic stress, not connected to your computer, not your emails,

01:04:20.560 not the workday that never ends. Terrible for us. And the best manifestation is erections because

01:04:26.800 erections will fall if you're under stress too. Penis has a mind of its own, according to Da Vinci.

01:04:31.700 I had a guy come in 25 in San Francisco, a startup guy, and he comes in and says,

01:04:37.320 I got to see you. I said, why? He said, I lost my erection yesterday. He's 25. He said,

01:04:42.260 first time? He said, yes. I said, all right, come on in. So he comes in and he's got his act together.

01:04:48.860 It looks good. And I said, what happened? He said, I just lost my erection. It's never happened to me

01:04:54.660 before. I think something's wrong. And I said, okay, tell me about yourself. He's just getting a round

01:04:59.180 of funding. He's traveling half a million miles a year. He sleeps three or four hours a night,

01:05:03.360 if any, and he's constantly running. And I said, congratulations, welcome to the human race.

01:05:08.820 And she's like, what are you talking about? You're not impervious. Stress has its effects.

01:05:14.160 So clearly fertility. Oh, the great study was a moderate exercise, moderate exercise, man.

01:05:21.440 I wrote a blog on this called, Can You Be Too Fit to Be Fertile? Moderate exercise went to extreme

01:05:27.060 measured as two hours a day of VIO2, 80% maximum capacity. So pretty heavy workouts for 12 week

01:05:34.000 periods. So moderate to extreme, and then back to moderate. Sperm counts fell by 40% when moderate

01:05:40.200 to extreme and testosterone fell by 50% and then went back up. And there's also military studies of

01:05:46.460 men under acute stress during hell weeks and training where they were taking their testosterone and

01:05:51.080 they were dropping by about 50% with severe stress. And that's okay for a day or two or a week.

01:05:58.100 But when you're doing it chronically, we're not built for that, Peter. We're not built for chronic

01:06:01.800 stress. That's a longevity issue. Yeah. Let's talk about the use of anabolic steroids. Let's talk

01:06:10.180 about it more broadly with the three most commonly used approaches to testosterone replacement. The way I

01:06:16.160 see it is the three most common approaches are using either clomiphene or enclomiphene, using HCG,

01:06:23.340 or using exogenous testosterone in one of its derivatives. Would you agree that those are kind

01:06:28.340 of the big three? Okay. We'll just briefly highlight for everybody why each is a little

01:06:32.500 bit different. Exogenous testosterone, you're just giving testosterone. The body senses it and

01:06:38.060 immediately shuts down the hypothalamus. All natural production.

01:06:40.740 Yep. So LH and FSH will go to zero. Testosterone will be as high as you want it to be. There's no

01:06:47.980 limit to how high it goes. I've had a couple of people on this podcast who have blown my mind with

01:06:52.660 how much testosterone they've talked about taking. Not clear how that's possible, but nevertheless,

01:06:58.320 they're doing it. HCG is synthetic luteinizing hormone. So you give a person HCG, they will make

01:07:06.120 testosterone. So it's endogenously produced, but they're making so much of it that they'll also

01:07:12.240 suppress LH and FSH. So LH and FSH will come down. Testosterone will go up. And then clomiphene or

01:07:19.140 enclomiphene block the signal of estrogen at the level of the hypothalamus. So the hypothalamus

01:07:26.140 doesn't see any. Oh my gosh, we need more testosterone. It ramps up FSH and LH production,

01:07:31.580 which has the same effect as making more testosterone, but you'll now see high normal

01:07:37.000 FSH and LH. Yeah. And the two different classes are the LH and clomid versus testosterone. So

01:07:42.040 unlike testosterone shutting off the natural production, the LH, the HCG and the enclomiphene

01:07:47.780 and clomiphene will stimulate natural production. So you keep your testicular size, you maintain your

01:07:53.280 fertility, whereas the others, you're going to shrivel up your testicles and not maintain your

01:07:57.720 fertility. And you can't generate levels that you can with the exogenous testosterone with these.

01:08:04.140 You'll never get to 3000. You can't do that. It's tightly regulated.

01:08:08.040 So question one, if a guy is taking exogenous testosterone, and let's just say he's been on

01:08:14.040 it now for a few months, is he able to create sperm?

01:08:19.560 95% chance he's not.

01:08:21.280 Wow.

01:08:21.740 While he's on it.

01:08:22.600 Yep. Understood.

01:08:23.460 But can he create it once he stops?

01:08:24.580 And we'll definitely address that. But just to be clear, even a couple of months on exogenous

01:08:30.320 testosterone in any form, injection, topical, oral, whatever, you basically have shut off the

01:08:37.240 ability to make sperm because your testes themselves have shut down.

01:08:43.120 Right. No signals, no gas to the engine. It's nuanced. There are formulations that are topical

01:08:48.580 that are less potent that way, less inhibitory than injectables. So there are variations in the

01:08:54.920 spectrum of exogenous testosterone that will maintain some of your fertility.

01:08:59.460 I don't want to go so far as to call it the marketing material, but for lack of a better term,

01:09:03.220 the marketing material is suggestive that the more frequently delivered variants. So for example,

01:09:10.700 the intranasal variant, which is delivered three times a day, the oral variant delivered twice a day,

01:09:16.060 have less of a negative impact because they're producing far lower surges than if you did a

01:09:22.160 weekly injection. Is that what you're referring to?

01:09:24.880 Yeah. So they do more physiologic. They're in the normal range more. What gives you side effects

01:09:29.720 from testosterone, including sterility, is too much.

01:09:33.260 Yeah. So in your experience, has that borne out?

01:09:36.440 Yeah.

01:09:36.920 You've seen men taking Natesto three times a day, doing a nasal-

01:09:41.220 Keeping their sperm count.

01:09:42.160 Keeping their sperm counts.

01:09:42.940 Okay. That's interesting to note. What about the oral testosterone, the twice a day?

01:09:47.220 Love it. Testosterone, I can't wait. And it was not available in America for 50 years. It was

01:09:54.180 available in Europe. And a couple of researchers at UCLA, a husband-wife team, beautiful. What

01:09:59.580 happened was we were worried when we took oral testosterone-

01:10:02.160 Yeah, we'd go to the liver.

01:10:03.000 Right, to the biliary system and go to the liver, cause liver cancer. So it was always verboten.

01:10:07.640 Even though there was no evidence this was happening in Europe for 50 years?

01:10:10.260 Yeah, not much. It's FDA approved. The EEA approved it. So this group came up with a

01:10:15.180 way to get it metabolized through the lymphatics. So it can absorb through the lymphatics and

01:10:19.160 never hits the liver. And it's really good. I mean, there is a non-response rate of around

01:10:23.380 10%. So it's 10% of men. Some like gels too. 15% won't respond. There's groups that won't

01:10:29.260 respond that well, but it is really good.

01:10:32.200 Do you prescribe it?

01:10:33.160 Oh, yeah.

01:10:33.460 I'd be interested to hear your experience with it. We have prescribed it now to

01:10:37.800 maybe a half a dozen patients. One of the silly challenges we have with it is we actually have

01:10:43.000 no idea if they're therapeutic because trying to get their blood drawn to figure out when to draw

01:10:48.020 their blood to actually see the level. For example, if a guy takes the drug at eight o'clock in the

01:10:53.220 morning and then at one o'clock in the afternoon, which is sort of what we're told is a great window

01:10:57.140 to take it so that you get that mid-dose. Mid-dose, right? If he does his blood draw at

01:11:02.800 seven o'clock the next morning, he's been 18 hours off drug. He has unmeasurable testosterone. He's

01:11:08.820 going to show up at 200. He's going to look like I did 50, 20 years ago. His LSH and FSH are still

01:11:14.680 completely suppressed because that doesn't go away over 18 hours. But I don't know how to interpret

01:11:19.600 what is he walking around at during the day, which is what I care about.

01:11:23.160 So it's hard to know. Usually you don't want to do it right away too. So you want to give him a

01:11:27.660 couple of weeks to stabilize hemostatically, right? But usually you can get pretty good levels because

01:11:32.300 the half-life isn't that short. They say it peaks in five hours. So I don't know what the half-life

01:11:37.660 is. The half-life would be- Probably like 12, more like 12. You wouldn't dose it at 100% decay. You

01:11:42.340 would dose it at 50%. So he's probably not responding. We can check it at different times, but it's probably

01:11:47.940 not much of a response. And what are you dosing it at? It comes in 100 and 200. It depends.

01:11:52.860 I usually go to the mid-dose, 298 twice a day, and then you can double it or whatever. I usually

01:11:58.820 start out at not the lowest dose. And it depends what you're trying to solve too and the problem,

01:12:03.800 right? If you want them, you're not going to get them to 800 or 1,000 very easily. You can get them

01:12:09.020 400 to 600, 600, 700 pretty well, but no side effects. I haven't seen anything that maybe a couple

01:12:14.860 dozen men really well tolerated. Interesting. So this is not something you used when you're trying to get a

01:12:20.420 guy from 300 to 1,000. You could, but probably not the first choice, yeah. And now you're taking

01:12:25.880 500 twice a day or something crazy like that. Yeah. And twice a day is a big deal for men.

01:12:30.580 It is. What about Natesto? How are you- I've never- You've never prescribed- No one tolerates

01:12:35.660 that. What's the experience like? We've never used it. Well, have a flu and try to get your

01:12:40.100 testosterone level up. You can't do it. You have to spray it in your nostril, each nostril three times a

01:12:44.860 day. And it's gooey and it's gel-like and men within a week, we'll call and say, I can't do this.

01:12:50.580 Yeah. We've had more luck getting women to use this.

01:12:53.340 So the other big differences between the two types of testosterone replacement or supplements,

01:12:59.020 one is we'll call it the natural ones versus the exogenous ones, is side effect profiles differ

01:13:05.180 widely. It's very difficult to get polycythemic or thickening in your blood with the physiologic

01:13:10.580 levels. It just doesn't happen very often. I've seen it once or twice, but if you take

01:13:14.720 testosterone misogynously, you're at risk for polycythemia or blood thickening. So testosterone

01:13:19.100 stimulates epipotent in the kidney, you make more blood. Athletes love it. But if you're on a long

01:13:24.620 flight and you're dehydrated, you're going to throw a clot. And people look at it for longevity and it's

01:13:30.040 like, be careful. Because I've seen 70-year-old men want longevity in taking this stuff and then they

01:13:35.440 have a clot and they have a stroke and now they're 71.

01:13:37.860 And do you find that the clot risk is proportional to hemoglobin hematocrit simply?

01:13:42.780 At what level are you saying?

01:13:44.100 So, I mean, the studies aren't broad, but Ramasamy just did another paper on it. The most significant

01:13:48.440 event occurring with testosterone replacement or supplementation is polycythemia and events.

01:13:55.760 The high level for hemoglobin 17, hematocrit 50, you start seeing events happen about 18,

01:14:02.400 definitely 19.

