podcast Peter Attia 2025-06-02 topics

#351 ‒ Male fertility: optimizing reproductive health, diagnosing and treating infertility, and navigating testosterone replacement therapy | Paul Turek, M.D.

Audio

Show notes

This is part one of a two-part mini-series on fertility and reproductive health, with next week’s guest, Dr. Paula Amato, focusing on the female side of the equation. Paul Turek is a world-renowned expert in male fertility and reproductive health, the founder and medical director of the Turek Clinic, and host of the Talk with Turek podcast. In this episode, Paul explores the topic of male fertility, offering a detailed look at the complex and highly coordinated process of conception and the many challenges sperm face on their journey to fertilizing an egg. He shares fascinating insights into how sperm work together to navigate the female reproductive tract, how environmental factors like heat, stress, and toxins impact sperm quality, and what men can do to improve their reproductive health. Paul also dispels common myths about testosterone replacement therapy and its effects on fertility, providing strategies for preserving fertility while on TRT. The episode also highlights cutting-edge advances in reproductive medicine, from genetic testing and sperm sorting to emerging treatments for infertility.

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We discuss:

The incredibly complex and hostile journey sperm must take to fertilize an egg [3:00];
How sperm are made: meiosis, genetic variation, and the continuous renewal influenced by environmental factors [9:00];
The built-in filter that weeds out genetically abnormal sperm [14:45];
How sperm are finalized in form and function: tail formation, energy storage, and chemical sensing abilities [18:30];
How to optimize conception through the timing of sex, ejaculation frequency, and understanding the sperm lifecycle [26:30];
Male infertility and Paul’s diagnostic approach: detailed history, a physical exam, and identifying red flags [33:30];
Viral infections that can affect the testes and potentially lead to sterility [40:30];
Semen analysis: morphology, motility, and hormonal clues to male fertility [45:45];
Effects of medication, microplastics, stress, and exercise on fertility [57:15];
Testosterone replacement therapy (TRT) and male fertility [1:06:00];
Restoring fertility after prolonged use of exogenous testosterone [1:25:00];
Effects of heat and cold exposure on fertility and sperm quality [1:36:00];
How different levels of exercise—especially cycling—affect male fertility [1:41:45];
How alcohol, marijuana, and nicotine affect male fertility [1:46:00];
Why Type 2 diabetes is a risk factor for male infertility [1:50:00];
How varicoceles—a common cause of male infertility—are diagnosed and treated [1:51:15];
Genetic factors that affect fertility [1:54:00];
The impact of lifestyle and environmental exposures on fertility [1:56:30];
The evidence (or lack thereof) behind stem cell and PRP therapies for male infertility, and how lifestyle and non-invasive interventions often lead to successful conception [2:00:30];
Considerations for sperm banking, and how paternal age impacts fertility planning and offspring health [2:05:00];
Semen quality as a biomarker: linking male fertility, longevity, and preventative health through Medicine 3.0 and epigenetics [2:14:45]; and
More.

Show Notes

Notes from intro :
Dr. Paul Turek is a world renowned expert in male fertility and reproductive health
You can think of this as part 1 of a 2-part miniseries on fertility and reproductive health With this one on the male system Next week, we’ll feature Dr. Paula Amato who is the female expert on this topic
Paul is the founder and medical director of The Turek Clinic , specializing in cutting-edge treatments for infertility and men’s health
He is a pioneer in advancing research on sperm biology, genetics, and reproductive longevity
He hosts the podcast Talk With Turek
In this episode we explore the intricate and highly evolved process of conception
Discussing the challenges sperm face on their journey to fertilization This is important to understanding all the places where it can go wrong It’s not just an interesting story, it also explains how challenging it actually is
Paul shares insights into male fertility, including how sperm function in coordination to navigate the female reproductive tract
We discuss how various factors such as heat exposure, stress, and environmental toxins impact sperm quality
We talk about what men can do to optimize their reproductive health
Paul explains the effects of testosterone replacement therapy on fertility Debunking many myths Offering strategies for men looking to preserve their ability to conceive while on hormone replacement therapy
We talk about the emerging fertility technologies Including advanced sperm sorting techniques Genetic testing Innovative treatments that could redefine reproductive medicine
We talk about the differences between the risk in the aging male and the aging female This was one of the most interesting things Peter learned in this podcast
With this one on the male system
Next week, we’ll feature Dr. Paula Amato who is the female expert on this topic
This is important to understanding all the places where it can go wrong
It’s not just an interesting story, it also explains how challenging it actually is
Debunking many myths
Offering strategies for men looking to preserve their ability to conceive while on hormone replacement therapy
Including advanced sperm sorting techniques
Genetic testing
Innovative treatments that could redefine reproductive medicine
This was one of the most interesting things Peter learned in this podcast

The incredibly complex and hostile journey sperm must take to fertilize an egg [3:00]

Explain what’s involved in conception through the lens of sperm

Peter wonders how much of a challenge this is
Obviously there’s an enormous evolutionary pressure for this to go as easily as possible
But what is actually involved?
What happens for a sperm to fuse with an egg?
What are all the things that are standing in its way, so to speak?

Paul explains, “ Reproduction is an incredibly highly-evolved, million-year process, and remarkably conserved among mammalian species, even among land species and water species of animals. ”

Vaginas, cervixes, uteruses

The question is, why is it so much work for a sperm to get into the vagina?
And then have to go through a cervix
The immune system in the uterus is very active, because there’s a hole in the woman to the abdomen, so it has to be highly protected
Sperm have to go through the uterus, so there’s a 10-inch, 12-inch swim Which is equivalent to about a 20-mile swim for a human And they do that in minutes, which is crazy
It’s an interesting challenge that nature has kept in place for a million years
Paul really respects evolution, and it is why we’re here: to eat, sleep, reproduce
Which is equivalent to about a 20-mile swim for a human
And they do that in minutes, which is crazy

Basically with ejaculation, the penis is shaped to fit into the cervix

Everyone wonders, is it getting to the right spot?
It’s also interesting that the semen is coagulated, and then it liquefies And that’s because there’s a lot of species of lower phyla that they have to leave as soon as they have sex, otherwise they’ll get killed (like praying mantises and black widow spiders) Ejaculates in humans are sticky ‒ Paul has no idea why, no evolutionary explanation for this
A lot of men think they’re having trouble placing things
Paul doesn’t worry about it because the cervix and the penis expand to form a seal
And that’s because there’s a lot of species of lower phyla that they have to leave as soon as they have sex, otherwise they’ll get killed (like praying mantises and black widow spiders)
Ejaculates in humans are sticky ‒ Paul has no idea why, no evolutionary explanation for this

Challenges sperm face and the numbers that make it

1 – Sperm have to go through a crypt (a channel), and only a few sperm make it
So 100 million sperm may start out, maybe 5 million make it through the first barrier, which is the cervical barrier
2 – The vaginal fluid is acidic (pH 5) Semen is pH 7
It’s all buffered as a hostile environment, so it has to get out of there quickly
As soon as the sperm liquefies (there’s sugars in there), they go through the cervical path
So 5 million will make it
1 out of 20 makes it through the cervix
Then 100 make it to the fallopian tube, and then 1 will make it to the egg
These numbers were found by studies done in the 50s of women who had sex before hysterectomies Then different parts of the reproductive tract were swabbed These young women had hysterectomies for different reasons, not infertile
This is the basis for our move to technology, from 5 million moving sperm when we start doing inseminations versus sex Those are based on the numbers of sperm that reach the uterus
Everyone thought the vanguard sperm wins It’s the Phelps sperm that’s going to make it
There’s a company out of Boston called Arex Life Sciences , and they’ve discovered that sperm work in phalanxes
Semen is pH 7
Then different parts of the reproductive tract were swabbed
These young women had hysterectomies for different reasons, not infertile
Those are based on the numbers of sperm that reach the uterus
It’s the Phelps sperm that’s going to make it

Disclosure: Paul is consulting for Arex Biosciences

Because the immune system is so vibrant in the uterus, the first round of sperm gets through the cervix and typically absorbs the immune system, secretes Fc receptor

Peter asks, “ We’ve referred to the immune system a couple of times now… What is the barrier? ”

The full immune response: T cells, B cells, and antibodies
There’s also a mucus plug that exists for 28 days a month to prevent anything from going through, because it’s a hole into the woman’s body, and peritonitis is severe

⇒ The cervical mucus thins, and that’s to let sperm through for 2 days a month

It’s an incredibly detailed, perfectly-orchestrated system

It looks like the first round of sperm get through the cervix, get into the uterus, and they get demolished like a Roman phalanx

Maybe a second round goes through and they get demolished
They’re secreting the FCR receptor on the immunoglobulin, because that’s what female antibodies bind to

We don’t know how many phalanxes go through, but then it’s like a run up the middle, and then eventually a couple of sperm make it, and the immune system is deactivated and they get there (it’s wild)

That can be measured now, and there’s actually going to be an assay available to look at whether you’re doing this They’re calling it a sperm cycle Almost like ovulation, spermulation It’s an hour and a half cycle when the phalanx is working, sperm are deactivating the immune system, and then maybe they don’t There are jaculates (which is a group of sperm) and some of which do this well and some of which don’t
They’re calling it a sperm cycle
Almost like ovulation, spermulation
It’s an hour and a half cycle when the phalanx is working, sperm are deactivating the immune system, and then maybe they don’t
There are jaculates (which is a group of sperm) and some of which do this well and some of which don’t

⇒ That can be a whole reason for infertility ‒ if you’re not able to deactivate the system, you’re not going to be able to get through, because the immune system is active

Summary of the numbers of sperm

100 million ejaculated at the cervix
5 million get through the cervix, into the uterus
100-500 get to the fallopian tube
1 gets to the egg

Paul jokes about why you need so many sperm

The classic answer he used to give is they don’t like to ask for directions
But these numbers illustrate why

How sperm are made: meiosis, genetic variation, and the continuous renewal influenced by environmental factors [9:00]

An important consideration for sperm is it can only have half the genetic information contained within all other cells in the man’s body

When does that take place?

The testicle makes sperm
It takes about 60-70 days, and it’s a process called meiosis
So in a car assembly line, cars are mass produced, and you want it all to be the same
In meiosis (which is unlike mitosis ), you want things to be different and to be a little easy-peasy You get what’s called recombination , and that’s the source of evolution The chromosomes blend in a different way and separate in a different way
You get what’s called recombination , and that’s the source of evolution
The chromosomes blend in a different way and separate in a different way

⇒ Through that process, you get half the number of chromosomes, which is required to join the other half

But it’s not always the same half

Funny story about when Peter took the MCAT

Peter had to take the MCAT before doing any of the pre-med stuff, because he had studied engineering before deciding he wanted to do medicine
He didn’t want to spend 2 years preparing 1 year taking the post-bac and then the MCAT
He decided to just wing it and take the MCAT, having never taken a biology class since high school (he took freshman biology)
He’s studying his heart out for this, and the physics and chemistry are fine, but the biology is killing him
He bought this cheap study guide (he didn’t want to splurge for the official study guide)
And every time he encountered the word meiosis and mitosis, he assumed it was a spelling mistake because he bought a knockoff book (he thought it was just mitosis)
Finally, on the night before the exam, he realized they were 2 totally different things There’s a big difference
That realization might have gotten him into med school, because he thinks he barely got at 10 on the biology section It’s hard to get into a good med school if you get below that
1 year taking the post-bac and then the MCAT
There’s a big difference
It’s hard to get into a good med school if you get below that

To this day, Peter gets such a chuckle out of the confusion of the nomenclature

⇒ Mitosis happens when cells are dividing in our body, where they’re trying to create a perfect replica of the entire suite of DNA while meiosis only occurs in the creation of an egg or a sperm

Are women born with all of their eggs?