01:14:03.180 One of the things we do with patients who are injecting testosterone cipionate, and we

01:14:08.000 have some patients who love doing this. I think it would drive me nuts if I were trying

01:14:12.060 to do this. They inject it every day. So they'll do 10 to 15 milligrams every single day. And

01:14:17.600 it actually produces the same effect, which is they don't have the polycythemia.

01:14:21.340 Right. Because they don't hit the peaks.

01:14:22.360 They never hit these crazy peaks. 10 years ago, everyone I saw that was prescribing this

01:14:28.060 was prescribing the standard was 200 milligrams every two weeks, which was crazy.

01:14:31.760 Highest risk, yeah.

01:14:32.580 Yeah. So what is your typical injection schedule?

01:14:36.280 So once a week, and I think twice a week, you can have the dose, right? So that is a little

01:14:41.340 safer, but then it becomes the intensity and just, I can't do it like that or whatever.

01:14:46.280 I want a pellet instead.

01:14:47.520 Do you put pellets in?

01:14:48.380 Oh, yeah, yeah. I do them all.

01:14:49.360 The pellet also, I don't know the kinetics of it, but I would imagine you're pretty super

01:14:53.540 physiologic for a month or so, maybe?

01:14:55.260 Yep. So pellets are like the long-term contraceptives for women. You know, in the arm, they put it

01:15:01.420 subcutaneously. We put it in the butt and it's a couple minute procedure in the office. You

01:15:05.320 don't have to worry about anything. There's no compliance issues. We don't have a lot of

01:15:08.240 side effects or consequences from it. It's done with a trocar and a thick needle. And pretty

01:15:12.560 quickly within a couple of days, you'll get a level and then it'll slowly decay pretty much

01:15:17.580 half of it by three months or so. And then the rest by four to six. It's supposed to be a

01:15:21.940 six-month physiologic level, but normally it's four, four or five. And men feel great for a

01:15:27.640 while and they can feel it because it's slow, but it is even. And you do have this risk of

01:15:31.320 polycythemia and things like that. But there's a three-month peri-baric risk. And then usually

01:15:35.200 when you're in the normal range, it kind of goes away. So I don't see a lot of consequences with

01:15:39.720 that if it's six months. I really don't.

01:15:41.940 So let's go back to the Clomid-HCG route. What is the extent to which fertility is preserved

01:15:47.600 when a man is on one of those agents?

01:15:49.300 So Clomid is, we give it for fertility all the time. So it's very good. It might even

01:15:53.780 improve it. HCG depends on the dose. So like you said, high doses suppresses. Normally

01:15:59.640 fertile, you want LH and FSH going to the testicle. You want the water and the sunlight. You want

01:16:03.900 the testosterone. If you've got the testosterone, but your FSH is, if you don't have any sunlight,

01:16:08.040 you're not going to bloom. So I usually add Clomid to HCG if the dose is above 1,500 units

01:16:12.860 three times a week, because that's going to start suppressing the FSH and Clomid will keep

01:16:16.920 it going. And then your fertility is preserved.

01:16:19.320 1,500 three times a week of HCG is a whopping dose. You're saying beneath that, you typically

01:16:26.680 don't have issues with FSH and LH suppression?

01:16:29.140 Right. LH you will, because it's LH, but not FSH.

01:16:33.340 Maybe 1,000 to 1,500, you start seeing it. So that's where you protect the fertility.

01:16:38.360 And what dose of Clomid will you give on top of that regimen?

01:16:41.720 Depends. I mean, usually half a pill a day.

01:16:43.900 Half a 25, half a 50?

01:16:46.020 50 milligram pills. Yes. Usually half.

01:16:48.280 You'd give 25 every day?

01:16:51.460 These are staggering doses. How high are these guys' testosterone getting?

01:16:56.100 The testosterone is driven mainly by the HCG. I shoot for the normal range of 500 to 1,000.

01:17:01.200 I'm not an anabolic guy. I'll note it today.

01:17:03.140 Yeah, yeah, yeah. No, it's interesting. I mean, we don't like Clomiphene at all just because,

01:17:08.240 well, there are a whole bunch of reasons, but they have to do with kind of lipid stuff.

01:17:10.860 Even when we would use it, we would probably use 53 times a week. So that's about the same,

01:17:15.980 right?

01:17:16.240 Yeah, 25 a day.

01:17:16.660 25 a day. But for most guys, that would be sufficient alone, even without HCG.

01:17:22.140 Well, it's HCG that's driving the T. We're just trying to protect it. If you said,

01:17:25.620 what do you give on isolation as monotherapy?

01:17:28.200 Yeah. What would you give for Clomid monotherapy?

01:17:29.400 12 and a half to 25, typically, depending on how sensitive the system is.

01:17:33.020 And do you prefer Clomid and Clomiphene?

01:17:35.040 So it's very interesting. Clomiphene's really good. It's an interesting FDA story. So Clomid

01:17:40.300 is not approved for men, and Clomiphene isn't either. Clomid's approved for women, and Clomiphene's

01:17:45.460 not approved for either. Clomiphene's compounded. Clomid is available for 50 years, so a lot more

01:17:51.160 data. And once a cis isomer, and once a trans isomer, so they're different. And the estrogenic

01:17:55.320 effects are slightly different. So I have enormous experience. I have 560 men on Clomid,

01:17:59.920 and I have fewer in Clomiphene. But it was developed for older men to preserve their

01:18:06.320 testosterone levels as they age, because the signaling tends to get weaker. The pituitary

01:18:11.320 tends to get lazier. And this is to keep your testosterone levels up more physiologically than

01:18:15.740 taking testosterone. So it went through some very good randomized trials that were published.

01:18:20.900 This was Clomiphene?

01:18:22.020 Clomiphene citrate. And they were done by reputable people in the field and published. And then it

01:18:27.640 went to the FDA for approval for secondary hypogonidism, sort of age-related changes,

01:18:32.080 not primary testicular failure, in age-related androgen deficiency of the aging male or ADAM.

01:18:37.420 FDA sat on it for a couple of years and said, nope.

01:18:39.820 What?

01:18:40.620 Good question. So it's published. They're good trials. It's safe. It's as good as Clomid.

01:18:45.780 And that didn't approve it. And I think it's hard to know. But I think the reason was that

01:18:51.580 there's such an uproar about testosterone in America right now. And the FDA doesn't like what's

01:18:57.120 happening. What happened is you can advertise your drug to the consumer now. So you know all the

01:19:02.500 biological response modifiers for psoriasis. All those drugs go on and they give you five seconds

01:19:07.420 on the benefits and the lesions go away. And then 25 seconds on side effects, right? So you can do that.

01:19:12.040 If you do that with testosterone, what you hear is, do you fall asleep after dinner? Are you not as

01:19:16.760 athletic as you used to be? Are your erections not as good as they used to be? There's 10 questions

01:19:20.640 in the ADAM questionnaire. And everyone who ages-

01:19:22.980 Every guy's going to be like, yeah.

01:19:24.320 Everyone who ages has those issues, right?

01:19:26.540 So it's like no brainer if they go on TV and they're going to want this stuff.

01:19:31.140 So the cat's out of the bag. They're stuck. And so now when any testosterone trial comes back,

01:19:37.020 they're going to point out, the FDA makes sure that we point out the dangers of testosterone

01:19:41.320 replacement. So this is part of that energy, which is, you know, we don't want another testosterone.

01:19:46.200 So I think there's another reason, Paul, and it's everything you just said, but HCG and testosterone

01:19:53.160 are schedule four.

01:19:55.100 True.

01:19:55.800 Which means you cannot prescribe them through these testosterone clinics that don't even see

01:20:02.200 patients and are literally just not being doctors. They're just sort of giving it to anybody who

01:20:06.900 shows up and pays. It's a coin-operated testosterone dispensary. But Clomid, and I assume by extension,

01:20:13.980 and Clomiphene are not scheduled, which means you can coin-operate those. And my guess is that's

01:20:20.780 probably why the FDA is saying what it's saying. It's already bad enough that the Clomid cat is out

01:20:27.320 of the bag, but we don't want to put another one of these unscheduled drugs out there in the

01:20:33.120 land of shady medicine.

01:20:35.580 The indications are pretty clear and they're really safe. They're really safe drugs. My effect

01:20:40.780 is someone comes in who's young, who maybe wants kids, hasn't had them, and they have a low

01:20:47.900 testosterone of 220. You measure their LH, which no one does. It's low. Secondary hypogonism. So it's

01:20:54.060 not a testicle failing.

01:20:55.340 Right.

01:20:55.460 It's a signaling issue. And that's probably stress. So I said, get rid of your stress. And

01:20:59.920 they say, how do I do that? It's like, okay. So exercise, acupuncture, massage, or yoga. I mean,

01:21:04.760 for men, I say physical activity is the best thing for sex. So as an aside, during COVID,

01:21:09.420 I had two groups of men. They said, what do I do? My life's a mess. You know, everyone's life's a

01:21:13.140 mess. So half of them had drinks at five o'clock, started drinking a lot. And the other half went out

01:21:18.700 for runs or got a Peloton, which most of the country did. That's a great story, the Peloton story.

01:21:22.540 And then about six months later, these guys realized it's not working. And they started

01:21:27.200 shifting over to exercise. So I was very proud of them. These guys, I was really happy with,

01:21:31.900 like nice, because that's the best way to handle stress is when you have no control over things,

01:21:37.280 go for a run, go for a walk, get out there. So good for you. It's just decompressing,

01:21:42.780 hold, get your mind off something, anything, surfing, whatever. They don't do that. So I said,

01:21:47.340 well, let's do this. I think what's happening is this. I think it's just stress. Maybe try traveling

01:21:52.220 less or whatever. And then I'll give them clomid. I'll say, let's try this for three to six months.

01:21:57.080 And let's see how you feel. Sometimes it's sexual health issues. Erections aren't typically

01:22:01.840 that dependent on testosterone. Typically it's other things. I'll give you the benefit of the

01:22:06.680 doubt. Maybe you were higher before and we don't know that, but let's do something pretty safe

01:22:11.100 and easy. And I'll double your testosterone or triple it. Let's see how you do. And then I'll check

01:22:15.880 in with them at three and six months. How are you feeling? I feel great. Or, hey, it's not working.

01:22:19.780 I feel the same. It's like, well, it's not testosterone related. Whatever the symptom

01:22:23.380 is you're having, you wouldn't have it with a testosterone. We know levels of testosterone

01:22:28.220 above which you should not have symptoms. We know libido, we know erections, we know fertility,

01:22:33.840 things like that. And what are the approximate levels for each of those?

01:22:36.620 I don't know. Erections, I would say the best study is about 290.

01:22:39.660 Yeah. So most guys that are having difficulty with erections are above 290. There's some other issue.

01:22:45.400 Usually. But you have to prove it to them. And I'm fine with that as long as it's safe.

01:22:48.940 You're convincing them. And then what about libido?

01:22:52.000 Libido, I'd say 350 is sort of a range. It's pretty sensitive and it's harder to call.

01:22:57.520 Libido is driven by so many different things. Fertility, I'd say 300 is a good one. You start

01:23:02.120 seeing issues. With how much FSH and LH? I don't know.