5 million eggs at conception
1 million eggs at birth
You basically ovulate 1000 eggs in your lifetime 1 a month But you actually produce 10 a month, so you lose 10 eggs every month
By the time you’re 45, you’re out of eggs
There’s a lot of waste
The eggs are stuck in a stage of perpetual space, and they get older but they don’t evolve
They mature at the time they are asked to
1 a month
But you actually produce 10 a month, so you lose 10 eggs every month

But sperm are constantly renewed

Peter asks, “ Is that just a mass space problem? Because the testes, if we did the same thing women did, would we just have to have an enormous set of testes? ”

Paul jokes, “ Why do you think out of the box like that? ”

He’s not sure
There’s a whole issue of what’s the source of human evolution
It’s really sperm because they are constantly dividing, constantly influenced by the environment And they’re throwing off mutations and epigenetic changes
And they’re throwing off mutations and epigenetic changes

What’s most interesting for Paul for this talk is that whatever happens in sperm, happens to offspring

It’s transgenerational

Does that mean that the father is more likely to pass on environmental stressors than the mother?

Probably
That’s definitely been shown

⇒ The sperm is the actual cell

Where do sperm get the little tail from, and what is the other part of the cocktail?

“ One of the most magnificent transformations of a cell in the body is the making of a sperm .”‒ Paul Turek

It starts with a spermatogonial stem cell , which looks like other cells
That spermatogonial stem cell is actually the first and the bottom of a tube There’s 12 stages of spermatogenesis
That cell is remarkable; it’s actually the human male embryonic stem cell
Paul has a patent on that cell, because if you take that cell and you put it in a niche environment like an embryonic stem cell, it’ll become embryonic almost like it can become multipotent You can form tumors, and you can form bone, mesoderm , ectoderm , and endoderm You can do all three layers of the body with that adult spermatogonial stem cell
There’s 12 stages of spermatogenesis
You can form tumors, and you can form bone, mesoderm , ectoderm , and endoderm
You can do all three layers of the body with that adult spermatogonial stem cell

Peter asks “ Is there any other cell in the body that is capable of that? ”

No
There are stem cells in the bone marrow
There might be stem cells in fat, but none of this
Paul has shown that the capability of this cell is magnificent

The male embryonic stem cell has yet to be taken advantage of with cell-based therapy ‒ it’s really incredible what this cell can do

And a man potentially has access to this cell his entire life
The spermatogonial stem cell usually reproduces mitotically, and then at puberty, it’ll go down the path of meiosis This involves halving and mixing up the chromosomes And the newness of the genome introduces mutations Most mutations are bad, and some are good
This involves halving and mixing up the chromosomes
And the newness of the genome introduces mutations
Most mutations are bad, and some are good

The built-in filter that weeds out genetically abnormal sperm [14:45]

When the cell that is becoming a sperm undergoes meiosis and it divides, what’s the fraction of times when this becomes an aneuploidic sperm, and what’s the process by which that thing gets discarded?

⇒ If you look at healthy human sperm for chromosomal content and what’s correct and what’s incorrect, probably 2% of them are off

They’ll still be made because it doesn’t really click the system to negate it
We don’t know at what level of chromosome abnormalities the system will say, “ This is a bad product. ”
Making sperm is very logarithmic
Probably 1 out of 4 that are being made go through the epididymis Which is a collecting duct after the testicle where it matures (for 10 days), gets epigenetically modified You’ll see different epididymal zones There’s a lot of post-production modification, not of DNA essentially,
There’s a filter going on where a lot of the bad aneuploidy comes out, because if you look at the chromosomal abnormality rate in testicular sperm before it goes through the rest of the system and compared to ejaculate, it’s 2-3-fold higher
When we talk about aneuploid sperm , instead of having 1 copy of each chromosome, an aneuploid sperm either has none, or 2, or anything that’s not 1 of each
Which is a collecting duct after the testicle where it matures (for 10 days), gets epigenetically modified
You’ll see different epididymal zones
There’s a lot of post-production modification, not of DNA essentially,

When aneuploidy occurs in the fusion of sperm and egg, can we figure out if it’s maternal or paternal in origin?

If you look at the embryo, it’s kind of hard to tell
There are some markers of paternal and maternal origin
It depends on where you’re going back in mitosis and meiosis
You’re really going to have to look at the sperm, and if you see a translocation, some characteristic change in sperm, and you see it in the embryo, then you know it’s paternal, but not usually

⇒ 98% of sperm are typically normal, and in a guy with infertility, it might be 95%

Example: you have a patient with Kleinfelter syndrome , a male with an extra X chromosome in every cell in their body (or a transgenic model with that feature)

This is a man who is XXY instead of XY (47 chromosomes not 46)
Phenotypically, he had a distinctive look only 10% of the time 90% of the time, you would never know That’s a MCAT question
90% of the time, you would never know
That’s a MCAT question

Every cell in their body has an extra X chromosomes but only about 10% of their sperm will have an extra X chromosomes

Meaning most sperm will have an X or a Y, just like everyone else

Peter asks, “ The only difference is they have a two-thirds chance of producing an X and a one-third chance of producing a Y, I’m assuming, instead of 50/50? ”

Paul doesn’t think we know that
That’s math and biology is not math

Paul operated on 2 Kleinfelter’s patients yesterday

They’re not doing pre-implantation genetic diagnosis of the embryos that they’re going to create from their sperm, because the chance is not that high
In mice, there is a 0.1% chance of normal men having an XY sperm (or an aneuploid sperm) to 1% chance of abnormal sperm
In humans it goes from 1% or so to 10%

But 90% [of sperm is normal] and that is remarkable

How sperm are finalized in form and function: tail formation, energy storage, and chemical sensing abilities [18:30]

Back to the process of how sperm is made in the testicle

The testicle is an amazing machine

Weird question: Why is it out in the breeze like that?

Peter assumed it was temperature related
Why does it need to be a little cooler?
Peter guesses that it’s so energetically demanding, that it’s giving off more heat in the process of creating something that is going to be so efficient to be able to swim 20 miles effectively And that’s very glycolytic, he’s assuming (the amount of ATP that must be generated)
And that’s very glycolytic, he’s assuming (the amount of ATP that must be generated)

⇒ There are 75 mitochondria per sperm ‒ that’s like an electric motor on each wheel

It’s Peter’s guess that if you tried to keep those guys inside, you’d have an overheating problem
Paul thinks overheating could be translated to oxidative stress, which is a cause of a lot of infertility
We don’t know the answer
It’s interesting that ovaries are inside
Men get in hot baths and they’re cooked, women can get in hot baths and they’re okay

Funny story

Peter had a buddy over who does not have kids but would like to have kids
Before they went into the sauna, he went to the freezer and came down with ice packs
They were sitting in the sauna and he’s got ice packs all over his groin
Peter immediately understood why he was doing that
They’ll come back to whether or not that is an important strategy for men in saunas who want to have kids

Spermatogenesis is the whole process

Spermatogenesis is when you go from the round cell stage, and you get half the number of chromosomes
Then you have to make a tail and then whole motor assembly That is the most profound transformation of a cell in the body It takes about 3 weeks to go from that stage We’re learning now, a lot of it’s vitamin A driven
The whole process is 6 or 7 weeks, then it’s complete and nonmotile and it’s packaged
That is the most profound transformation of a cell in the body
It takes about 3 weeks to go from that stage
We’re learning now, a lot of it’s vitamin A driven

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

Probably similar to half the size of a lymphocyte, or half the size of a red blood cell, a couple microns
35 micron tail

It’s really a magnificent engineering feat

It’s got microtubules in the middle, and there’s these links to the tail
It’s like a kite, and the engine runs it, and tail wags
300 genes control movement of sperm alone
There’s mitochondrial DNA in there, all that stuff

⇒ Sperm are wildly compact, 10x more compact than any other cell in the body

From a mitochondrial density standpoint
From a cytoplasmic standpoint
From a nuclear standpoint, it goes from histones to protamines : that DNA is condensed a lot more It’s got to be packaged really well to survive outside the body and be in good shape, because it’s transgenerational
A lot of energy in that
It’s got to be packaged really well to survive outside the body and be in good shape, because it’s transgenerational

Peter asks, “ Where is the ATP, or carbohydrate, or whatever, the glucose stored in the sperm? ”

Probably in the cytoplasm and in the tail
Peter compares it to a rocket ship with its payload ‒ it’s packaged for that one shot He assumes it’s the same here, there’s no transporters to bring in glucose or anything Correct ‒ it has solid fuel and one shot
He assumes it’s the same here, there’s no transporters to bring in glucose or anything
Correct ‒ it has solid fuel and one shot

There’s a 2 week period where sperm stay in the epididymis

[B and C in the diagram below]

Figure 1. Anatomy of the testicle showing the (A) head of epididymus, (B) body of epididymus, (C) tail of epididymus, and (D) vas dererens . Image credit: KDS444 at Wikipedia

The epididymis is a 35-foot tubule, with estrogen
There’s a lot of post-modification of the sperm
700 feet of tubules are in the testis
The epididymis is a comma-shaped organ in the back of the testis
This is prone to infection, and that will factor into infertility
The epididymis has been relatively understudied, but it has actually become very important, epididymisomes And there’s a lot of modifications we don’t really understand Paul wrote the chapter for a textbook on reproductive physiology , and it really is a lot of work in the ’50s and ’60s
And there’s a lot of modifications we don’t really understand
Paul wrote the chapter for a textbook on reproductive physiology , and it really is a lot of work in the ’50s and ’60s

⇒ Now we’re beginning to understand DNA fragmentation and the quality of sperm is driven by the epididymis

A lot of the quality of sperm, not the shape and stuff like that
Meaning the residence time within the epididymis and other environmental factors there
It’s more susceptible to drugs, exposures, heat, etc.
The testis are very walled off Very little happens in the testis, because the Sertoli cells that line the tubules have a blood-testis barrier , same as the brain (blood-brain barrier)
Harvey Cushing at Yale did that in the late 19th century, took brain-dead patients, injected them with dye (maybe methylene blue) The blood brain barrier came about when nothing went into the brain, and nothing went into the testicle 2 areas of the body that were completely immune from normal transport processes
Very little happens in the testis, because the Sertoli cells that line the tubules have a blood-testis barrier , same as the brain (blood-brain barrier)
The blood brain barrier came about when nothing went into the brain, and nothing went into the testicle
2 areas of the body that were completely immune from normal transport processes

The 2 things that we know happen in the epididymis after production of sperm are motility improves, and they learn how to smell

Sperm begin to learn progressive motility They start moving forward, as opposed to not moving, or moving in circles
And the most curious thing is they learn how to smell They track a chemical signal in the follicular fluid
If you take testicular sperm and inseminate it into a uterus with insemination technology, it’ll just be killed
If you take an epididymal sperm, and you do that from the top of the epididymis, it’ll maybe run in circles, and it’ll be killed by the immune system of the female
Once it’s at the end of the epididymis (where it is stored) ‒ that sperm knows where to go and it’ll move forward It takes 10-14 days for sperm to make their way through the epididymis 600 million sperm live in a bucket, a pot of soup called the epididymis, and you ejaculate from that pot
That sperm is like a shark sensing blood in the water
They start moving forward, as opposed to not moving, or moving in circles
They track a chemical signal in the follicular fluid
It takes 10-14 days for sperm to make their way through the epididymis
600 million sperm live in a bucket, a pot of soup called the epididymis, and you ejaculate from that pot

⇒ 1 part per billion of follicular fluid can be sensed by a sperm (that’s incredible)

It’s literally an olfactory sense that sperm have for the follicular fluid so they know exactly where to go

Peter asks, “ Do we know what the chemoreceptor is? ”

It was published in Nature ; it’s an olfactory type receptor

Peter wonders, “ What is the most noxious thing that we can smell with our nose, and at what concentration can we detect it? ”

Paul has no idea
[discussed in Physiology and Behavior ]
Peter has always thought about this because he likes to hunt Anyone who’s ever bow hunted knows that animals can smell at a level that we can’t even fathom They can smell us literally a mile away, if the wind is just blowing their direction It’s always seemed like we have really, really insufficient noses We were given lots of superpowers in many ways, but smell wasn’t really one of them
If you block a sensory bank of the 5, the others increase remarkably Paul is a micro surgeon and this stuff matters a lot, but he can’t read braille He thinks about people who are deaf ‒ hearing and smell can crank up
Anyone who’s ever bow hunted knows that animals can smell at a level that we can’t even fathom
They can smell us literally a mile away, if the wind is just blowing their direction
It’s always seemed like we have really, really insufficient noses We were given lots of superpowers in many ways, but smell wasn’t really one of them
We were given lots of superpowers in many ways, but smell wasn’t really one of them
Paul is a micro surgeon and this stuff matters a lot, but he can’t read braille
He thinks about people who are deaf ‒ hearing and smell can crank up

Back to sperm

Sperm detect 1 part per billion of follicular fluid

⇒ The base of the epididymis is basically the launchpad where half a billion sperm are stored

That’s enough for 5 ejaculations

Peter asks, “ What’s the time to rebuild that? What’s the rate at which you fill? ”

Paul doesn’t know
There must be a frequency of ejaculation that is too much

How to optimize conception through the timing of sex, ejaculation frequency, and understanding the sperm lifecycle [26:30]

If a guy is ejaculating every single day, is that insufficient to get a complete replenishment? Where if he’s having infertility, you would say, “ You got to move it to every other day. ”

⇒ Typically, Paul recommends 2 days of abstinence, and sex every other day to optimize conception

It depends how old you are and your biology
Most men need a day or 2 to recharge completely, and that’s sort of a generalization
Some men are fine every day
Paul had a guy once who had to bank sperm for hepatitis treatment, and he was like Mickey Rourke, and he had a wooden leg and he’s about 50 When Paul told him to abstain for a couple days to do this semen analysis, he looked at his partner, and she grabs him and says, “ He can’t do that. He’s every day, he can’t do that. I don’t know what he’s going to do .” He was panicking that he had to hold off for a day Paul asked, “ How often do you have sex? ” He said, “ Twice a day, every day .”
Paul had another man, a wonderful orthopedic surgeon at Stanford, who he asked on his questionnaire, “ How often do you have sex? ” He wrote 0.00001356 weekly (Avogadro’s number) ‒ which meant he was so frustrated
When Paul told him to abstain for a couple days to do this semen analysis, he looked at his partner, and she grabs him and says, “ He can’t do that. He’s every day, he can’t do that. I don’t know what he’s going to do .”
He was panicking that he had to hold off for a day
Paul asked, “ How often do you have sex? ”
He said, “ Twice a day, every day .”
He wrote 0.00001356 weekly (Avogadro’s number) ‒ which meant he was so frustrated

For semen analysis, for diagnostics, for infertility, when you abstain longer, your sperm count will rise but your motility will fall (because it’s older)

There’s a min-max curve you’re optimizing for, and 3 days would be about right You’re not going to lose that much motility after that
You’re not going to lose that much motility after that

There’s biological variability, which we try to minimize when we do the semen analysis

2-4 days of abstinence
That’s a different period than what we’re recommending for sex (which is every other day)
That’s based on a NEJM paper where they looked at about 700 couples They had them keep diaries of how they had sex, when they ovulated, and when they got pregnant They said, “ Do what you normally do and then give us the diaries. ” Say ovulation is day 15 of the cycle, they found when people started having sex on days 9, 11, 13, there were significant pregnancy rates And [having sex] every other day was the optimal interval But if you waited until ovulation and then had sex, that accounted for about 20% of conceptions
They had them keep diaries of how they had sex, when they ovulated, and when they got pregnant
They said, “ Do what you normally do and then give us the diaries. ”
Say ovulation is day 15 of the cycle, they found when people started having sex on days 9, 11, 13, there were significant pregnancy rates
And [having sex] every other day was the optimal interval
But if you waited until ovulation and then had sex, that accounted for about 20% of conceptions

Paul’s advice ‒ when you get the [ovulation] kit, predict in front of it; it’s very important to front load the sex

Why is that?

There’s a reservoir effect in this uterus, it’s managed
Sperm will survive for a day or 2

Peter asks, “ If ovulation is day 15, how could a day 11 sperm survive four days? It’s nurtured once it’s past the vagina. But how many of them are surviving? Is it literally the lone wolf, or is it the last hundred? ”

Probably
Maybe some of the sperm bind to the oviduct (the fallopian tubes ) and wait They bind to the endothelium and just park If there’s no egg, they’ll just sit there
They bind to the endothelium and just park
If there’s no egg, they’ll just sit there

Going back to our moon [rocket] analogy, this is after you’ve done stage 1, stage 2, stage 3, you’re now out of gravity

It’s actually not an energetics problem anymore
Sperm have escaped the hostile environment, in this case of gravity
Now it’s in a fun place, the right pH, it’s warm

Peter wonders what is the longest duration a sperm could survive for conception

If you had a large number of women that you knew were going to ovulate on day 15, and then you would have them have intercourse on day 7, 8, 9, 10
And you create a distribution of the frequency of pregnancy across those days, and ask what’s the bottom 5th percentile (which is the theoretical possibility)?
That experiment hasn’t been done That’s a good one
You want to develop the bell curve of the whole thing
That’s a good one

⇒ We know that once the egg is ovulated, after about 8 hours it’s over (it’s dead)

The egg only survives for about 8 hours
That’s a very left-tail curve

You want the sperm there ahead of time

Paul explains, “ 80% of conceptions naturally who are at home occur when sex is front-loaded as opposed to reacting to ovulation. And most of the apps that are available nowadays will tell you that. ”

More physiology about sperm

Studies of spermatogenesis

There was a study published in Science in the ‘60s where men drank tritiated water , and then they biopsied their testicles Which would never be done nowadays
Paul did a study at Berkeley where he gave men deuterated water for a week That was not radioactive, but you could measure it They gave them a dose of deuterated water and watched their ejaculates weekly They looked for when the hydrogen showed up in the DNA, and it was an average of 74 days Some men it was as quick as 42 days, and that’s going through the epididymis and getting ejaculated
Which would never be done nowadays
That was not radioactive, but you could measure it
They gave them a dose of deuterated water and watched their ejaculates weekly
They looked for when the hydrogen showed up in the DNA, and it was an average of 74 days
Some men it was as quick as 42 days, and that’s going through the epididymis and getting ejaculated

⇒ Normally it takes about 3 months to make a sperm (74 days on average)

Paul mentioned early that sperm spend maybe 2 months in the testis and a week or 2 in the epididymis, and then maybe a couple of weeks to ejaculate

So when you do anything to a man fertility-wise, you’re not going to expect to see any change for at least 2.5 months; and when you talk about full replacement of that semen, it probably takes 90 days

That’s the limitations in a man
A 42-year-old woman wants now, but it takes 3-6 months

Paul did a study on fixing varicocele

This is an infertility problem in men, it’s surgery
[Varicocele is discussed in Paul’s blog ]

He looked at the meantime to conception, and it was about 7 months after repair (which is 2 cycles of sperm production)

Male infertility and Paul’s diagnostic approach: detailed history, a physical exam, and identifying red flags [33:30]

⇒ Infertility is defined as the inability to conceive after one year (using sex)

It doesn’t have to be timed intercourse, just has to be whatever the couple does when they think they’re trying to conceive

When someone shows up in your office, is it usually after they’ve gone down the rabbit hole of troubleshooting the female partner?

Or are people doing this in parallel?

There’s a large bias in Western worlds about how infertility is evaluated
Paul’s practice is not typical Most of his patients have been through a lot before they come to him
Typically, Keith Jarvi’s data was good, and about 23% of men get a formal evaluation for infertility before couples go through IVF in North America
Most of his patients have been through a lot before they come to him

Peter asks, “ How does that differ from the rest of the world? ”

That hasn’t been studied in the rest of the world, but there are countries like Germany and Spain with single insurers and the government pays
It’s also recommended that both partners get evaluated simultaneously By society guidelines, like American Society of Reproductive Medicine, WHO, etc.
But the bias is that the female gets very evaluated, for lots of money
Men typically may get a semen analysis, but may not And there’s a very complex reasoning there It’s a different beast There’s a lot of denial It does get at your masculinity a little bit to get checked out and things, and it can be a little bit of a problem
Lately, with large insurers coming in (Progeny, Maven, and things like that), you’re seeing a lot more men upfront Which is fabulous
By society guidelines, like American Society of Reproductive Medicine, WHO, etc.
And there’s a very complex reasoning there
It’s a different beast
There’s a lot of denial
It does get at your masculinity a little bit to get checked out and things, and it can be a little bit of a problem
Which is fabulous

Paul’s workup. What do you do when a guy comes in, and what are the things you want to know about him?

Usually a guy is dragged in by their partners
Paul does 1 visit in person and everything else where they are It’s a different kind of practice; he doesn’t ask them to come in a million times He tries to get everything done in 1 visit because it’s rare to get them there
He does a very thorough history (usually preceded by a questionnaire) He give 200 questions, and that has all the hot bath stuff and all the exposures they have, and they have to do that before they see him That’s a really important part of it
If you could pick one in a multiple-choice question, what matters the most is probably the history History of paternity matters, a history of exposures matters, etc.
It’s a different kind of practice; he doesn’t ask them to come in a million times
He tries to get everything done in 1 visit because it’s rare to get them there
He give 200 questions, and that has all the hot bath stuff and all the exposures they have, and they have to do that before they see him
That’s a really important part of it
History of paternity matters, a history of exposures matters, etc.

⇒ 1-5% of male infertility can be due to a major medical issue (testis cancer, diabetes, things like that)

The physical exam, very important Varicocele is very important You can be missing a vas deferens : 1 in 500 men have perfectly normal testicles, but they have a natural vasectomy It’s a congenital absence of the vas, they’re going to be sterile or infertile
Varicocele is very important
You can be missing a vas deferens : 1 in 500 men have perfectly normal testicles, but they have a natural vasectomy It’s a congenital absence of the vas, they’re going to be sterile or infertile
It’s a congenital absence of the vas, they’re going to be sterile or infertile

We haven’t talked about how a vasectomy works and why a guy still ejaculates, but is infertile. Explain what the vas deferens, how the whole thing works and the plumbing

We also didn’t answer the question: what does semen consist of?

Semen is 10% basal fluid with sperm
It’s about 80% seminal vesicle fluid, which is an accessory sex gland in the back of the prostate, and about 10% prostate
Typically during ejaculation, prostatic fluid (which is clear and sticky) will grease the barrel of the urethra as “pre-cum”
Then during the ejaculation process, the pellet of sperm gets pumped from the vas deferens into a chamber called the ejaculatory duct (this happens quickly) [the figure below shows the male anatomy]
Then the seminal vesicle (which is like a bladder) contracts, and sends sperm into the prostatic urethra There’s two valves One is the bladder neck ‒ it closes One is the urethral sphincter that we pee through ‒ that opens and it gets forced out with muscular contractions in seconds
[the figure below shows the male anatomy]
There’s two valves
One is the bladder neck ‒ it closes
One is the urethral sphincter that we pee through ‒ that opens and it gets forced out with muscular contractions in seconds

Figure 2. Male reproductive anatomy . Image credit: K. D. Schroeder at Wikipedia

Therefore, if the vas deferens is clipped [in a vasectomy ], you’re getting essentially 90% of the volume You’re just missing the 10% of the volume that contains the payload [the sperm]
You’re just missing the 10% of the volume that contains the payload [the sperm]

Paul explains, “ In 3,000 men I’ve done vasectomies on in 30 years, 2 men have said, ‘My volume went down. ’”

He had semen analysis before and after and he did go down by 15% (and he noticed)
So it can be noticeable, but not usually The color is the same The opacity is the same The whole process of liquefaction is the same Viscosity, etc.
The color is the same
The opacity is the same
The whole process of liquefaction is the same
Viscosity, etc.