01:23:04.940 Okay. Obviously the other thresholds would be anabolic capacity, like muscle mass and things

01:23:09.480 of that nature. And mood tends to be a lot more variable in my mind.

01:23:13.120 Absolutely. I think there's nits around testosterone and those are some of them, but

01:23:16.900 is sort of a Morgan Taylor and equilibrium story where if you're low, you have symptoms

01:23:22.260 and you're low, those symptoms will get better when you go up. But then there's a point where

01:23:25.740 it flattens out. There's no increase or improvement in symptoms. Sexual health symptoms are classically

01:23:32.020 ascribed to that. There are also, it's a linear relationship between testosterone and that

01:23:35.680 would be blood and muscle. Yep.

01:23:37.120 So more is better for making blood doping and also blood doping and also for muscle. Absolutely

01:23:42.840 linear. Yeah. I'll tell you why I find that interesting, Paul. And I only learned that

01:23:46.620 really in talking to bodybuilders who were taking 500 to 2,500 milligrams of testosterone a week.

01:23:54.480 Because my initial reaction to that was you've already saturated the androgen receptor probably

01:24:00.360 five logs. I mean, not five logs, but like at least one or two logs earlier. But they convinced

01:24:07.060 me, no, no, no. There's a real difference between 500 and 1,000 and 2,500 in terms of muscle mass,

01:24:12.480 which it sounds like you agree with. And I don't understand the physiology of how that's possible.

01:24:15.900 I don't, I mean, how many androgen receptors would you need? You'd have to upregulate them when

01:24:19.820 in fact you'd be downregulating them. So I'm not sure, but the effect is indirect.

01:24:24.660 Effective testosterone muscle mass is indirect. It's not that you're going to do it and create mass.

01:24:28.640 So you don't just create mass. What it allows you to do is recover from injury.

01:24:32.760 So if you push the system and you need two days to recover, you can go to one day,

01:24:36.700 you can push it again harder. So that's what testosterone does in the primitive world.

01:24:41.280 There's even studies that show, by the way, that high enough doses of testosterone will

01:24:44.600 increase muscle protein synthesis absent the stimulus, absent the lifting stimulus.

01:24:48.820 So it's the potential to recover that is improving. I'm not sure that's receptor driven

01:24:53.180 at all. Like it might be several pathways going on that are logarithmically better,

01:24:57.580 but it allows you to push the system and go back and then push it again. And that's how you build

01:25:02.020 muscle. All right. So now let's talk about the guy who comes to see you. He's been on

01:25:06.120 exogenous testosterone for three years. So he was given poor advice three years ago. He went to some

01:25:12.960 shady back alley website. He was 27 years old at the time. I mean, this is tragically a very common

01:25:19.500 story by the way, right? So this guy's been on 200 milligrams of testosterone a week for the past

01:25:24.420 three years. He's now 30 years old. He's met the love of his life. Lo and behold, they can't seem

01:25:29.060 to get pregnant. So he's in your office. During the history, you find out pretty quickly, he's been

01:25:33.400 on 200 milligrams of testosterone for three years. Tell me what his sperm analysis looks like. Presumably

01:25:40.700 there are no sperm. I would bet 95% confidence that he would have no sperminous semen. Okay. So what

01:25:47.280 are you telling him now? How are you going to solve this problem? So it's funny because a lot of guys

01:25:51.100 come in and they look good. When I examine, I'll say, are you taking anything? Because they never

01:25:56.780 put it on their medications, right? They never write it out on the history. You always have to

01:26:01.260 get it out of it. If they're super jacked, but then they have shriveled testes. Yeah. And they're

01:26:05.640 zero. And they're wondering what, you know, right? So I will look them in the eye. So are you taking

01:26:11.200 testosterone? And I'll look them in the eye until they answer. And if they look down and they don't say

01:26:16.440 anything, I know they're on it. If they look me in the eye and say, no, then I know they're not,

01:26:19.920 but they'll always look away. It's this verboten thing. This is the same, by the way,

01:26:24.640 as I'm sure you experienced as a resident in the ER, the people that come in with foreign rectal

01:26:29.920 bodies and abdominal pain, that's the one thing they emit from their history. They tell you, you

01:26:35.040 know, this is the last time I ate. This is this, this is this. But then you get the x-ray back and

01:26:38.920 there's like a candlestick in their colon. And then you say, yeah, yeah. What about this candlestick?

01:26:44.080 And they're like, oh, I totally forgot to mention that. Yes. Yes.

01:26:47.680 It was lit when I went in. Yeah. Yeah. Yeah. Yeah. So my theory is about this is why is he

01:26:52.220 taking it? So if he's taking it for anabolics and you know, he probably has a pretty good idea.

01:26:56.340 I want to give you a little research we're doing on the lifespan of anabolic steroid users. So remind

01:27:02.120 me to, at the end of the story, give you a little brief about what I know about that. So how he takes

01:27:06.560 it matters. So if he's been in constant use injectables, that's the most suppressive of

01:27:12.100 fertility. And if you turn a gland, like a testicle off long enough, it's off. So I gave a lecture to

01:27:18.960 the Ennegrine Society on recovering men from hypogonadism in young men. And I asked them a

01:27:25.100 question at the end. My whole procedure comes from steroid users. I take notes when the anabolic

01:27:31.020 guys come see me because they're really smart and they know a lot about reactions, biology.

01:27:34.920 Yeah. It's incredible.

01:27:35.620 So not everything, but it's a science. Some of them are PhDs. I took notes for years and

01:27:40.580 it came up my approach along with what I know. So it's very much in concert with concert with

01:27:45.840 them. So everything I say is built on a large experience and it's called getting off the

01:27:50.280 juice, the blog. And I have people read that blog, do it and say, get about 80% of the way

01:27:54.900 and then call me and say, I need help here. Now I'm here.

01:27:57.560 We'll link to this in the show notes for sure.

01:27:59.040 Getting off the juice. And there's a PowerPoint in it.

01:28:01.780 So the recovery is usually possible in young men, but it depends on how much they took,

01:28:08.340 how long they took it and how they took it. If they do it like a cycling effort, that's the best.

01:28:13.660 So if you cycle steroids, you recover the pituitary, you get back to normal and then you hit it again.

01:28:18.280 That's actually quite smart. Constant use is not. Constant use for longevity or whatever is not a

01:28:23.240 good idea for fertility. So that's going to be much more suppressive. Injections are worse than

01:28:27.920 orals or any gels. So the next thing is how long, so I asked the Endocrine Society, since I answered

01:28:34.160 all their questions, I said, I have a question for you. Can you turn a testicle off like in a thyroid

01:28:37.940 or an adrenal gland? If you suppress it enough, can you turn it off for good? And they said, yeah,

01:28:42.000 that's an important question of ours. We can do that. And I said, because we believe it's always

01:28:45.300 reversible in the field of infertility in men. And so that got me a little worried. And so now I kind

01:28:49.700 of worry about five to 10 years of use. After five or 10 years of use, you may not get it back.

01:28:55.360 Either the ability to make sperm or the ability to make testosterone.

01:28:58.960 We typically tell men in our practice, two years would be the absolute ceiling. Are we too

01:29:04.580 conservative? Maybe.

01:29:06.040 Okay. Depends on dosing and everything, right? If they're doing 250 a week.

01:29:09.460 No, I mean, in our practice, it would be 50 twice a week.

01:29:11.760 Yeah. Published a study when I was a fellow in Houston of a guy who took it for 25 years

01:29:16.120 and we drove at him with gonadotropins, that's HCG and FSH. And we didn't get anything,

01:29:22.480 but we got a low number of sperm back. And I just had a guy from Louisiana come in,

01:29:27.520 25 years of chronic use. I did a mapping procedure to find sperm in his testicle and he's going to be

01:29:33.420 having a kid, but he made a couple of sperm. But you pump him full of HCG and synthetic FSH.

01:29:39.180 And get nothing. And then you have to look in the testicle because production can be low enough to

01:29:43.180 be there, but not coming out. But this is the rescue protocol. It's LHFSH.

01:29:46.740 LHFSH. Basically, there's three ways to do it. One is never stop the testosterone suddenly.

01:29:52.280 Interesting. Because men will hit the doldrums and go

01:29:53.960 and they'll flop over like they have the flu. They'll feel like shit and they'll get right back

01:29:57.920 on it. They'll feel terrible because they have nothing going on. If you take the testosterone

01:30:02.700 away, their system's turned off. They're not making their own. It takes time to get the system to

01:30:07.300 reactivate. So that's the hardest. So I always taper testosterone.

01:30:11.600 Over what period of time?

01:30:12.380 Six weeks, typically, you have the dose for two, have the dose for two, and then off for two.

01:30:16.600 And then you measure. And that's getting out of the white water into the green wall a little bit.

01:30:20.460 So that's a little smoother. So taper. And then I offer him two options. One option is taper alone,

01:30:25.560 taper with Clomid or Enclomiphene, which is a little quicker getting the pituitary to turn back on.

01:30:31.800 So that will soften the blow of the feeling of feeling completely fatigued. Or more aggressively,

01:30:38.860 HCG and Clomid. And then I usually check them at about six weeks.

01:30:43.580 It's interesting. If you give Clomid, the pituitary will make FSH and LH?

01:30:49.580 Yeah. It takes a while.

01:30:50.680 Well, that's a way more cost-effective approach than giving, because synthetic FSH is pricey.

01:30:55.440 Yes. A couple thousand a month in America.

01:30:57.620 Yeah.

01:30:58.000 So is there any reason to do that over the Clomid approach, or is it just that it's faster?

01:31:01.480 I think you might gain a couple of weeks of time.

01:31:04.720 So for most people, that's not a price worth paying.

01:31:07.680 With that taper over a month or two, I usually check their T levels

01:31:10.560 at around two weeks off of the last testosterone, and that's the lowest they'll be.

01:31:15.660 And if they're in a good range there, you can use that as a predictor of their response.

01:31:19.220 What would be good?

01:31:20.460 If they're in normal range.

01:31:21.720 Oh, really? Okay. We want within a couple months to see them back to 600.

01:31:26.960 300 would be okay.

01:31:28.240 To make sperm.

01:31:29.100 Okay. All right.

01:31:29.800 But then to get them to where they want to be, depends on their symptoms and what they're happy

01:31:33.700 with, you won't know. So you wait longer to see how high you can get them. That's the lowest they'll

01:31:38.600 be, but they'll be off of testosterone. And if they go along that taper and they're not

01:31:42.380 tolerating, I try to tell them, don't go back. Just stay there because time will help you.

01:31:47.340 You're not going to feel maybe that great, but try to do this. Because if you don't, if you go back,

01:31:52.140 then we have to start over. But if you can just maintain it for a while, you'll feel better.

01:31:55.480 And some of them dip a little bit, but remarkably, most men do really well with that taper.

01:31:59.800 Now, I want to get onto some of the other topics here, but just to close the loop on this,

01:32:04.560 do you ever advocate crazy ideas for guys that are using testosterone to use lower doses and then

01:32:11.520 combine it with HCG, just as we were talking about the Clomid plus HCG approach?

01:32:15.220 All the time.