For the physical exam, do you need an ultrasound?

How are you able to detect if a person is congenitally missing a vas deferens?

Pure physical exam
You feel it The vas deferens is like a piano wire It is different than anything else in the cord
Paul did a study: a third of his men with absent vas deferens only found out having procedures until he saw them He usually does the exam; it’s an expertise thing It’s not like the PCP can figure this out ‒ you have to be doing this all day every day
The vas deferens is like a piano wire
It is different than anything else in the cord
He usually does the exam; it’s an expertise thing
It’s not like the PCP can figure this out ‒ you have to be doing this all day every day

⇒ 1 in 500 men are congenitally missing their vas deferens

The most common genetic disease in America is cystic fibrosis [ affecting 1 in 2,500-3,500 whites in the US, and most have congenital absence of the vas deferens]
The big implication is these men can’t conceive naturally They have a natural vasectomy
Paul uses sperm retrieval techniques and IVF, but they definitely have the chance of passing on cystic fibrosis to a child [because cystic fibrosis is an autosomal recessive disease ]
[ affecting 1 in 2,500-3,500 whites in the US, and most have congenital absence of the vas deferens]
They have a natural vasectomy
[because cystic fibrosis is an autosomal recessive disease ]

Peter asks, “ What is the Venn diagram of cystic fibrosis and congenital lacking vas deferens? ”

The genes for that were discovered, and it’s at chromosome 7 There’s 17, 1,800 mutations, maybe 2,000 They cloned the genes and got the variants in the late ‘80s
Then they found there’s another group of men who are perfectly healthy, do not have cystic fibrosis (which is a major metabolic disease with a short life expectancy)
Those men had absent vas deferens in the absence of disease They took the gene sets and looked at them, and they were the same, just not as many So you have homozygous or heterozygous
There’s 17, 1,800 mutations, maybe 2,000
They cloned the genes and got the variants in the late ‘80s
They took the gene sets and looked at them, and they were the same, just not as many
So you have homozygous or heterozygous

A carrier for cystic fibrosis will have an absent vas deferens, but a full-blown CF patient, cystic fibrosis patient, will have no vas deferens too

In other words, when you identify a man who does not have CF with a congenitally absent vas, there’s a very good probability he’s a carrier of CF?

Yes, and you can usually define it
We can genetically test easily
If you’re a carrier, there’s a 4% chance in America that your partner might carry it
With 2 carriers there is a 1 in 4 chance of having an affected child [with cystic fibrosis]
That’s a big concern in Paul’s practice, and he’s proud to say, “ In 30 years, we have no CF children. It’s all about good engineering and doing it right. ”

Viral infections that can affect the testes and potentially lead to sterility [40:30]

What else on the physical exam are you looking for?

Cancers, infections, epididymitis

Tell me about epididymitis (what’s the infection?)

Mumps
There’s aren’t many viruses that get into the testicle
Very little gets into the testicle, similar to the brain
But the mumps virus does it about a third of the time
When you’re a child with mumps The parotid gland infection It’s a glandular disease
It really only matters when you’re pubertal and you get mumps ‒ then it goes to lots of glands It goes to your pancreas and causes diabetes It can go to the salivary glands It can go to the testicles
The parotid gland infection
It’s a glandular disease
It goes to your pancreas and causes diabetes
It can go to the salivary glands
It can go to the testicles

Peter adds this public service announcement, “ Just one more reason why everyone should really get the MMR vaccine when they’re a child, notwithstanding the tragedy of children dying from preventable diseases. But this is another non-lethal, but significant complication of mumps .”

It will cause viral necrosis and edema of the testis
Similar to a brain, it’s in a calvarium The brain is in a fixed space; so when it swells, you got to do something because you can die if it swells too much
The testicle’s a fixed cavity with the tunica albuginea If it swells too much, it necroses and then you get fibrosis, and then you get sterility
Paul has techniques where he can find sperm in lots of these men (very little pockets)
But most of it you’re ablating the testis It’s going to scar and die from ischemic necrosis
The brain is in a fixed space; so when it swells, you got to do something because you can die if it swells too much
If it swells too much, it necroses and then you get fibrosis, and then you get sterility
It’s going to scar and die from ischemic necrosis

Other viruses that can affect the testis

Zika , Ebola , the CDC called Paul when these were coming around
Zika’s been transmitted through semen It causes the anencephaly issues when these pandemics recurring
He got a call that there was an Ebola patient who survived, went to the institute, survived hemorrhagic fever and then a year later transmitted Ebola to a partner who transmitted it to 6 other men It was another outbreak in South Africa
It causes the anencephaly issues when these pandemics recurring
It was another outbreak in South Africa

Peter asks, “ Meaning the patient that survived Ebola, the virus managed to survive in the testis? ”

Somewhere, but was transmitted sexually a year later when he was well

Peter asks, “ When he was asymptomatic? He had already developed immunity? ”

Right
We don’t know about testis
But we know that mumps will do that to the testis
Zika is also persistent in the semen
You have to think wherever the virus hung out, it had to be very immune privileged Or at low levels, like low viral loads where there’s no disease
These are concerning cases
It may be bulbourethral gland
Maybe it’s seminal vesicle ; it’s hard to know
But most viruses don’t go there
The big one would be COVID There was a big deal about the ACE receptor being in the lung and being in the testicle And maybe COVID infection would make you sterile
There was one Zika paper in Nature that looked at if you infect mice with Zika, the testicles shrivel up and they get infertile That caused a huge scare in the field, but we really didn’t see it We’re not sure why it did it in mice
It’s a blood-testis barrier thing It’s an amazing barrier and nothing really gets through, including viruses, but mumps does, only at puberty Zika does in animals, but we didn’t see it in humans Zika could be seminal (just in the semen itself, not in the sperm) Like Ebola is probably seminal, not testicular It’s not on sperm; it’s around sperm or in the fluid
For COVID, the big worry was when this Chinese paper came out It binds the ACE receptor in the lung The testicle has this receptor too Is it going to make men sterile forever? [see also a review Paul co-authored on the effects of COVID-19 on fertility]
There were cases of infertility with bad infections Was that just the fever, which typically does it even after a flu? Or was that COVID specific? And we didn’t know
A couple of Paul’s colleagues did some papers
One which impressed him was out of Cedars was a bunch of men (maybe not reproductive age) died with florid COVID They got autopsies and they looked for virus in different locations in the body Out of 10 men [it was 8 men], 1 had it in the testicle So these are the men with the highest viral load you can imagine and only 1 of them had it [in his testicles]
Or at low levels, like low viral loads where there’s no disease
There was a big deal about the ACE receptor being in the lung and being in the testicle
And maybe COVID infection would make you sterile
That caused a huge scare in the field, but we really didn’t see it
We’re not sure why it did it in mice
It’s an amazing barrier and nothing really gets through, including viruses, but mumps does, only at puberty
Zika does in animals, but we didn’t see it in humans Zika could be seminal (just in the semen itself, not in the sperm)
Like Ebola is probably seminal, not testicular It’s not on sperm; it’s around sperm or in the fluid
Zika could be seminal (just in the semen itself, not in the sperm)
It’s not on sperm; it’s around sperm or in the fluid
It binds the ACE receptor in the lung
The testicle has this receptor too
Is it going to make men sterile forever?
[see also a review Paul co-authored on the effects of COVID-19 on fertility]
Was that just the fever, which typically does it even after a flu?
Or was that COVID specific? And we didn’t know
They got autopsies and they looked for virus in different locations in the body
Out of 10 men [it was 8 men], 1 had it in the testicle
So these are the men with the highest viral load you can imagine and only 1 of them had it [in his testicles]

There’s a fertility risk with COVID, but of the 1,000 men Paul has seen since COVID, there were 2 cases [of infertility] that were unexplained

Where men were either fertile or had normal semen quality then had a bad COVID infection (maybe hospitalized), and 3 months later were sterile
There’s a low perfusion rate there

Peter asks, “ What’s the phenotype of their sterility, aside from the presentation that they can’t get someone pregnant? ”

No sperm in the semen
It’s a primary problem

Semen history is the 3rd thing Paul does when he sees patients

After gathering the history and conducting the physical

The 4th thing is to check hormones

Production of sperm is driven by the brain
Nothing nothing happens to sperm being made without the brain telling it what to do Similar with eggs and controlling It’s all a homeostatic mechanism with negative feedback
Similar with eggs and controlling
It’s all a homeostatic mechanism with negative feedback

Semen analysis: morphology, motility, and hormonal clues to male fertility [45:45]

Back to semen analysis , you’re looking for the count and motility. What else do you look for?

Paul considers it a sort of “poker hand”

There are several features
There’s the volume of semen
There’s a count , concentration of sperm (numbers per mL)
There’s motility , which is percent motion You do a forward progression and see how good is the quality of motion
Some measure of shape, called morphology
There’s 3 liquid issues: liquefaction, agglutination, and viscosity
Then you look for other cells that aren’t sperm They are called round cells Either they’re going to be puss cells or immature germ cells that are ejaculated early Less than a million is normal
You do a forward progression and see how good is the quality of motion
They are called round cells
Either they’re going to be puss cells or immature germ cells that are ejaculated early
Less than a million is normal

Paul explains how he looks at semen analysis, “ I look at it as a poker hand with each card has a meaning, but they have a look. ”

If the volume is low, it’s one of 5 things You’re always going to find something 1 – It’s at the collection error (Paul calls this the first sample syndrome) 2 -Low testosterone can cause it 3 – There’s an absent vas deferens, which means you have an absent seminal vesicle 4 – There’s ejaculatory obstruction Peter asks, “ Do you ever have that on one side and not the other? ” No It’s very variable, segmental
When Paul sees a low volume of semen, as a surgeon, he’s going to find something
You’re always going to find something
1 – It’s at the collection error (Paul calls this the first sample syndrome)
2 -Low testosterone can cause it
3 – There’s an absent vas deferens, which means you have an absent seminal vesicle
4 – There’s ejaculatory obstruction Peter asks, “ Do you ever have that on one side and not the other? ” No It’s very variable, segmental
Peter asks, “ Do you ever have that on one side and not the other? ”
No
It’s very variable, segmental

Semen analysis is a blunt instrument for fertility ‒ unless it’s zero, you can’t really say much about their fertility because people can conceive at all levels

Are there certain null states that don’t exist where everything is amazing, but this one thing is horrible?

Do you see scenarios where everything is remarkable, perfect motility but bad morphology?

Yes
Or isolated things
Syndromic sperm shape problem : you can have a perfectly normal semen analysis, count, motility volume, progression, and the sperm looked terrible
There are rare conditions (1 in 5,000) where you might have globozoospermia or two-tailed sperm or pinhead sperm

⇒ If you look at shape, 4% should look normal (which is terrible)

That means 96% of the sperm don’t look normal (could be pinhead, double-tail, amorphous, or tapering) Pinhead means there’s no nucleus Most of them are going to be amorphous, head’s a little rounder, head’s a little narrower Those are called stress patterns Some things like hot baths and varicoceles and smoking will do that
We can have a discussion about why 4% of human sperm being normal is normal when 99% of animal species in the wild have normal looking sperm But it’s all a construct of someone decided what normal is If you look at marine species, 99.9% look perfect in the wild
In men who have large abnormal forms, if they’re 1% normal, you’ve got to look at the 99% The story is in the [larger] chunk, and if they’re all looking the same, then it’s syndromic and then you have a problem
The more homogeneous the failures are, the more likely that you have a clear etiology, and that’s hard to fix They’ll fail with sex They’ll fail with insemination They’ll fail with IVF
Sometimes with globozoospermia (where they’re called lollipop sperm), they just have a big round head with no acrosome, there’s all nucleus and there’s some of the components, they’ll just bounce off an egg They’ll never work naturally And to get them to work with IVF, you have to single sperm inject them into the egg and then shock the egg with calcium, do a calcium or piezoelectrics to get it to actually fertilize Because the sperm is important, but fertilization, not only has to bind, but the calcium channels are regulated by sperm And what shuts the doors to polyspermy in an egg is calcium activation
This is the reason why even if you launch 100 sperm at an egg, it’s only one that can get in, because the first guy that breaches sets off the calcium channel that shuts the [egg to further sperm entry]
Pinhead means there’s no nucleus
Most of them are going to be amorphous, head’s a little rounder, head’s a little narrower Those are called stress patterns Some things like hot baths and varicoceles and smoking will do that
Those are called stress patterns
Some things like hot baths and varicoceles and smoking will do that
But it’s all a construct of someone decided what normal is
If you look at marine species, 99.9% look perfect in the wild
The story is in the [larger] chunk, and if they’re all looking the same, then it’s syndromic and then you have a problem
They’ll fail with sex
They’ll fail with insemination
They’ll fail with IVF
They’ll never work naturally
And to get them to work with IVF, you have to single sperm inject them into the egg and then shock the egg with calcium, do a calcium or piezoelectrics to get it to actually fertilize
Because the sperm is important, but fertilization, not only has to bind, but the calcium channels are regulated by sperm
And what shuts the doors to polyspermy in an egg is calcium activation

Morphology can matter a lot, but it’s rarely the cause of infertility

Paul sees this in his practice maybe twice a year
There’s not much he can do to treat it He can try sperm sorting technologies (which are new in the market), microfluidics and things like that Sometimes it works; sometimes it doesn’t
He can try sperm sorting technologies (which are new in the market), microfluidics and things like that
Sometimes it works; sometimes it doesn’t

Is that something that we know the genetic underpinning of?

We’re getting there
PLC-zeta deficiency is one that was recently discovered That runs the calcium channel It tends to be associated with a certain look, like globozoospermia
That runs the calcium channel
It tends to be associated with a certain look, like globozoospermia

Peter remarks, “ Think about that for a second from an evolutionary perspective. That is the single least desirable genetic mutation you could acquire… this is a dead end to the genome. ”

Peter asks, “ Does that mean it is only an acquired mutation, never inherited? I mean, it can’t be inherited presumably, unless it’s homozygous, but even still .”

That’s 1 of the 50 we throw off each generation (50 mutations)

Paul emphasizes how fluid evolution actually is, and it’s sperm driven and it’s transgenerational

“ Sperm matter a lot. A lot. A lot more than we’ve given them credit for. ”‒ Paul Turek

On the semen analysis, what if motility is the problem?

In Paul’s analogy of the poker hand, if everything looks good, but the motility is low, he thinks of short-term toxins , severity Things like exposures, so medications He would think about habits, behavior, lifestyle: pot, smoking, hot baths He would look for an exposure in that individual, basically picked up on the history, varicoceles and exposure, things like that
And if the count is down and the motility is down, he thinks of a longer severe exposure
There’s royal flushes and there’s four of a kind
Things like exposures, so medications
He would think about habits, behavior, lifestyle: pot, smoking, hot baths
He would look for an exposure in that individual, basically picked up on the history, varicoceles and exposure, things like that

Paul’s goal when he sees that semen analysis and sees that patient is to figure out, “If he’s not normal, why?”

Do you get that analysis the day he’s in the clinic with you? Or is that something you follow up on an appointment with?

Paul has this when he sees the patient

Is this something that’s standardized and automated through microfluidics? How is the assay actually done?

It used to be done manually
Now it’s done with the hemocytometers; it’s done with machines Computer-assisted semen analysis does most of them in IVF groups It’s standardized
When Paul has semen analysis repeated, he usually has someone do it by hand because there’s observations he likes For example, “ 1% morphology, but all the others look like this .” Those comments are incredibly valuable that you don’t really get from a computer-assisted semen analysis
But the computer-assisted semen analysis is faster and you don’t have a lot of human effort involved with a computer
Computer-assisted semen analysis does most of them in IVF groups
It’s standardized
For example, “ 1% morphology, but all the others look like this .”
Those comments are incredibly valuable that you don’t really get from a computer-assisted semen analysis

Are they using AI for this yet?

Some people are for sperm selection
That will be really helpful for morphology to standardize it because one man named Kruger in South Africa correlated bad sperm shape with IVF outcomes and did not find that they were good when the sperm looked bad That’s where the 4% came from
But it’s really hard to do that every time and do it well
Paul hopes AI, machine learning can help standardize the look, because sperm [morphology analysis] is hard
That’s where the 4% came from

LH and FSH are important. What else are you looking at? Testosterone?

⇒ To make normal amounts of sperm, you need proper amounts of testosterone and FSH

Think of it as flowering a plant: you need the water and you need the sunlight Testosterone, FSH are key
Testosterone, FSH are key

⇒ To get normal amounts of testosterone, you’re going to need LH, which drives it

Same in women
These are all named in females
There are cases of genetic infertility (like Kallmann syndrome ) where men aren’t making any sperm, but they’re just not sending the signals down These men are not making FSH and LH They have virtually no testosterone or sperm
But you can just give them the signals with injections Give them hCG, FSH injections, and they will be fertile
These men are not making FSH and LH
They have virtually no testosterone or sperm
Give them hCG, FSH injections, and they will be fertile

Peter asks, “ Is the problem in the pituitary, not the hypothalamus? ”

No. It’s the olfactory node in the hypothalamus So they don’t smell either
So they don’t smell either

Peter asks, “ Could you give the Clomid and they would make…”

No, the pituitary is not working (the GnRH is not)

Does estradiol play a role?

Estradiol is sort of a mild poison for male infertility
Everyone needs an estradiol level (female hormone)
Testosterone gets converted to estradiol That’s a byproduct of it along with DHT
That’s a byproduct of it along with DHT

⇒ Estradiol goes to the brain and is a feedback for the brain to know how much testosterone it’s making

It’s a negative feedback and will cause the body to make less testosterone
High estradiol will lower your testosterone
When estradiol is made, it gets metabolized differently than testosterone It goes to the liver or to fat, and aromatases convert it to something else Or testosterone gets converted to female hormone aromatases
So you can get high levels [of estrogen] being obese or having liver dysfunction So alcoholic cirrhosis, hepatitis will rev up the estradiol level
Some medications that do it too And that will act and lower your testosterone, which will lower sperm production because you’re not “watering the plant”
It goes to the liver or to fat, and aromatases convert it to something else
Or testosterone gets converted to female hormone aromatases
So alcoholic cirrhosis, hepatitis will rev up the estradiol level
And that will act and lower your testosterone, which will lower sperm production because you’re not “watering the plant”

If a guy has normal FSH, LH and testosterone, is there an estradiol level by itself that is problematic?

Not usually
It’s really only high estradiol in the context of suppressed testosterone That’s when you could say, “ You need to lose 100 lbs. ” You can also give aromatase inhibitors like weightlifters use to keep their [estrogen] levels down
That’s when you could say, “ You need to lose 100 lbs. ”
You can also give aromatase inhibitors like weightlifters use to keep their [estrogen] levels down

Effects of medication, microplastics, stress, and exercise on fertility [57:15]

When investigating infertility, is there anything else besides the history, the exam, the semen analysis, and the hormones (the 4 big pillars)?

“ Usually do 2 semen analyses, 3 weeks apart or more to get a sense of things because it varies quite a bit… any feature of that semen analysis is varied by 50 to 100% .”‒ Paul Turek

Paul does a lot of consulting for the FDA and they do medications in reproductive age men
They’re trying to show the semen analysis
Paul tells them, “ Garbage in, garbage out .” There’s so much variability, you really can’t say anything
You have to do at least two samples, and it still varies quite a bit There’s inter-observer variability, who does the semen analysis There’s biological variability on what your system’s like
That’s the big problem with studies
There’s so much variability, you really can’t say anything
There’s inter-observer variability, who does the semen analysis
There’s biological variability on what your system’s like

What percentage of drugs that are going through an FDA approval process are having a semen analysis as part of the evaluation?

Not many
Usually the indications aren’t reproductive age men and women, for some of them
If they do, they’ll do animal models They won’t do human studies They’ll do mice and beagles; and if there’s no fertility effects They don’t really look at semen analysis in those They’ll look at fertility effects in animals
If there’s nothing there, then they’ll probably not require human studies
If there’s any suggestion of a problem in the animal models, which is $1 million of work
They won’t do human studies
They’ll do mice and beagles; and if there’s no fertility effects
They don’t really look at semen analysis in those
They’ll look at fertility effects in animals

Why Paul patented the spermatogonial stem cell

He wanted an in vitro test for human infertility that we could use instead of animal models
Save the animals; save $1 million

Do an in vitro spermatogenesis model and see if there’s an effect at all

Peter points out that in this day and age, people are reproducing at older and older ages, we shouldn’t just assume that because we’ve developed a drug for blood pressure or diabetes that it’s not going to be used by people with fertility

For example, have GLP-1 agonists been tested for fertility?

No, because it’s an off-label use of a diabetic medication Even though it’s no longer off-label
It looks like it might be helping with fertility
But it’s just one example of a drug that was initially approved for people who were not thought to be having kids
The truth is you’re going to have lots of people that are trying to reproduce on many of these drugs
Even though it’s no longer off-label

There are 80,000 chemicals out there that have not been studied reproductively that are commonly in use in industry

The European Commissions are a little better off They’ve screened them and they’ve warned about them
But America, negative It’s attention to detail It’s under the purview of the FDA and maybe the EPA Or maybe everyone’s thinking it’s the other person’s job (Paul is not sure) They’re untested and they’re out there
They’ve screened them and they’ve warned about them
It’s attention to detail
It’s under the purview of the FDA and maybe the EPA
Or maybe everyone’s thinking it’s the other person’s job (Paul is not sure)
They’re untested and they’re out there

Microplastics

Peter recently did a podcast on this topic ( AMA #67 )
He didn’t touch on fertility because he didn’t see any great evidence
He talked more about things where there was a little bit more evidence
With the microplastic story, there’s quite a bit of smoke, but there’s no real fire
Peter’s conclusion from the analysis was there is enough smoke that takes steps where they are reasonable and reduce your exposure to these things

⇒ So everything from microplastics to PFAS chemicals to phthalates and even the PM 2.5 ‒ there’s no reason to expose yourself unnecessarily to this

If you can take relatively straightforward steps to eliminate 60 to 80% of them in your life, do it

Tell me what your impression is of the effect of any or all of the above on fertility

Although sperm are made constantly and are susceptible to that, we know the testicles are a pretty good place and insulated from exposures
There’s a lot of smoke there and it needs to be sorted out
Especially with the 60 to 80,000 chemicals that are being used that aren’t really tested at all

Paul thinks the only way to know is to do stem cell in vitro testing as much as you can before you put it on at the investigational drug stage

Not at the final stages for clinical trials, but early on do it So you’re screening way in advance of getting into clinical trials and when the money gets big
So you’re screening way in advance of getting into clinical trials and when the money gets big

Paul thinks there are windows of susceptibility in men

Unlike maybe with women whose eggs are constantly exposed to toxins, men have windows

One of those windows is birth and early development, the first 12 weeks of life

When all organ systems are developing, including testicles
Shanna Swan did a study on maternal beef consumption, estrogenized beef consumption Their sons had lower sperm counts when they were 20 years later or something
Paul thinks that’s a window of susceptibility
Their sons had lower sperm counts when they were 20 years later or something

He also thinks puberty is a window of susceptibility, when things turn on

Exposures in those moments are probably going to matter the most to men; he doesn’t know about other times

What is your advice to a guy when you’re giving him counsel on everything he can do?