01:32:15.880 Okay. Not an unreasonable approach to combine Clomid with testosterone at low doses to preserve

01:32:22.620 testicular function.

01:32:24.080 Yesterday, I operated on a man, testicular sperm retrieval, and a man who's azoospermic for

01:32:28.780 genetic issues. And he was on testosterone for 10 years because he needed it. His testicles

01:32:35.100 were failing. And I said, you're not going to make sperm on this. So we put him on HCG,

01:32:41.760 which didn't do anything for him, felt terrible, and did that for a year. And he said, I can't do

01:32:46.040 this anymore. I said, okay, or maybe it was six months. And I said, I need a little more time

01:32:50.360 for you to be off testosterone. But since you've been on HCG for six months.

01:32:54.260 And what dose did you have him on?

01:32:55.600 3,000, three times a week.

01:32:57.260 That's a whole vial a week.

01:32:58.840 Yeah.

01:32:59.420 Wow.

01:33:00.220 Then I said, okay, let's add in a low dose T-gel, testosterone gel, get your testosterone

01:33:05.960 up, and we're going to lower the HCG to 500 three times a week, twice a week. And I did

01:33:10.460 a sperm retrieval yesterday. Boom. Plenty of sperm.

01:33:13.080 How old was he?

01:33:13.900 35.

01:33:15.580 Interesting.

01:33:15.980 You can maintain whatever's going on in the testicle with HCG and take any testosterone

01:33:23.560 you want.

01:33:24.240 That's an important lesson. Yeah.

01:33:26.060 Here's the catch though. The caveat is it was done in, I think, Finnish bodybuilders. They

01:33:31.200 were doing a cycle of steroids, huge amounts. They took low dose HCG 500 twice a week. And

01:33:37.140 John Amory has worked out and Washington has worked out all the exact doses, but 250 to 500

01:33:41.580 twice a week is a good dose for that. It keeps your intratesticular testosterone high, keeps

01:33:46.940 your sperm production going. And they went on both concurrently for 12 weeks and their

01:33:52.140 sperm counts were normal the whole time at any dose of T. Now, what happened after that

01:33:57.400 is people start saying, you can preserve your fertility on testosterone replacement,

01:34:01.020 which is possible.

01:34:01.920 They missed half the story.

01:34:03.020 But it was only 12 weeks. And if you're doing it for three years and you miss your dose of

01:34:06.600 HCG, boom, you're done. You're cooked. You're going to go to zero. So unopposed testosterone

01:34:11.000 without it. So you'd have to be 95% compliant.

01:34:15.960 Do you think that there's a difference between HCG and Clomid in that effect as the adjunct?

01:34:19.900 The Clomid doesn't work.

01:34:21.000 HCG is the one.

01:34:21.940 Yeah. Clomid doesn't improve intratesticular testosterone levels like HCG does. It's ineffective.

01:34:27.180 Got it.

01:34:27.560 It will potentially make you more recoverable. If you do it 80%, you'll be zero, even though

01:34:33.840 you thought you might have a sperm count, but your recovery will be faster because it's done

01:34:38.120 something. But the only way to maintain your current fertility is you have to be 100% compliant

01:34:43.680 with dual therapy. You can't go on monotherapy with testosterone.

01:34:47.400 Outside of fertility, given the popularity of testosterone replacement therapy today,

01:34:53.240 is there another advantage to just doing dual therapy? Obviously for fertility, we wouldn't

01:34:57.880 be talking about it, but can you think of any other reason why it might be advantageous if a guy

01:35:02.500 can deal with the hassle and the cost?

01:35:05.080 Yes. Depends on the indication though.

01:35:06.680 Everything but fertility, like any other health benefit?

01:35:09.440 Well, I think muscle mass. So with aging, it's a great one. I mean, it used to be like growth

01:35:14.720 hormone with age-wasting syndrome, things like that. I mean, muscle mass is a key for men.

01:35:19.380 But I'm saying as opposed to just being on testosterone injectable to do the dual therapy

01:35:24.060 versus just monotherapy.

01:35:25.280 Oh, you mean if you're going to do some kind of therapy-

01:35:27.520 Yes. If you've committed to doing therapy-

01:35:29.020 No, I think the only reason would be if you want testicles to be big.

01:35:32.840 Okay. So just volume.

01:35:33.640 I just created a new procedure to make testicles larger naturally by putting a fat injection in

01:35:38.340 the hydrosteal space in men on testosterone because they don't like their small testicles.

01:35:42.720 So it's the equivalent of the Brazilian butt procedure for the testes.

01:35:46.100 Yeah. So it's all natural and there's no prosthetics and you can't tell and it makes

01:35:49.500 them nice and big and testes fat grafting and it's fabulous.

01:35:53.040 Medicare improved?

01:35:54.000 No.

01:35:54.520 Yeah.

01:35:56.180 Creatively approved.

01:35:57.060 So let's shift gears and talk about other modifiable factors. Let's talk about heat. We've

01:36:02.820 talked about it a little bit.

01:36:03.580 So for fertility.

01:36:04.420 Yes, for fertility. So tell me about the impact of cold plunging and sauna and hot tubbing

01:36:11.880 on fertility for men.

01:36:13.540 Okay. So the testes is outside the body. It's three degrees cooler than the rest of the body.

01:36:18.020 So 95 versus 98 degrees Fahrenheit. And then there's a reason for that unknown. We had that

01:36:23.180 conversation and don't really know why, but it may be that it's an immunologic sanctuary and that's

01:36:27.680 the only way to do it and that God or Darwin could figure out. But if you heat up the testicle,

01:36:32.520 it's also close to the skin. So it's a radiator. So when the heat comes down, the arterial blood,

01:36:37.060 it has to cool. So it raises and lowers. And there was an article in the Journal of

01:36:40.980 Irreproducible Results about 20 years ago. A man went to Big Sur and wore nothing and he measured

01:36:47.580 ambient temperature and then he marked on this leg with a marker where his scrotum hung how

01:36:53.080 low it hung. And he could tell the ambient temperature by how high or low his scrotum

01:36:57.620 hung. He became a thermometer. So it does go up and down. Is that Peter or T. Olafic?

01:37:05.580 Journal of Irreproducible Results.

01:37:07.440 Oh God.

01:37:07.820 Really cool. But it showed that it's very temperature sensitive and it goes up and down to regulate it

01:37:13.460 closer to the body when you want it warmer, et cetera. You go into a cold shower or a plunge,

01:37:17.380 wear your testicles. They're way up there.

01:37:19.000 In my abdomen. Yeah.

01:37:20.120 And that's all the cremasteric muscle and it's all temperature driven. So it spends all of its

01:37:25.020 time regulating its temperature to stay at 95. Now, saunas, baths, hot tubs, jacuzzis,

01:37:30.840 steam rooms change that. The worst one of those is anything underwater, submerging underwater

01:37:36.240 because you're one centimeter away. You're a liquid. It's a liquid. You're going to turn that

01:37:41.860 temperature, maybe not the inner part of your body, but little kids going into hot tubs, right?

01:37:46.040 They overheat.

01:37:46.540 So you get into a 105 degree hot tub, which is a very typical temperature for a hot tub is 105 to

01:37:52.760 110. You're saying within a relatively short period of time, your testes will assume that

01:37:56.980 temperature.

01:37:57.700 Absolutely. You're 70% liquid. This is right at the surface. So I did a study published in the

01:38:02.760 Brazilian Journal of Urology. I published 200 studies. This was the hardest one to get in.

01:38:07.420 Everyone said, we know that it affects fertility, so we're not going to publish it. So American

01:38:12.120 so I went into Brazilian Journal of Urology. It then went to the New York Times as a press

01:38:16.320 release. That's how popular it was. It's probably my most cited paper ever, and it's certainly

01:38:21.060 not my best. It's very interesting. I took infertile men with low sperm counts and stopped

01:38:25.660 the tubs. They were in hot baths because I used the word jacuzzi. Jacuzzi called me up and said,

01:38:29.640 stop. Don't use that word. So I don't use that word. So hot baths or tubs. And I told them

01:38:35.700 out and they went up 300%. Semen quality went up 300%, total mold count in three months or four

01:38:42.260 months and 600% in six months. They have to give us some time. And that's that curve, the recovery

01:38:47.460 curve. And we didn't look at fertility. We just looked at that recovery. And someone were zero

01:38:51.820 and went up to close to normal.

01:38:54.060 What was the age range of these men?

01:38:55.520 35.

01:38:56.560 So fertile men.

01:38:57.540 Yep. Trying to conceive.

01:38:58.740 Yeah. These are men who are not able to conceive. You're making the diagnosis. I think it's your hot tub.

01:39:04.000 Let's get you out of there. And they have a six-fold increase in sperm count.

01:39:08.180 Total modal sperm count, meaning count motility, mainly driven by motility.

01:39:12.100 Interesting. So it's motility that the price-

01:39:13.920 The biggest one, but also count might have doubled,

01:39:16.080 chili may have gone up three-fold kind of thing. So six-fold increase overall.

01:39:20.500 Then I calculated after that, I calculated a lethal dose of tubbing. So what's the lethal dose?

01:39:25.800 Yeah. What's the LD50? Yeah.

01:39:27.480 So lethal dose to me means you're zero. You do it enough, you have no sperm. And it came out to

01:39:33.600 be 20 minutes of a hot bath or a tub, 20 minutes, 104 degrees, three times a week would probably make

01:39:39.840 you zero.

01:39:40.660 There have to be a lot of guys out there who are spending at least three times 20 minute sessions

01:39:47.260 in a hot tub that's at least 104 degrees a week.

01:39:52.380 Interesting. The largest group of people in tubs in Northern California, we did the study,

01:39:55.680 were environmental lawyers. Is your job that stressful? It's a kid. It is. I mean,

01:39:59.780 it probably is in California. All right. So the only study ever done prior to that was a PhD thesis

01:40:05.420 at Vassar College where someone had a guy dip their testicles into a bucket for 20 minutes at

01:40:12.780 really hot and looked at their sperm counts or their fertility and they went, that was the only,

01:40:16.860 and I couldn't even find it, it wasn't published. You had to figure out this thesis thing. But that's

01:40:21.360 how little was written about it. And they gave me so much flack for publishing this, it was really

01:40:24.760 funny. And the New York Times had an article said, drew a condom and it drew birth control pills and

01:40:29.680 it drew a guy in the tub. It's like, pick your contraceptive. So it's huge. I'd say 10% of my

01:40:35.580 population's in it. And then the next question is, what about saunas? So saunas is not underwater,

01:40:40.160 it's not submersion, but saunas are, you're in a hot room, it's going to affect it. And I would say

01:40:45.020 the effect is one quarter to one third as profound as a hot bath or submersion.

01:40:49.340 So my friend was absolutely right to have those ice packs on his scrotum.

01:40:55.540 I think he's reading.

01:40:56.560 Yeah. He's listening to the Turek Protocol.

01:40:59.140 Yeah.

01:41:00.160 And then I would say steam rooms, showers are probably fine. You're in an ambient temperatures

01:41:05.320 normal. And I think steam rooms are probably between saunas and depends how much time you

01:41:09.900 spend, but it's probably not normal, but not a hot bath. Hot baths are terrible.