Should you stop drinking Starbucks coffee in those plastic cups with plastic lids
Should you get a reverse osmosis filter in the house
Where do you draw the line?
Paul is not great at that because the stress level goes up so much, and the stress counterbalances any amount of microplastics you save

⇒ You’ve doubled the stress in a man and his testosterone level will fall and then the sperm production falls for a whole different reason

Peter recalls his testosterone level when he left residency He was 33 and his total T was 220 ng/dL He’s sure his FSH and LH were low but doesn’t remember what they were Free testosterone of 3 to 4 The sleep deprivation, the stress
He was 33 and his total T was 220 ng/dL
He’s sure his FSH and LH were low but doesn’t remember what they were
Free testosterone of 3 to 4
The sleep deprivation, the stress

Effects of stress

Stress is the sympathetic nervous system : it’s fight or flight You’re running from a wooly mammoth
It doesn’t know what you’re running from
It doesn’t know whether it’s sleep or travel or financial or emotional
It’s just the body We are cats and dogs We have the same binary nervous system Either you’re on or you’re off
You’re running from a wooly mammoth
We are cats and dogs
We have the same binary nervous system
Either you’re on or you’re off

⇒ And when you’re on, do you want testosterone? No. You want cortisol

You’re running for your life
And do you want fertility when you’re running for your life in any species? No You’re trying to save your life So cortisol goes on Testosterone is nowhere to be found Fertility’s nowhere. You turn off all that stuff
Then when you outrun the wooly mammoth and you’re behind a rock and you grab the berries and you catch a nap, boom, testosterone shoots up because it’s rest and restore and you have to rebuild for the next run
You’re trying to save your life
So cortisol goes on
Testosterone is nowhere to be found
Fertility’s nowhere. You turn off all that stuff

Peter asks, “ How quickly do you think that occurs in humans? ”

Days, easily
Chronic stress is [the problem]
We love acute stress All species love acute stress We love that starvation, intermittent fasting It’s really healthy
But not low-level chronic stress Not connected to your computer, not your emails, not the workday that never ends It’s terrible for us
All species love acute stress
We love that starvation, intermittent fasting
It’s really healthy
Not connected to your computer, not your emails, not the workday that never ends
It’s terrible for us

⇒ The best manifestation is erections because the erections will fall if you’re under stress too

The penis has a mind of its own according to da Vinci

Paul’s patient in San Francisco illustrates the effects of stress on the ability to maintain an erection

He was 25
A startup guy
He said, “ I lost my erection yesterday… It’s never happened to me before. I think something’s wrong .”
Paul asked, “ Tell me about yourself. ” He’s just getting his A round of funding He’s traveling a half a million miles a year He sleeps 3-4 hours a night (if any), and he’s constantly running
He’s just getting his A round of funding
He’s traveling a half a million miles a year
He sleeps 3-4 hours a night (if any), and he’s constantly running

Paul explained, “ Congratulations. Welcome to the human race. You’re not impervious. Stress has its effects. ”

Exercise

There was a great study on moderate exercise this went to extreme exercise Extreme measured as 2 hours a day of 80% maximum capacity for 12 weeks Exercise went from moderate to extreme and then back to moderate
Paul wrote a blog on this called Can You Be Too Fit to Be Fertile?
Extreme measured as 2 hours a day of 80% maximum capacity for 12 weeks
Exercise went from moderate to extreme and then back to moderate

Sperm counts fell by 40% when moderate to extreme, and testosterone fell by 50% and then went back up

There’s also military studies of men under acute stress during “Hell Weeks” in training where they were taking their testosterones and LH They were dropping by about 50% with severe stress
And that’s okay for a day or two or a week, but when you’re doing it chronically, we’re not built for that
They were dropping by about 50% with severe stress

“ We’re not built for chronic stress. That’s a longevity issue. ”‒ Paul Turek

Testosterone replacement therapy (TRT) and male fertility [1:06:00]

The 3 most commonly used approaches to testosterone replacement (TRT)

Are using either clomiphene or enclomiphene, using hCG, or using exogenous testosterone in one of its derivatives
1 – Exogenous testosterone , you’re just giving testosterone The body senses it and immediately shuts down the hypothalamus, shuts down all natural production LH and FSH will go to zero Testosterone will be as high as you want it to be Peter has had a couple of people on this podcast who have blown his mind with how much testosterone they’ve talked about taking [episodes #274 and #335 ]
2 – hCG is synthetic luteinizing hormone So you give a person hCG and they will make testosterone It’s endogenously produced, but they’re making so much of it that they’ll also suppress LH and FSH So LH and FSH will come down Testosterone will go up
3 – Clomiphene or enclomiphene block the signal of estrogen at the level of the hypothalamus So the hypothalamus thinks it doesn’t see any and needs to make more testosterone It ramps up FSH and LH production, which has the same effect as making more testosterone You’ll now see high normal FSH and LH
The 2 different classes are the LH and the Clomid versus testosterone
The body senses it and immediately shuts down the hypothalamus, shuts down all natural production
LH and FSH will go to zero
Testosterone will be as high as you want it to be
Peter has had a couple of people on this podcast who have blown his mind with how much testosterone they’ve talked about taking [episodes #274 and #335 ]
[episodes #274 and #335 ]
So you give a person hCG and they will make testosterone
It’s endogenously produced, but they’re making so much of it that they’ll also suppress LH and FSH
So LH and FSH will come down
Testosterone will go up
So the hypothalamus thinks it doesn’t see any and needs to make more testosterone
It ramps up FSH and LH production, which has the same effect as making more testosterone
You’ll now see high normal FSH and LH

Paul explains, “ Unlike testosterone shutting off the natural production (that LH), the hCG and the clomiphene, enclomiphene will stimulate natural production. So you keep your testicular size. You maintain your fertility. Whereas the others, you’re going to shrivel up your testicles and not maintain your fertility. And you can’t generate levels that you can with the exogenous testosterone with these. You’ll never get to 3,000. You can’t do that. It’s tightly regulated. ”

If a guy has been taking exogenous testosterone for a few months, is he able to create sperm?

95% chance he’s not while he’s on it

Peter’s takeaway ‒ even a couple of months on exogenous testosterone in any form, injection, topical, oral, whatever, you basically have shut off the ability to make sperm because your testes themselves have shut down

Paul explains the nuance

There are formulations that are topical that are less potent that way, less inhibitory than injectables
There are variations in the spectrum of exogenous testosterone that will maintain some of your fertility
The marketing material is suggestive that the more frequently delivered variants, for example, the intranasal variant, which is delivered 3x a day The oral variant, delivered twice a day, have less of a negative impact because they’re producing far lower surges than if you did a weekly injection Correct They’re in the normal range more
What gives you side effects from testosterone (including sterility) is too much
The oral variant, delivered twice a day, have less of a negative impact because they’re producing far lower surges than if you did a weekly injection
Correct
They’re in the normal range more

Men taking Natesto 3x a day (intranasal) keep their sperm counts

What about oral testosterone twice a day?

Testosterone undecanoate was not available in America for 50 years
It was available in Europe
Study out of UCLA on oral testosterone [that led to the FDA approval of oral testosterone replacement in the US]
We were worried when we took oral testosterone that it would go to the liver and cause liver cancer There was no evidence this was happening in Europe for 50 years
It’s FDA approved; the EEA approved it
This group came up with a way to get it metabolized through the lymphatics It is absorbed through the lymphatics and never hits the liver
It’s really good, there is a non-response rate of around 10% of men
Some men like gels too 15% won’t respond There’s groups that won’t respond that well, but it is really good
Paul prescribes it
There was no evidence this was happening in Europe for 50 years
It is absorbed through the lymphatics and never hits the liver
15% won’t respond
There’s groups that won’t respond that well, but it is really good

Peter has prescribed testosterone undecanoate to maybe half a dozen patients, and one of the challenges is they don’t know when to time the blood drawl to see the level of testosterone

For example, if a guy takes the drug at 8:00 in the morning and then at 1:00 in the afternoon ‒ if he does his blood draw at 7:00 the next morning, he’s been 18 hours off drug He has unmeasurable testosterone He’s going to show up at 200 He’s going to look like Peter did 50, 20 years ago His LSH and FSH are still completely suppressed because that doesn’t go away over 18 hours
Peter doesn’t know how to interpret what is he walking around at during the day, which is what he cares about
Paul explains that you usually want to give them a couple of weeks to stabilize hemostatically You don’t want to test it right away
Usually you can get pretty good levels because the half life isn’t that short They say it peaks in 5 hours The half life is probably more like 12 hours You wouldn’t dose it at 100% decay; you would dose it at 50%
Paul thinks he’s probably not responding We can check it at different times, but it’s probably not much of a response
He has unmeasurable testosterone
He’s going to show up at 200
He’s going to look like Peter did 50, 20 years ago
His LSH and FSH are still completely suppressed because that doesn’t go away over 18 hours
You don’t want to test it right away
They say it peaks in 5 hours
The half life is probably more like 12 hours
You wouldn’t dose it at 100% decay; you would dose it at 50%
We can check it at different times, but it’s probably not much of a response

What is Paul dosing testosterone undecanoate at? (It comes in 100 and 200)

He usually goes to the mid-dose 298 twice a day, and then you can double it or whatever
He doesn’t start out at the lowest dose, and it depends what you’re trying to solve in the problem If you’re not going to get them to 800 or 1000 very easily, you can get them 400 to 600, 600, 700 pretty well, but no side effects
Paul hasn’t seen anything, maybe a couple dozen men, really well-tolerated
If you’re not going to get them to 800 or 1000 very easily, you can get them 400 to 600, 600, 700 pretty well, but no side effects

Peter’s takeaway: this is not something you use when you’re trying to get a guy from 300 to 1000

You could, but this is not Paul’s first choice
Because now you would be taking 500 twice a day or something crazy like that
Twice a day is a big deal for men

Are you using Natesto ?

Paul has never prescribed it
No one tolerates that
You have to spray it in each nostril 3x a day And it’s gooey and it’s gel-like.
Within a week, men will call and say they can’t do this
Peter has had more luck getting women to use this
And it’s gooey and it’s gel-like.