01:41:14.920 Okay. And then what about the cold?

01:41:16.760 I don't worry about cold. I remember Surfer Magazine called me and said,

01:41:19.820 I'm a Northern California surfer, right? Not LA surfer. The editor of Surfer Magazine called me

01:41:23.820 and said, are surfers infertile? I said, is that water bad for them? Because California water is

01:41:28.340 60 degrees.

01:41:29.300 I said, no, I've never met an infertile surfer. So I don't think it's bad at all.

01:41:34.480 All right. So the cold is okay.

01:41:36.180 Especially plunge where you're talking seconds.

01:41:37.980 Yeah. Yeah.

01:41:38.500 You know, your testicles are going to go up and you're going to be able to maintain that heat.

01:41:42.540 I think if you did it all the time, it would probably be bad. Yeah.

01:41:46.220 Because enzymes work in the testicle at that one temperature. They work optimally.

01:41:51.860 Okay. Let's talk about exercise. You mentioned one example of exercise that can be problematic,

01:41:58.140 which was, I believe you said in a study where men were ramped up to two hours a day of exercise

01:42:05.820 that was above 80% of VO2 max, which is pretty strenuous. That's right.

01:42:09.820 That was enough to put a dent in their fertility. Tell me about riding a bicycle.

01:42:14.240 I'm a biker. I have old vintage bikes that I used to race in Connecticut and I had them rehabbed

01:42:20.180 and they're all Italian and they're all steel and they weigh a ton. And the seats are from Britain

01:42:24.780 and they've got 10,000 miles on them and they weigh four pounds as much as like-

01:42:28.300 Like a Brooks saddle, these Brooks leather saddles.

01:42:30.380 Yeah, Brooks leather saddles. And, you know, all worked out. And it's like that saddle nowadays

01:42:34.800 is about half the weight of carbon bike, but I love it. And I'm, I was thinking of maybe going

01:42:39.480 senior league and doing this gorgeous steel frames and trying to keep up with those guys. Cause it's

01:42:44.260 not about the bike really. It's like when you get golf clubs and I get $150 set of golf clubs,

01:42:49.300 I'm going to be as bad a golfer with thousand dollar clubs as 100. So it's really about the biker,

01:42:53.560 but there are some differences. I'm, you know, in terms of momentum and the wheel force and all

01:42:57.360 that, but I love my old steel bikes and they see this. It's like hanging at my office when I come

01:43:01.760 to work in the morning and I bike in San Francisco and then I have the seat and it's like, that's a

01:43:05.740 bad saddle. And so the issue really is it got started that biking was bad for reproductive health

01:43:11.600 with a Spanish competitive cycling study. Competitive Spanish cyclists, Tour de France caliber

01:43:17.560 cyclists, their sperm counts were examined.

01:43:19.740 But what was the control group? Did they have a control group of runners?

01:43:22.620 I don't remember. I don't think so.

01:43:23.740 So in other words, it could have been the exercise. It could have been the intensity

01:43:26.380 of their exercise.

01:43:26.880 Not a good group to study.

01:43:27.860 Yeah.

01:43:28.380 So their sperm counts were low, their morphologies were off and they're extreme athletes. So we know

01:43:32.640 that and we know maybe they were on drugs. Maybe they're, you know, it's a big industry.

01:43:36.800 They're super fit. They're certainly exercising two hours. And so they said, look at these guys who

01:43:42.880 are really healthy and look at their sperm counts. But this other day didn't come out. So I did a blog

01:43:47.620 called cycling into childlessness. And I looked at a more comparable study, which was British

01:43:52.960 commuting cyclists, everyday people bicycling to work in Britain on different saddles. And I looked

01:43:58.700 at their fertility and their fertility was far better than the average Brit.

01:44:01.860 So even if they were taking some hit off the bike, it was probably more than compensated for by their

01:44:10.240 healthy lifestyle, which included probably riding the bike. But obviously there's a healthy user bias

01:44:14.960 because anybody who's riding their bike to work is probably consuming less Guinness, fewer fish and

01:44:19.720 chips, smoking less. In other words, riding a bike is a proxy for being healthy. But in spite of that,

01:44:26.760 it didn't offset that health risk unless we found people who were equally healthy, who didn't ride

01:44:32.500 a bike. Yeah. I don't remember what they controlled for, but I think they did a lot of the socioeconomics.

01:44:35.960 It may just been activity, but the bicycle. So is this a myth? Yes. Now, if you said,

01:44:41.280 am I worried about bicyclists? Yes. So I worry about sexual health. I worry about the pudendal nerve and

01:44:47.180 I worry about seat anatomy. So the best seat for a bicyclist. So if you're biking a lot, that's good.

01:44:52.700 If you're biking and you're getting pelvic numbness, that's bad. Okay. So you need to get

01:44:58.160 a better seat. The best seat was studied by the NACH, the NA, I forgot it. It was Dr. Schrader at

01:45:04.280 the NIH. The best seat is the saddles that are shaped like this are bad for your sit bones because

01:45:09.360 they come into the middle where the arteries and nerves are to the penis. So it's an erection issue.

01:45:14.200 Those aren't good saddles. The saddles with the two little tongs that hold your iliac crest bones

01:45:19.140 with no nose. Perfect. So it's pressure where the pressure is outside facing, leaning in.

01:45:25.460 So he gave those to police in Washington, the bicycling police done in National Cathedral area

01:45:30.240 in the parks. And they all gave the seats back a week later and said, you're not doing this.

01:45:34.840 He said, what's going on? He said, we don't know where the seat is. We go sit down and it lands

01:45:38.760 somewhere. You have to have the nose for bicyclists because they use it to guide when they sit down,

01:45:44.200 they use it to guide where they sit. So the best saddle is flat or gel in the back,

01:45:50.060 cut out in the middle and some kind of lean in like this. So cut out saddles. And then you should

01:45:54.860 get your bones fit. You can do this online. You can ask them to send you a pressure pad and you sit

01:45:59.600 on it and then you send it back and they measure the distance. And there's only a couple of different

01:46:03.580 saddles, maybe 12 widths that you could do and you get it done. Or like me, you use a saddle used for

01:46:08.860 30 years and it's perfect, but it weighs four pounds.

01:46:11.220 That's because it's a leather saddle and it fit to you. Yeah. Yeah. Yeah. Iconic.

01:46:14.840 Okay. Let's talk about alcohol specifically and let's talk about any other recreational drugs.

01:46:21.760 So fertility wise, I'd say the government wants men. I'm going to talk about men to less than two

01:46:27.540 glasses of alcohol a day is okay. They consider for binging. Now alcohol is a small molecule,

01:46:34.920 goes right into the brain, goes right into the testicle. It's definitely a poison. It goes everywhere.

01:46:39.220 The testicle doesn't limit it. So I worry about it a lot. The effects I see are direct when it's

01:46:45.520 abused. So I would say you see morphology, motility and count issues. So that's a direct effect as a

01:46:52.120 direct toxin. It's one of the few things that's into the testicle. Second would be a hormonal effect.

01:46:58.220 So alcohol use tends to cause the liver to rev up, tends to cause more estrogenization. So you tend

01:47:04.200 to get low testosterone from that. So it's a hormonal effect and a direct effect.

01:47:08.700 Any evidence that it's having an epigenetic effect?

01:47:11.380 Probably. I don't know about evidence, but I'm sure it does.

01:47:14.360 Let's talk about common recreational drugs. Let's start with marijuana.

01:47:17.540 That's the worst player for me. So THC, same thing, count motility, morphology,

01:47:22.580 and it probably has an effect. We know it has an effect on fragmentation, which is a quality

01:47:27.420 measure of sperm, not only the way it looks descriptively, but quality. And also probably

01:47:32.160 an epigenetic effect. Some of the early studies on sperm epigenetics showed alterations with nicotine

01:47:36.440 and with pot. What I don't like about pot is you ingest it and however you ingest it,

01:47:42.120 you get a peak, you feel it, it goes away. You feel it's out of your system like nicotine,

01:47:46.220 but it sits in your fat for a month or three weeks and it's a depot effect and it keeps coming back.

01:47:51.660 So you get a low level toxicity, which I don't like at all. So I am not a fan of pot. The other thing

01:47:56.940 that really concerns me about pot and reproductive age men is I wrote a couple of blogs on this,

01:48:01.460 called the weed worries. And there's some compelling evidence from epidemiology in two

01:48:07.260 studies, 10 years apart, validating each other that chronic pot uses associated with testis cancer.

01:48:14.100 And we think that that's causal?

01:48:15.600 I don't know. It just worries me. Weed worries me.

01:48:19.280 Interesting, given that it otherwise seems kind of benign. I personally can't stand this stuff,

01:48:25.140 but I know so many people that use it so frequently that seem to have relatively few effects.

01:48:30.300 It's a interesting phenomenon. It's medical marijuana, right? So medical means safe.

01:48:33.860 But I asked someone, I have a lot of pot growers in the Emerald City up in Northern California,

01:48:37.880 and they have the artisanal stuff that wins awards and stuff. And it's like,

01:48:41.320 which is worse for driving, being stoned or being drunk?

01:48:45.020 Undoubtedly being drunk.

01:48:46.480 Yeah. So it looks like reflexes, but you know, like he said to me,

01:48:49.860 well, we tend to stop at stoplights and wait for them to turn when we're stoned.

01:48:54.060 It's like, who can I?

01:48:54.760 Yeah. I'm not saying that one is driving stoned is good,

01:48:57.840 but there are probably far fewer people that die at the hands of a stoned driver than a drunk driver.

01:49:02.560 Probably. And I think the signs, the LA story signs, and they have the lit up signs about

01:49:07.880 open season traffic in the movie LA story. They do say now, drunk or stoned, watch out.

01:49:13.400 We're going to get you.

01:49:14.380 What do you think is the mechanism of action by which THC is having these negative fertility impacts?

01:49:19.260 Not sure. I don't think it's the mechanism. I don't think it's the root. So I don't think it's

01:49:23.960 toking or edibles, but it might just be the chronic exposure. And I don't see,

01:49:29.300 there's some evidence that THC acts like LH and binds the receptor and blocks it.

01:49:34.640 But blocks it from LH.

01:49:35.400 So you can get low testosterone, but it's not been that profound.

01:49:39.420 What about nicotine, either synthetically or in the form of tobacco?

01:49:44.340 Bad actor at high doses, I think too.

01:49:46.920 Either one?

01:49:47.400 Yep. It's nicotine is the issue.

01:49:49.340 Nicotine per se.

01:49:50.120 Is the issue. And it doesn't last as long as THC. It does have count motility effects and

01:49:55.640 fertility effects. We think probably both of these are oxidants. It's the oxidants that do it.

01:50:01.420 It's oxidizing things.

01:50:02.920 You mentioned diabetes earlier as part of your history and physical. What is it about diabetes?

01:50:08.540 Is it the high levels of glucose? Is it the microvascular damage? Is it the inflammation that

01:50:14.420 typically travels in parallel with it? Why is type 2 diabetes a risk factor for infertility?

01:50:19.480 Probably all of them. I don't think we know exactly, but I'd say that I diagnose diabetes

01:50:24.900 in a lot of infertile men. I make the diagnosis.

01:50:27.400 What's the physical finding you're seeing in the testes that tells you? Like, you know how an

01:50:30.720 ophthalmologist will often make the diagnosis because they're looking into the eye?

01:50:34.020 Okay. So for me, it's usually their weight and their count motility or low. I'm looking for a

01:50:42.080 chronic exposure. And then they have polyuria or polydipsia or something like that where they're

01:50:47.520 drinking a lot and they're peeing a lot because the sugar is dragging it out. And you check their

01:50:51.260 UA and it's full of sugar. And then some of them have an A1C that's a little pre-diabetic.

01:50:56.400 But I think a lot of it is neurogenic too. They can develop an ED. A third of type 2 diabetics

01:51:02.040 have low testosterone. So that's a clue. And that's secondary. So you give them clomid,

01:51:06.440 you can bend them right back. But that's probably the common one is the look, the sugars,

01:51:11.860 and then the low T and the low sperm count. It's kind of a picture.

01:51:15.480 And then we've kind of talked about sleep and stress, obviously metabolic health in general.

01:51:20.260 What are some of the other modifiable things that you see?

01:51:23.340 The most common is a varicocele.

01:51:25.140 Okay. Tell people what a varicocele is.

01:51:27.440 You can develop varicose veins in your leg and need treatment. And this is the same thing in the

01:51:31.980 scrotum, but it's not related. And it happens typically at puberty. You'll develop this.

01:51:36.780 You won't know it sometimes unless it hurts. It's a reflux of blood in the wrong direction.

01:51:41.080 So the testicle drains to the kidney, which is uphill, and it wants to drain back down.

01:51:45.620 The reason why it drains back down is because as a species, we stood up a half a million years ago,

01:51:49.920 maybe three quarters of a million years ago. And when you're an animal, your kidney and your

01:51:53.300 testicle drains this way. There's no gravity. But when you stand up, you're now draining uphill.

01:51:57.540 The system was never made for valves. And if you said to me, what's the reason our sperm

01:52:02.580 counts are falling? I would say we stood up as a species. Probably not a good idea for male

01:52:07.660 fertility because that bud that's supposed to be staying up there comes back down to the testicle,

01:52:12.440 pulls around it like a hot bath is warmer. And usually the first sign is a testicle on that side,

01:52:18.080 which is the left, usually is smaller than the right. So the physical exam will be a testicular

01:52:23.020 discrepancy in size. That's the first thing you see. And then you feel above it and you feel a bag

01:52:27.220 of worms.

01:52:28.240 But sorry, there are no valves in that vein?

01:52:30.200 Correct.

01:52:30.700 So what's the head it has to climb? That's got to be this.

01:52:33.460 30 centimeters.

01:52:34.540 So how is it doing that without a valve?

01:52:37.660 I don't know.

01:52:38.400 That's a pretty big distance to travel without a valve.

01:52:40.080 They don't, it does it at night. I don't know.

01:52:41.680 Yeah. Interesting. Okay.

01:52:42.680 But there might be a few during puberty, but the growth spurt, those blow. The angle of the

01:52:47.280 renal vein and there's a right angle. The right side has a natural valve off the

01:52:51.260 V in a cava. So it's kind of has to go around 270 degrees. So you don't reflux on the right.

01:52:55.700 Left-sided lesion in most men. You can be perfectly fertile with it. If you look at statistically,

01:53:01.140 85% of men conceive naturally without varicoseils, 80% will conceive naturally about a year.

01:53:06.900 So the curves are very similar clinically, maybe insignificant, but there is a difference

01:53:11.240 and it's statistical. But if you multiply that by millions of people, it becomes important.

01:53:15.400 And you'll figure that out easily on a physical exam.

01:53:17.480 The best way is easy. I don't order oversounds. If I can palpate it,

01:53:20.860 then it's clinical. That's an office repair.

01:53:23.640 It's an outpatient surgery. It takes an hour. We do microsurgery.

01:53:25.740 Oh, it is. Okay. Yeah. So it's more involved than a vasectomy.

01:53:28.660 Yes, it is. And you're doing it at microsurgery at the level where you don't cut muscle.

01:53:32.820 You want them to recover quicker. It's an involved area with lots of veins.

01:53:36.540 But he's not under general.

01:53:37.640 I use a twilight sedation.

01:53:38.720 Twilight-y sedation.

01:53:39.520 Yeah.

01:53:40.060 So that's the most common. That's 40%.

01:53:41.700 That's the most common thing. Wow.

01:53:42.600 And most men are fertile. But so again, you look at the semen analysis as a poker hand

01:53:46.800 and you see count and motility being down, nothing else going on. And you see a varicocele

01:53:51.580 and it's implicated.

01:53:52.840 All right. Have we missed any other of the major...

01:53:55.120 Yeah, I'd say the major ones are varicocele. And then I would look for hormonal issues.

01:53:59.220 So varicocele is maybe 40. Hormonal, maybe 10 or 15. Genetics.

01:54:02.760 So they're non-modifiable now.

01:54:04.660 Right.

01:54:05.240 Okay. So you talked about a few of those already. What are some other ones on the genetic side?

01:54:10.600 The most common one is for zero sperm is Klein-Filter is X-X chromosome. The most common

01:54:15.640 one for low sperm count is Y-chromosome deletions. This is an interesting area.

01:54:20.000 What does that phenotype look like?

01:54:21.860 No phenotype. In general?

01:54:23.560 Yeah.

01:54:24.020 No phenotype. Normal.

01:54:25.620 A Y-chromosome deletion male?

01:54:27.700 Yeah. Because it's only the long arm and it's only a couple of floors on the building.

01:54:31.820 There's regions that are missing.

01:54:33.600 I see. Okay. I'm sorry. I thought you meant a complete deletion of the Y-chromosome.

01:54:36.980 Yeah, yeah, yeah. Got it. Partial.

01:54:37.800 So it's the long arm and it's deletions, regions. Yeah. Rymal deletion, you're right.

01:54:42.240 So Randy Raiopera found at MIT 20, 30 years ago now that the Y-chromosome is a hall of mirrors.

01:54:49.260 And in meiosis, every chromosome has a partner, except the Y and the X in a man. The Y plays with

01:54:56.140 itself. It combines with itself. Instead of finding a partner, it has to do the dance too.

01:55:00.260 And so it changes a lot. So it's very adaptable. It actually comes from the X through evolution.

01:55:06.380 So there's a lot of X genes that are on the Y and the Y, we thought it was sort of a wasteland,

01:55:10.560 maybe hairy ears and tooth decay and things like that. But now it's probably more important.

01:55:16.020 So there are regions on the long arm of the Y. The short arm of the Y is very important. It has a

01:55:19.980 gene called SRY, which makes you male. The SRY is the male sex-determining gene. If you have that

01:55:25.860 gene, your phenotype will be male. If you don't have that gene, you're probably going to be female.

01:55:29.600 Now, it's complicated now, but that's sort of what it is. But the long arm has these genes that

01:55:34.800 control fertility and some of them. So typically we ordered in men with a low sperm count of below

01:55:38.860 5 million. So that would be a pretty common cause of a sperm count lower than 5 million. And I

01:55:43.540 published a study that if you have a Y-chromosome deletion and you have a varicocele and they both

01:55:49.520 cause low sperm counts and you fix the varicocele, you're not going to improve because it's non-modifiable

01:55:55.720 in all ways. It's who you are. But if you didn't have the bichromosome deletion and you fixed the

01:56:00.780 varicocele, you'll expect a good response. Two-thirds will improve, one-third or more will

01:56:05.180 conceive naturally. So you could take guys with low sperm counts and you can fix them or not,

01:56:09.500 but the driver's genetics. And the phenotype in offspring is simply inherited as a Y-chromosome

01:56:15.380 deletion. It'll either be, I just had a couple from Texas actually. He had a Y-chromosome deletion.

01:56:20.400 He conceived with help of technology with a low sperm count. Sons have it. They have no sperm.

01:56:26.480 So you can inherit the deletion, but it might increase. So you're going to get what your dad

01:56:31.100 had or it might be worse because mutations tend to get larger. And until they try to conceive,

01:56:37.000 they would never know this. Right. Everything else is normal. Right. So then there's environmental

01:56:41.320 lifestyle things. So I think obesity is a big one. And do you think that that's mostly propagated

01:56:46.000 through the endocrine system then? Yeah, that's a big one in terms of the percent of sperm

01:56:50.200 with the lifestyle issues. And then lousy diet is probably something that, so obesity and diet,

01:56:55.400 lifestyle, recreational drugs. What else do I review with them? Toxic exposures at work. So any

01:57:00.240 smelly solvents, I'm really worrisome. Airport fuels, airline stuff, machine shop, oils, anything

01:57:07.280 benzene derivatives. Used to be pesticides and stuff like that, but they're pretty well controlled.

01:57:12.640 So environmental exposures are kind of an unknown. I think viruses have a role. It's how you

01:57:18.660 recently wrote about HPV. And I've been thinking about that for years because there are men,

01:57:24.320 it used to be half the men who came in when I entered the field 30 years ago, we didn't know

01:57:27.620 what was going on with them. But now it's probably like 10 or 20% with lifestyle issues and stuff like

01:57:32.380 that. You can pretty much sort it out. It's not that unknown. But there are men who are like,

01:57:37.120 what is going on here? He's a perfectly healthy guy. Practicing in California is incredible because

01:57:43.060 everyone's so healthy. You have to look elsewhere and you have to ask other questions. And when

01:57:48.900 there's obesity, it's always the elephant in the room, but everyone is so healthy in eating.

01:57:53.240 So I get to poke around places where no one else goes because I have to explain it and there's

01:57:57.880 nowhere to go. But I did a study. So HPV is the most common. We wrote about that. Is that,

01:58:03.720 what's the link? It's hard to know. There's herpes, very common. The STDs that we know about,

01:58:08.020 like the 11 common beasts, chlamydia and gonorrhea and syphilis. Those we know a little

01:58:13.340 more about and they're pretty obvious. But some of these trichomonas and stuff are pretty subtle.

01:58:18.280 I was really concerned about this because one guy 20 years ago, and now it's a professor at UCSF,

01:58:22.560 he sent me a picture of electron photograph of a sperm with a hexagonal herpes virus in it. And I

01:58:27.520 don't even know if it was Photoshopped, but there's this virus in a sperm. Like, yeah,

01:58:30.880 it looks like there's a virus in the sperm. You think that's what's causing it? I said, I don't know.