The other big differences between the 2 types of testosterone replacement or supplements is the side effect profiles differ widely

Comparing what we call the natural ones versus the exogenous ones
It’s very difficult to get polycythemia (or thickening in your blood) with the physiologic levels It just doesn’t happen very often Paul has seen it once or twice
But if you take testosterone exogenously you’re at risk for polycythemia or blood thickening
Testosterone stimulates erythropoietin in the kidney, you make more blood Athletes love it But if you on a long flight and you’re dehydrated, you’re going to throw a clot
People look at it for longevity, but you need to be careful
Paul has seen 70-year-old men who want longevity in taking this stuff, and then they have a clot and they have a stroke and now they’re 71 and…
It just doesn’t happen very often
Paul has seen it once or twice
Athletes love it
But if you on a long flight and you’re dehydrated, you’re going to throw a clot

⇒ The clot risk is proportional to hemoglobin hematocrit

Ramasamy just did another paper on it
The most significant event occurring with testosterone replacement or supplementation is polycythemia and events
The high level for hemoglobin 17, hematocrit 50, you start seeing events happen about 18, definitely at 19

Testosterone injection schedule

Some of Peter’s patients who are injecting testosterone cypionate, inject 10-15 mg every single day They don’t have the polycythemia They don’t hit those crazy peaks
10 years ago, everyone was prescribing 200 mg every 2 weeks (which is crazy) Highest risk [for polycythemia]
They don’t have the polycythemia
They don’t hit those crazy peaks
Highest risk [for polycythemia]

Paul’s typical injection schedule

Once a week
Twice a week is a little safer
Often patents want a pellet instead He offers that too
He offers that too

Testosterone pellets

Peter doesn’t know the kinetics of it but would imagine that you’re super physiologic for a month or so

Paul explains, “ Pellets are like the long-term contraceptives for women in the arm .”

They put it subcutaneously (he puts it in the butt), and it’s a couple minute procedure in the office
You don’t have to worry about anything There’s no compliance issues You don’t have a lot of side effects or consequences from it
It’s done with a trocar and a thick needle
And pretty quickly within a couple days, you’ll get a level, and then it’ll slowly decay Pretty much half of it by 3 months or so and then the rest by -f months
It’s supposed to be a six-month physiologic level, but normally it’s 4 or 5
Men feel great for a while and they can feel it because it’s slow, but it is even
You do have this risk of polycythemia and things like that, but there’s a 3 month period of risk and then usually when you’re in the normal range, it kind of goes away
Paul doesn’t see a lot of consequences with that if it’s 6 months
There’s no compliance issues
You don’t have a lot of side effects or consequences from it
Pretty much half of it by 3 months or so and then the rest by -f months

Use case for Clomid (and the generic clomiphene), and levels of testosterone associated with different symptoms

Back to the Clomid-hCG route, what is the extent to which fertility is preserved when a man is on one of these agents?

Paul gives Clomid all the time for fertility It might even improve it while hCG depends on the dose
It might even improve it while hCG depends on the dose

⇒ High doses of hCG suppress [FSH]

Normally you want LH and FSH going to the testicle Analogy: you want the water and the sunlight
You want the testosterone
If you’ve got the testosterone, but your FSH is [low] (if you don’t have any sunlight), you’re not going to bloom
Analogy: you want the water and the sunlight

⇒ Paul usually adds Clomid to hCG if the dose is above 1500 units, 3x a week [to preserve fertility]

Because that’s going to start suppressing the FSH
And Clomid will keep it going, and then your fertility is preserved

Peter reacts, “ 1500, 3x a week of hCG is a whopping dose. You’re saying beneath that you typically don’t have issues with FSH and LH suppression? ”

Right
You will because it’s LH but not FSH
Maybe 1000 to 1500, you start seeing it
That’s why you protect the fertility

What dose of Clomid will you give on top of that regimen?

It depends
Usually half a 50 mg pill a day 25 mg every day Peter thinks these are staggering doses
25 mg every day
Peter thinks these are staggering doses

How high does testosterone get for these guys?

The testosterone is driven mainly by the hCG
Paul shoots for the normal range of 500-1000 (not anabolic)

Peter’s experience prescribing clomiphene (the generic form of Clomid)

Peter doesn’t like clomiphene for a whole bunch of reasons that have to do with lipid stuff
He would prescribe it 3x a week About the same as 25 mg per day
For most guys, that would be sufficient alone (even without hCG)
Peter would give 12.5-25 mg for isolationist monotherapy
About the same as 25 mg per day

Paul explains, “ It’s hCG that’s driving the T. We’re just trying to protect it .”

Do you prefer Clomid or clomiphene?

Clomiphene is really good

It’s an interesting FDA story

Clomid is not approved for men and neither is clomiphene
Clomid is approved for women, and clomiphene is not approved for either
Clomiphene is compounded
Clomid has been available for 50 years so there’s a lot more data
And once a cis isomer was a trans isomer ‒ they’re different, and the estrogenic effects are slightly different

Paul has enormous experience

He has 560 men on Clomid
He has fewer on clomiphene

Clomiphene citrate was developed for older men to preserve their testosterone levels as they age

Because the signaling tends to get weaker, the pituitary tends to get lazier, and this is to keep your testosterone levels up more physiologically than taking testosterone
It went through some very good randomized trials that were published
It went to the FDA for approval for secondary hypogonadism For age-related changes Not for primary testicular failure in age-related androgen deficiency of the aging male (or ADAM)
For age-related changes
Not for primary testicular failure in age-related androgen deficiency of the aging male (or ADAM)

The FDA sat on it for a couple of years and said, nope (they didn’t approve it)

⇒ There are good trials; it’s safe; it’s as good as Clomid

It’s hard to know why the FDA didn’t approve it

“ I think the reason was that there’s such an uproar about testosterone in America right now, and the FDA doesn’t like what’s happening .”‒ Paul Turek

What happened is you can advertise your drug to the consumer now
So all the biological response modifiers for psoriasis, all those drugs go on and they give you 5 seconds on the benefits and the lesions go away and then 25 seconds of side effects
If you do that with testosterone, what you hear is: Are you falling asleep after dinner? Are you not as athletic as you used to be? Are your erections not as good as they used to be? There’s 10 questions in the ADAM questionnaire
Are you falling asleep after dinner?
Are you not as athletic as you used to be?
Are your erections not as good as they used to be?
There’s 10 questions in the ADAM questionnaire

Everyone who ages has those issues, and if they advertise on TV, they’re going to want this stuff

So now when any testosterone trial comes back, they’re going to point out the FDA, make sure that we point out the dangers of testosterone replacement

This is part of that energy, which is we don’t want another testosterone

Peter thinks there another reason

It’s everything Paul just said
But hCG and testosterone are schedule IV
Which means you cannot prescribe them through these testosterone clinics that don’t even see patients and are literally just not being doctors They’re just sort of giving it to anybody who shows up and pays It’s a coin operated testosterone dispensary
But Clomid (and Peter assumes by extension for clomiphene) is not scheduled, which means you can coin operate those
That’s probably why the FDA is saying what it’s saying
They’re just sort of giving it to anybody who shows up and pays
It’s a coin operated testosterone dispensary

It’s already bad enough that the Clomid cat is out of the bag, but we don’t want to put another one of these unscheduled drugs out there in the land of shady medicine

⇒ The indications are pretty clear, and they’re really safe

Paul’s use-case

When someone comes in who is young, who maybe wants kids but hasn’t had them and they have a low testosterone of 220
You measure their LH (which no one does), and it’s low ‒ it’s secondary hypogonadism It’s not testicle failing It’s a signaling issue That’s probably stress
If Paul tells them, “ Get rid of your stress; ” they ask, “ How do I do that? ” Exercise, acupuncture, massage, or yoga
It’s not testicle failing
It’s a signaling issue
That’s probably stress
Exercise, acupuncture, massage, or yoga

“ For men, I say physical activity is the best thing for sex .”‒ Paul Turek

Aside on the benefits of physical activity for improving sex

During COVID, everyone’s life was a mess, and Paul had 2 groups of men
Half of them started drinking a lot
The other half went out for runs or got a Peloton
Then about six months later, these guys realized it’s not working, and they started shifting over to exercise
Paul was very proud of them
Because the best way to handle stress is when you have no control over things go for a run, go for a walk, get out there It’s just decompressing, hold to get your mind off something, anything surfing, whatever
When men don’t do that, Paul will give them Clomid Hell ask them to try it for 3-6 months and see how they feel
Sometimes it’s sexual health issues
It’s just decompressing, hold to get your mind off something, anything surfing, whatever
Hell ask them to try it for 3-6 months and see how they feel

⇒ Erections aren’t typically that dependent on testosterone; typically it’s other things

Paul gives them the benefit of the doubt ‒ maybe their testosterone was higher before (we don’t know that)
Let’s do something pretty safe and easy to double or triple your testosterone [Clomid]
He’ll check in with them at 3 and 6 months Either they feel great or they feel the same (and it’s not testosterone related)
We know the levels of testosterone above which you should not have symptoms For erections it’s about 290
Either they feel great or they feel the same (and it’s not testosterone related)
For erections it’s about 290

Most guys that are having difficulty with erections have a testosterone level above 290, so there’s some other issue but you have to prove it to them

Paul is fine with that as long as it’s safe (you’re convincing them)

The levels of testosterone above which you should not have symptoms

Erections: 290
Libido: 350 range
Fertility: 300
Mood tends to be a lot more variable
Other thresholds would be anabolic capacity, like muscle mass and things of that nature

Paul explains, “ I think there’s myths around testosterone and those are some of them, but is sort of a Morgentalor and equilibrium story where if you’re low, you have symptoms and you’re low, those symptoms will get better when you go up. But then there’s a point where it flattens out. There’s no increase or improvement in symptoms. ”

Sexual health symptoms are classically ascribed to that
For things like blood and muscle, it’s a linear relationship between testosterone So more is better for blood doping and also for muscle
So more is better for blood doping and also for muscle

What Peter recently learned talking to body builders who were taking 500-2,500 mg of testosterone a week

His initial reaction was, you’ve already saturated the androgen receptor, at least 1 or 2 logs earlier
But they convinced him, no, no, no
There’s a real difference between 500 and 1000 and 2500 in terms of muscle mass, which it sounds like Paul agrees with
Peter doesn’t understand the physiology of how that’s possible How many androgen receptors would you need? You’d have to up regulate them when in fact you’d be down regulating them
How many androgen receptors would you need?
You’d have to up regulate them when in fact you’d be down regulating them

Paul is not sure, but thinks the effect of testosterone on muscle mass is indirect

It’s not that you’re going to do it and create mass
You don’t just create mass

⇒ What it allows you to do is recover from injury

So if you push the system and you need 2 days to recover, you can go to 1 day, and you can push it again harder That’s what testosterone does in the primitive world Paul is not sure that’s receptor driven
Peter recalls studies that show that high enough doses of testosterone will increase muscle protein synthesis absent the stimulus, absent the lifting stimulus
It might be several pathways going on that are logarithmically better, but it allows you to push the system and go back and then push it again, and that’s how you build muscle
That’s what testosterone does in the primitive world
Paul is not sure that’s receptor driven

Restoring fertility after prolonged use of exogenous testosterone [1:25:00]

Let’s say he was given poor advice 3 years ago
He went to some shady back alley website
He was 27 years old at the time
This is tragically a very common story
This guy’s been on 200 milligrams of testosterone a week for the past 3 years
He is now 30 years old; he’s met the love of his life, and they he can’t seem to get pregnant

Tell me what his sperm analysis looks like

Peter presumes there are no sperm
Paul has 95% confidence that he would have no sperm in his semen

How are you going to solve this problem?

A lot of guys come in, they look good, they never put it on their medications or write it out in their history You always have to get it out of them Paul will look them in the eye and say, “ Are you taking testosterone? ” He’ll look them in the eye until they answer If they look down or don’t say anything, he knows they’re on it If they look him in the eye and say no, he knows they’re not But they’ll always look away
Peter compares this to the ER ‒ people that come in with foreign rectal bodies and abdominal pain That’s the one thing they omit from their history You get the x-ray and there’s a candlestick in their colon They’re like, “ I totally forgot to mention that, yes .”
You always have to get it out of them
Paul will look them in the eye and say, “ Are you taking testosterone? ”
He’ll look them in the eye until they answer
If they look down or don’t say anything, he knows they’re on it
If they look him in the eye and say no, he knows they’re not
But they’ll always look away
That’s the one thing they omit from their history
You get the x-ray and there’s a candlestick in their colon
They’re like, “ I totally forgot to mention that, yes .”