01:58:34.520 I don't know. But normally when you see infections as a cause, viral or bacterial,

01:58:39.500 as a cause of semen analysis, you'll see pus cells. So you'll see what's called pyospermia,

01:58:43.800 leukocytospermia, the round cells we talked about. And the semen analysis will show up in higher

01:58:48.000 numbers. They tend to be destructive and they tend to lower motility. So you tend to see a certain look

01:58:52.580 to the semen analysis. Volume, normal count. Motility is really low. A lot of the sperm are dead

01:58:57.320 because they've been wiped out by these cytokines and all the white cells. And then maybe you'll find

01:59:01.980 the pathogen somewhere. But culturing, mycoplasma, CMV, all these viruses. So Joe DiRisi, really bright

01:59:09.960 guy at UCSF, one of MacArthur Ward, he took my patient's semen. This was back when microwaves

01:59:15.120 were popular in the 2000s. And he had like 2,000 all mammalian viruses on his chip, everything.

01:59:22.460 And we ran fertile guys and we ran infertile guys and looked at semen, not sperm. And 99%

01:59:29.460 of the infertiles were positive for something and 98% of the normals were positive for something.

01:59:34.620 So ubiquitous was the word. And so it left us high and dry because you can't really do much with that.

01:59:39.920 So it's out there. But I do agree with your assessment that the pathologic phenotypes,

01:59:45.280 the worst ones, are probably doing something. The question is, how do we measure it? What do we look

01:59:49.680 for? And the semen analysis, as I said earlier, is a blunt instrument. It varies a lot. It's tough to do

01:59:54.980 it, but I'd love whether we do genotyping on, is it in sperm? Probably not. I don't know. And when

02:00:01.280 you look at HPV, it's probably one of those things that might be in the ejaculate after ejaculation,

02:00:05.520 might be coming from another fluid source and not in the sperm itself. So its effect would be

02:00:10.500 post-ejaculation, which could still have a fertility effect, but it won't be probably as deep.

02:00:16.400 And what if, for example, a guy has prostatitis and the prostatic fluid has

02:00:20.480 pus in it, then that could sabotage the whole thing. Right. I mean, the problem with the male

02:00:25.240 system is it's all through the same tube. So urine comes through that tube and semen comes through

02:00:29.500 that tube. So you have to look for infections in the urinary tract and anything like that when

02:00:34.280 you're doing fertility, because pus cells kill whatever they see. So if your urine's infected,

02:00:39.540 that's a big deal. Have you done work with intratesticular PRP and stem cells?

02:00:44.820 Just stem cells, but not PRP. Not a big fan. As a trained stem cell biologist and someone trying

02:00:51.820 to make sperm from skin and working with some of the best stem cell scientists in the world,

02:00:56.360 I have a lot of respect for them, but it's not that simple. There's 560 offshore stem cell companies

02:01:02.860 in the world that will take your money and do things like stick PRP in there. They'll stick

02:01:08.400 bone marrow aspirates fat in your testicle. And I'd say my experience has not been favorable.

02:01:13.240 Some of the toughest cases in the world and they come to me after that and I do my techniques and

02:01:18.200 I don't find anything and the trials aren't really real. Come here, we're going to do this. And then

02:01:23.200 we're going to do a micro dissection on your testicle, but they didn't have one beforehand.

02:01:26.780 So the chance of finding it even without that is X and they're finding X. So it's just not well done.

02:01:32.000 And I have my patients investigate all that. And I say, you do the work. You tell me who you found.

02:01:37.460 Let me call them. I'll let them be the workers. And then I'll call them and I'll say, hi,

02:01:41.960 I was just wondering about, do you have any papers or what's the science behind it? And

02:01:45.540 they usually hang up or it's really interesting, but so far I'd say it's unfounded.

02:01:51.100 Yeah. I've had a very similar experience with a few of my friends and patients who have wanted me to

02:01:56.100 talk with some of their stem cell docs.

02:01:58.920 You're pretty evidence-based, Peter.

02:02:00.720 Well, yeah. And so I accept the fact that they're not going to have remarkable peer-reviewed data,

02:02:05.800 but it is amazing at how few individuals can provide even one cell layer of scientific reasoning.

02:02:15.660 It's a topic I'd like to explore more deeply on the podcast. My guess is there are some indications

02:02:21.020 for where it makes sense. I think I agree with that.

02:02:22.860 But boy, I'd like to figure it out without people wasting so much money.

02:02:27.620 There's a there there, but it's just not that easy.

02:02:29.660 Yeah. Let's just say for every hundred guys that walk in your office who are struggling with

02:02:36.200 infertility, what percentage of them will be able to conceive assuming they are able to fully comply

02:02:44.000 with the prescriptions that you provide, be it lifestyle or pharmaceutical, for example,

02:02:51.000 hormone modulation, et cetera, without requiring. And let's exclude the 40% varicoceles because you're

02:02:57.640 going to fix those guys and they're fine. So a hundred people who don't have a varicocele,

02:03:01.880 who don't have a genetic condition. I'm going to really simplify this. Okay. So these are a hundred

02:03:06.240 guys that presumably have showed up with some iatrogenic reason for infertility. How many of those

02:03:12.400 guys are going to be able to conceive without resorting to IVF? I would say that's the goal of my

02:03:19.500 practice. And I would say the answer is most. Wow. But the caveat is you got to tell me about the

02:03:25.440 woman because I will defer. This is the only data I can give you. So I did a paper where I saw men

02:03:30.620 for their infertility evaluation, got it done. And I thought they were fine. They had varicoceles and

02:03:35.940 stuff, but their semen analysis is normal. And my investigation of their risks, lifestyle,

02:03:40.060 everything was good. And I said, you're fine. You're cleared. No one's ever said that before.

02:03:46.440 And they went home and they said, Turk couldn't figure out what's wrong with us.

02:03:49.780 I said, it's not what I said. I don't do women. My expertise, I'm saying something positive here.

02:03:54.740 Most people would say, I'm not sure why you're not conceiving. I said, I'm pretty sure you're

02:03:59.280 not the problem. Didn't get interpreted like that. That got me a little angry. So I did a study with

02:04:03.360 USC and I took these men that I cleared and I called them up a year later. And I said, what happened

02:04:09.320 last year after Turk cleared you? I had a resident do this. And the answer was 65% had conceived naturally.

02:04:15.420 Another 15 to 20% conceived with IUI or IVF. These women were 35 years old, year and a half infertility.

02:04:21.160 They weren't going to wait around. Most conceptions occurred within six months.

02:04:24.080 I didn't do anything for them. I didn't fix the varicocele. I didn't touch some medication.

02:04:29.620 I just said, you're fine. So I published it as a lifestyle study, not that I was right.

02:04:34.520 And the idea was they probably made changes. They probably took a nutritional supplement.

02:04:39.460 They probably timed their sex better. They probably got out of hot tubs and all that stuff.

02:04:43.420 And they were taking pills. I have a list of what they did. I had a table in that paper that said that

02:04:47.580 65% natural pregnancy rate. That is higher than anything I can offer as a treatment that we have

02:04:55.000 published on. So if you fix their varicocele, you rarely get a 65% natural conception rate.

02:05:01.360 So I had a table of all the published conception rates for the technologies that work. And I'm saying

02:05:05.940 this is even better. So if that addresses your question, that's the only data I have.

02:05:10.000 Okay. What advice do you give a guy who comes in your practice? Maybe you don't see a lot of these

02:05:15.620 guys, but let's say you get a guy who comes in and says, Hey, look, I want to bank my sperm. I want

02:05:20.080 to freeze my sperm. Now, presumably you'll get a lot of that if a guy's undergoing therapy for

02:05:23.660 cancer or something like that. Is there anything a guy needs to know? And would you recommend a guy

02:05:28.500 do that if he's 40, doesn't have a partner, but says, look, I want to have kids. And isn't there

02:05:34.060 something to the idea that my sperm are better today than they will be in a decade?

02:05:37.920 It's a huge issue. Paternal age, paternal age and fertility, paternal age. So we can go there,

02:05:42.980 but I don't place value judgments. I say, good idea. A disclosure. I'm on a board of legacy.

02:05:48.440 I love their mission driven. I like the fact that going for military and exposed patients and this

02:05:52.980 and that and VA. I'm for that. I think it's the lowest hanging fruit in the field, obviously for

02:05:58.240 cancer survivors and things. I don't care what you think might happen with your cancer. I would still

02:06:03.620 bank it. I started a nonprofit called Banking on the Future. 16 year olds to

02:06:07.780 21 year olds with cancer. We'll do it for you. We'll pay for it for five years. Just give us a

02:06:12.820 sample because it's so much harder afterwards or not. So you would advise any male that hasn't

02:06:19.520 reproduced and who might want to, who's undergoing any chemotherapy for any cancer, just play it safe,

02:06:24.920 bank. For cancer, yes. Now, should anyone do it for any reason? Probably not. But again,

02:06:30.080 I don't pass the judgment. If they're worried about something, then they should.

02:06:33.520 What paternal age do you worry about?

02:06:35.920 And you look at national guidelines for sperm donation, 40 is considered older paternal age,

02:06:41.400 50 for sure. If you look at risks to offspring, miscarriages, stillborns,

02:06:49.020 autism, birth defects, things immediately related to conception, prematurity, those go up with paternal

02:06:55.520 age. Then you look at birth defects. When they're born, those go up one to twofold. And then the

02:07:01.280 worrisome ones are the single gene defects and the epigenetics like psychiatric morbidity. So the

02:07:08.000 autism, schizophrenia, dyslexia, bipolar disorder, potentially Alzheimer's in offspring. And they're

02:07:13.580 not detectable young. So big issues. I've written a lot about that, published on it. I was actually

02:07:19.760 having my second child at 50 when I was writing this thing. Should I be doing this? Writing a paper

02:07:25.080 on all these risks and with Alan Duchenko from University of Pittsburgh. But I think it's a

02:07:29.660 hockey stick curve for risk to offspring. And you think the inflection is 40 or 50?

02:07:35.040 I think it's more like 60. Okay. I think there's a slow linear increase in risk to offspring

02:07:39.340 from 25 to 50 or 60. And then there's an inflection and then there's the blade of the stick.

02:07:45.100 And I think that's logarithmic. Same curve as women with chromosomal.

02:07:51.300 Yeah. But they're shifted 20 years earlier or something like that.

02:07:53.580 Yeah. So it's a shorter curve, but the same thing, 40, 38 to 40 is kind of a point where

02:07:57.760 things really ramp up with chromosomes. The men's stuff is not chromosomal. If you take the curves

02:08:03.960 together, they're different spans, same shape. But I think the female curve is on top of the male

02:08:08.940 curve. This is not the same relative risk. So women, you go from 25 to 40, your chance of a

02:08:17.320 miscarriage. So it's chromosomal. It goes up quite significantly after that, very significantly. And

02:08:23.620 the consequence of women's issues with offspring-related health is basically miscarriage.

02:08:30.500 In many ways, it's almost easier to detect.

02:08:32.340 Very. They've been doing it for years.

02:08:33.600 It can be more dramatic.

02:08:35.260 And now prevented with pre-imputation genetic testing. Men are different.

02:08:38.480 You can't detect these things. There's single gene mutations. The machinery is constantly

02:08:42.740 working. It's getting old. The quality control of the process goes down and little gene mutations

02:08:48.180 get in there that are always being spun off in the heat of the engine. They're not getting vetted.

02:08:53.360 So the machinery is not doing a good job. So they're getting through and they're not going

02:08:57.400 to be lethal. They're going to be deleterious. So that's where you get things. And autism is a

02:09:03.080 classic one. Paternal age-related. Looks like that's the biggest risk factor for it.

02:09:07.700 And that worries me a lot. So the facts are that human evolution is entirely driven by sperm

02:09:13.380 because eggs are just sitting there correcting the problem. It's entirely driven by sperm.

02:09:17.680 And so 50 mutations a year, a generation usually gets spit out based on a nature paper,

02:09:22.460 probably between generations. And there's always mutations occurring in 14-year-old fathers,

02:09:28.120 but it goes way up with 60-year-old fathers. So the rate of mutations goes way up with age,

02:09:32.960 but it averages 50 over reproductive life. And most of them, half of the mutations that we are

02:09:39.060 throwing off as a species are not ears or hands or feet or height. It's all neurodevelopmental.

02:09:46.680 It's like half neurodevelopmental. So when you think about what we're seeing, you know,

02:09:50.700 the Martians from the 50s and the movies with big heads, that's kind of where we're headed. It's

02:09:54.220 autism, dyslexia, bipolar disorder. These are neurodevelopmental, neurodegenerative issues.

02:09:59.540 And why is that? Well, that's what's going on. I mean, that's where we're being stimulated. That's

02:10:04.160 where we're being asked to evolve. Look at the last 30 years. Funny. One of the biggest investors

02:10:09.220 in Salesforce said to me, I realized I was dyslexic when my son was born. And I said,

02:10:14.780 really? He said, yeah, but you know what? It helped me be the man I am to realize that Salesforce

02:10:18.980 is going to fly. Gave him the first 500,000, gave him the first million. They never took any more money.

02:10:24.000 And he said, it let me focus. So autism is one of those these is where you put out,

02:10:28.740 you ignore a lot of input and you find the gift. And it's amazing. If you go down the

02:10:34.980 rabbit hole of what they're good at, it's like their whole brain trust is there.

02:10:39.000 So is that a disease or is that where we're headed?

02:10:42.780 I mean, I think it exists on a spectrum. I think anyone who's probably spent time with kids using

02:10:47.860 ASD as an example, boy, mild versions of it, the way it can be defined, because it really has three

02:10:54.000 categories now in the DSM-5. I think the mildest version probably comes with more superpowers than

02:11:00.460 limitations or maybe equal amount, but clearly the more severe it gets, it's pretty debilitating.

02:11:06.400 This idea of paternal age-

02:11:07.260 But that's what we're calling it disease though.

02:11:08.560 Yeah.

02:11:08.960 But maybe it's not disease. Maybe it's where we're headed. Maybe it's the future. Maybe the

02:11:13.160 non-sequiturs that come out of those brains. Look at who's changing the world right now,

02:11:16.920 at least in Silicon Valley.

02:11:17.840 Yeah. But again, I would argue most of those people would be in category

02:11:21.300 class one, not class three.

02:11:23.500 Anyway, something to think about-

02:11:24.200 What's the thaw success rate? So if a guy is 40, he goes ahead, he freezes and banks his sperm.

02:11:30.820 Assuming they were good to go in, are they very high probability of thawing correctly?

02:11:36.140 So when you free sperm, it's about a 200-year-old process, regularly used for about 75. I forgot who

02:11:43.480 the Italian scientist was who froze sperm in snow and then thawed it and it was alive a couple

02:11:48.380 hundred years later after Lee Wenhoek came up with the microscope. They found it was moving

02:11:51.420 and it was possible. So egg thawing is very new. Egg freezing and thawing is very new. This is very

02:11:56.600 old. So everyone is thinking about sperm now because eggs are being frozen left and right.

02:12:00.940 But this is much older technology and the cell is much hardier than an egg. So it does a lot

02:12:05.740 better typically. When you freeze it, it's the freezing process that kills sperm, be from icicles on the

02:12:11.400 inside. And then while it's frozen, there's usually no issue. And then there's another problem when

02:12:15.640 you thaw, rapid temperature shifts. So that's where the kill rate comes from. In a good sample,

02:12:20.040 half of it should survive. Okay. So how much sperm would you tell a guy to bank if he has to do it,

02:12:26.940 if it's the definitive samples for his life? So meaning he's 40 or he's about to undergo chemotherapy

02:12:33.880 or some other exposure where he should just assume he will not have normal sperm again.

02:12:39.400 What do you tell him? So I usually say, depending on what technology you're going to use,

02:12:43.920 but if your sperm counts normal, three ejaculates is one kid's worth of sperm with insemination

02:12:49.340 technology where you would thaw it and then turkey based it. So 10 ejaculates for three shots on goal

02:12:55.060 for three kids, potentially. For three kids with low technology, but 10 ejaculates will give you most

02:12:58.960 of China with IVF. Got it. Oh, when you say low technology, you mean IUI or something like that.

02:13:04.200 So there's three levels, sex, no tech, high tech is IVF, and then in the middle is IUI.

02:13:08.940 That's the stuff that's turkey basting. It's relatively straightforward, relatively cheap.

02:13:12.960 I see. Three kids for that, but plenty of sperm for IVF.

02:13:15.480 So three ejaculates would be more than enough-

02:13:18.320 If they're normal.

02:13:19.140 For IVF.

02:13:20.100 Yeah. So the population you're talking about are maybe cancer survivors,

02:13:22.660 half of those will not be normal. They're really looking at IVF.

02:13:25.720 Yep.

02:13:25.940 So they don't need that many, but I'd say three is a good number,

02:13:28.420 but it's an insurance policy.

02:13:29.660 Yeah. Okay. Well, Paul, this has been a super interesting tour through the world of male

02:13:35.380 fertility. I can honestly say I knew very little about this coming in. Some of this stuff I understood

02:13:42.320 pretty well, the hormone stuff, but boy, a lot of this stuff I had no idea. So I will be studying

02:13:47.160 my notes from this. We're going to link to a lot of the stuff you've created. You've got a lot of

02:13:51.300 great content out there, so we'll make sure people know where to find you.

02:13:54.720 Yeah, a podcast too.

02:13:55.560 Tell me about that.

02:13:56.160 Well, we started a podcast last year because of the blog of 15 years, and we're just doing

02:14:01.260 timely topics. And it's me and my associate, Rob Clyde, who's a director in Hollywood. And

02:14:05.340 we're going to be the Anthony Bourdain of men's health. We're going to just take on the topics,

02:14:08.980 testosterone, et cetera, penis mitts, and just talk about stuff that everyone is asking questions

02:14:14.340 about, but no one's talking about. And like you, data-driven answers.

02:14:18.040 Okay. And what's it called?

02:14:19.140 Talk with Turek on all channels.

02:14:20.900 Got it. Okay. We'll make sure folks know that.

02:14:23.200 You have a clinic that you run up and down the coast of California. So obviously we'll make

02:14:28.580 sure folks know how to find you there. But presumably I think we've given folks a roadmap

02:14:33.520 for their local urologist as well, if they're getting the work up. Basically, it sounds like

02:14:38.220 if you're being worked up for fertility with your urologist and they're not going through the steps

02:14:42.600 that we've described, maybe you should find somebody else.

02:14:45.080 Yes. I think it should be done. That's the first step. There's a lot going on now that

02:14:50.420 the biomarker concept relates a lot to your views on Medicine 3.0. The paper came out two

02:14:56.640 days ago, looking at longevity based on the semen analysis in Danish, in the Rigola Hospital

02:15:01.740 at in Copenhagen. They looked at 74,000 men over 50 years and found that those guys with

02:15:07.780 say normal semen quality live three years longer, all causes, than men with low sperm counts

02:15:13.120 when they were younger. This was a single payer system. So they have all the data on it is very

02:15:18.720 much a landmark study. So if you ask me what excites me about the field, I would say as the

02:15:24.980 author of the biomarker concept early in my career, I would say, I'm really happy that we're scaring

02:15:30.840 couples to realize that their fertility is a measure of their health. And now we have our foot in the

02:15:36.740 door. If we can get a sperm count and get them in the office, we can actually tell them a little

02:15:40.540 bit about their trajectory. And that's becoming more and more every day. And we've never had a

02:15:45.780 chance to do preventative medicine with young men. So it's a men's health play in a big way because

02:15:51.260 their partners are bringing them in, but who cares? They're in the office. Your father had prostate

02:15:55.700 cancer when he was 50. Someone had colon cancer. So I have now an NP, Molly Jessup, who is medical.

02:16:02.780 And it's like, okay, there's metabolic stuff and you can pick up diabetes. And we have an opportunity

02:16:07.500 here we've never had ever is to get men at younger ages. And I was a professor at UCSF for 15 years

02:16:15.180 in Dao Chair. I left and I went to Yosan University, traditional Chinese medicine. I lecture there now.

02:16:21.200 We had a conference last week and I lectured and I liked it because I thought Western medicine,

02:16:25.960 maybe your view too, is too reactive. They're always trying to get men out of trouble or get patients out

02:16:31.920 of trouble, but we're not thinking about getting them from unhealthy to healthy, which is the

02:16:36.860 preventative aspect. We're just not very good at it. Your general surgery, every example you give is a

02:16:41.000 guy who does something bad, you get him back, whatever. But you got to think next step, like

02:16:44.520 kidney stones. Great. Urologists, we treat them all day. It's fun. It's endoscopic. It's lasers.

02:16:49.520 It's shock waves. But what are we doing about that stone? I mean, how come we're not preventing

02:16:53.860 these more? It's not on the radar. I go to Yosan University in traditional Chinese medicine,

02:16:58.620 fabulous place, and it's all holistic. So I see patients who get referred by acupuncturists and they

02:17:03.400 come in, their diet is under control, their stress is under control, they're doing acupuncture.

02:17:07.240 They're sorted out. And what do I find? Varicocele. Because they don't find those. But

02:17:11.200 the phenotype is totally different than the Western referral. I've loved that because that's 3.0.

02:17:17.340 That's medicine 3.0, which they're doing. They've been doing it for 4,000 years.

02:17:21.200 It's interesting how we don't give a lot of street cred to it. But in my view, a much of we don't

02:17:25.900 understand about fertility, certainly men, possibly women, is epigenetic. And the drivers of epigenetics,

02:17:31.980 which are marks on the DNA, not DNA mutations, 50 DNA mutations a generation doesn't explain it.

02:17:37.360 There's other stuff going on. Epigenetics is all lifestyle and diet-driven. It's all lifestyle

02:17:42.320 and diet-driven. It's everything in your book. Well, Paul, very interesting stuff. Thank you

02:17:48.440 again for making the trip out here. Thanks for sharing your insights. It's been great. Yeah.

02:17:51.680 Thanks, Peter. Thank you for listening to this week's episode of The Drive. Head over to

02:17:57.760 peteratiyamd.com forward slash show notes if you want to dig deeper into this episode. You can also

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The Peter Attia Drive - June 02, 2025

#351 ‒ Male fertility： optimizing reproductive health, diagnosing and treating infertility, and navigating testosterone replacement therapy ｜ Paul Turek, M.D.

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