Paul’s approach for guys taking testosterone for anabolics

Paul has been doing research on the lifespan of anabolic storage users (he’ll come back to these findings)

⇒ If he’s been in constant use of injectables, that’s the most suppressive of fertility; and if you turn a gland like a testicle off long enough, it’s off

Paul gave a lecture to the Endocrine Society on young men recovering from hypogonadism and asked a question at the end
Paul’s procedure comes from steroid users and it’s called Getting Off the Juice He takes notes when he sees anabolic guys because they’re really smart, and they know a lot about reactions biology (some of them are PhDs) His blog includes a PowerPoint
He takes notes when he sees anabolic guys because they’re really smart, and they know a lot about reactions biology (some of them are PhDs)
His blog includes a PowerPoint

⇒ Recovery is usually possible in young men, but it depends on how much they took, how long they took it and how they took it

If they do it like a cycling effort, that’s the best If you cycle steroids, you recover the pituitary, you get back to normal and then you hit it again That’s actually quite smart; constant use is not
Constant use for longevity or whatever is not a good idea for fertility That’s going to be much more suppressive
Injections are worse than orals or any gels
If you cycle steroids, you recover the pituitary, you get back to normal and then you hit it again
That’s actually quite smart; constant use is not
That’s going to be much more suppressive

Paul asked the Endocrine Society, “ Can you turn a testicle off like in a thyroid or an adrenal gland? If you suppress it enough, can you turn it off for good? ”

They said that was one of their board questions
They believe it’s always reversible in the field of infertility in men
That got Paul worried

He worries about 5-10 years of use: after 5-10 years of use, you may not get it back, either the ability to make sperm or the ability to make testosterone

Peter tells men in his practice that 2 years would be the absolute ceiling (at a dose of 50 twice a week) That might be too conservative It depends on the dosing and everything Paul thinks it would take a while at this dose
Paul published a study when he was a fellow in Houston of a guy who took testosterone for 25 years He treated him with gonadotropins such as hCG and FSH and didn’t get anything but a low number of sperm back
Paul just had a guy from Louisiana come in with 25 years of chronic use He did a mapping procedure to find sperm in his testicle, and he made a couple of sperm He’s going to be having a kid
You pump him full of hCG and synthetic FSH for a year and get nothing
Then you have to look in the testicle because production can be low enough to be there but not coming out
That might be too conservative
It depends on the dosing and everything
Paul thinks it would take a while at this dose
He treated him with gonadotropins such as hCG and FSH and didn’t get anything but a low number of sperm back
He did a mapping procedure to find sperm in his testicle, and he made a couple of sperm
He’s going to be having a kid

The rescue protocol is LH and FSH

There’s 3 ways to do it

⇒ Never stop the testosterone suddenly

Because men will hit the doldrums, and they’ll flop over like they have the flu
They’ll feel like shit, and they’ll get right back on it
They’ll feel terrible because they have nothing going on [no T] If you take the testosterone away, their system’s turned off, they’re not making their own. It takes time to get the system to reactivate
If you take the testosterone away, their system’s turned off, they’re not making their own. It takes time to get the system to reactivate

That’s why Paul always tapers [down] testosterone over 6 weeks

Typically, you have the dose for 2, have the dose for 1, and then off for 2, and then you measure

1 – Taper alone

2 – Taper with Clomid or Enclomiphene, which is a little quicker getting the pituitary to turn back on

That will soften the blow of the feeling of feeling completely fatigued

3 – Taper more aggressively with hCG and Clomid

Then he usually checks them at about 6 weeks

Peter asks, “ If you give Clomid, the pituitary will make FSH and LH? ”

Yeah, it takes a while
That’s a more cost-effective approach than giving synthetic because synthetic FSH is pricey (a couple thousand a month)

Is there any reason to do that over the Clomid approach or is it just that it’s faster?

You might gain a couple of weeks of time

⇒ With that taper over a month or two, Paul usually checks their T-levels at around 2 weeks off of the last testosterone and that’s the lowest they’ll be

And if they’re in a good range there, you can use that as a predictor of their response A good response would be if they’re in the normal range 300 would be okay to make sperm
But then to get them to where they want to be depends on their symptoms and what they’re happy with
You won’t know til you wait longer to see how high you can get them
A good response would be if they’re in the normal range
300 would be okay to make sperm

If they go along that taper and they’re not tolerating

Paul advises, “ Don’t go back. Just stay there because time will help you. You are not going to feel maybe that great, but try to do this because if you go back, then we have to start over. But if you just maintain it for a while, you’ll feel better .”
And some of them dip a little bit, but remarkably, most men do really well with that taper

Do you ever advocate crazy ideas for guys that are using testosterone to use lower doses and then combine it with hCG? Just as we were talking about the Clomid plus hCG approach?

All the time
It’s not an unreasonable approach to combine Clomid with testosterone at low doses to preserve testicular function
Yesterday Paul operated on a man (testicular sperm retrieval) who was exospermic for genetic issues, and he was on testosterone for 10 years because he needed it His testicles were failing Paul told him he was not going to make sperm on this
Paul put him on hCG (3000, 3x a week) for six months or maybe a year; the guy felt terrible and couldn’t maintain that
So Paul added a low dose of testosterone gel and lowered the hCG to 500, 2x a week
In the sperm retrieval he got plenty of sperm
This guy was 35-years-old
His testicles were failing
Paul told him he was not going to make sperm on this

“ You can maintain whatever’s going on in the testicle with hCG and take any testosterone you want .”‒ Paul Turek

Peter agrees, “ That’s an important lesson .”

Here’s the catch though

Paul thinks this was shown in Finnish bodybuilders
They were doing a cycle of steroids, huge amounts
They took low dose hCG (500 twice a week)
John Amory at the University of Washington, has worked out all the exact doses, but 250-500 twice a week is a good dose for that It keeps your intratesticular testosterone high, keeps your sperm production going
They went on both concurrently for 12 weeks, and their sperm counts were normal the whole time at any dose of T
Now what happened after that is people start saying, “ You can preserve your fertility on testosterone replacement ,” which is possible
It keeps your intratesticular testosterone high, keeps your sperm production going

But it was only 12 weeks

Do you think that there’s a difference between hCG and Clomid in that effect as the adjunct?

Oh, yeah, Clomid doesn’t work
hCG is the one
Clomid doesn’t improve intratesticular testosterone levels like hCG does; it’s ineffective
It will potentially make you more recoverable
If you do it 80%, you’ll be zero even though you thought you might have a sperm count, but your recovery will be faster because it’s done something

Paul explains, “ The only way to maintain your current fertility is you have to be 100% compliant with dual therapy. You can’t go on monotherapy with testosterone. ”

Outside of fertility, given the popularity of testosterone replacement therapy today, is there another advantage to just doing dual therapy?

As opposed to just being on testosterone injectable, to do the dual therapy versus just monotherapy

No, I think the only reason would be if you want testicles to be big

Paul just created a new procedure to make testicles larger naturally

By putting a fat injection in the hydrocele space in men on testosterone
For men that don’t like their small testicles
Peter jokes, “ It’s the equivalent of the Brazilian butt procedure for the testes. ”
Testes fat grafting is all natural and there’s no prosthetics, and you can’t tell
It makes them nice and big

Peter asks, “Medicare approved? ”

No, creatively approved

Effects of heat and cold exposure on fertility and sperm quality [1:36:00]

Tell me about the impact of cold plunging and sauna and hot-tubbing on fertility for men

The testes are outside the body and 3 degrees cooler than the rest of the body (95 versus 98 degrees F)
The reason for that is unknown It may be that it’s an immunologic sanctuary, and that’s the only way to do it and that God or Darwin could figure out
If you heat up the testicle It’s also close to the skin; so it’s a radiator
When the heat comes down, the arterial blood has to cool, so it raises and lowers
There was an article in the Journal of Irreproducible Results about 20 years ago about a man who went to Big Sur and wore nothing [not available online] He measured ambient temperature, and then he marked on this leg with a marker where his scrotum hung, how low it hung He could tell the ambient temperature by how high or low his scrotum hung He became a thermometer: it does go up and down
It may be that it’s an immunologic sanctuary, and that’s the only way to do it and that God or Darwin could figure out
It’s also close to the skin; so it’s a radiator
He measured ambient temperature, and then he marked on this leg with a marker where his scrotum hung, how low it hung
He could tell the ambient temperature by how high or low his scrotum hung
He became a thermometer: it does go up and down

It showed that the scrotum is very temperature sensitive and it goes up and down to regulate it

Closer to the body when you want it warmer, etc.
You go into a cold shower or plunge and you’re testicles are way up there
That’s all the cremasteric muscle, and it’s all temperature driven
It spends all of its time regulating its temperature to stay at 95
Saunas baths, hot tubs, jacuzzis, steam rooms change that

The worst one of those is anything underwater, submerging underwater because you’re one centimeter away, you’re a liquid, it’s a liquid

It’s like little kids going into hot tubs ‒ they overheat

⇒ Typically a hot tub is 105-110 F, and within a short period of time, you’re testes will assume that temperature

Paul published a study on wet heat exposure in the Brazilian Journal of Urology

Of the 200 studies he’s published, this was the hardest to get in
It’s probably his most cited paper Certainly not his best, but it’s very interesting
Certainly not his best, but it’s very interesting

He took infertile men with low sperm counts and stopped the hot baths ‒ semen quality went up 300%

These men were 35-years-old
Total MOT count [sperm motility] went up 300% in 3 or 4 months and 600% in 6 months You have to give it some time; that’s the recovery curve
He didn’t look at fertility, we just looked at that recovery Some were zero and went up to close to normal [see also Paul’s blog on this]
You have to give it some time; that’s the recovery curve
Some were zero and went up to close to normal
[see also Paul’s blog on this]

What’s the lethal dose (to sperm) from a hot bath (the LD 50 )?

To Paul, the lethal dose means you’re at zero (you have no sperm)

20 minutes of 104-degrees F, 3x a week would probably make you zero

Peter thinks there have to be a lot of guys out there who are doing this
Paul adds, “ The largest group of people in tubs in Northern California, we did the study, were environmental lawyers. Is your job that stressful? They said yeah, it is. ”
The only study ever done prior to that was a PhD thesis at Vassar College where someone had a guy dip their testicles into a bucket for 20 minutes at really hot and looked at their sperm counts or their fertility Paul couldn’t even find it published, it was a thesis thing But that’s how little was written about it And they gave Paul so much flack for publishing this
It’s funny, The New York Times had an article , drew a condom and it drew birth control pills and it drew a guy in a tub [shown below] It said, pick your contraceptive: “ Regular exposure to hot tubs can hurt male fertility, though the effects can be reversed .”
Paul couldn’t even find it published, it was a thesis thing
But that’s how little was written about it
And they gave Paul so much flack for publishing this
It said, pick your contraceptive: “ Regular exposure to hot tubs can hurt male fertility, though the effects can be reversed .”

Figure 3. Regular exposure to hot tubs can hurt male fertility . Image credit: The New York Times 2007

Paul explains the impact, “ It’s huge. I’d say 10% of my population’s in it. ”

What about saunas?

A saunas is not underwater, it’s not submersion
You’re in a hot room, it’s going to affect it
Paul estimates the effect is ¼ to ⅓ of a hot bath (or submersion)

Peter reflects, “ So my friend was absolutely right to have those ice packs on his scrotum… He’s a smart guy. ”

Paul thinks steam rooms and showers are probably fine

Urine and ambient temperature is normal
For steam rooms, it depends on how much time you spend in one, but it’s not as bad as a hot bath
Hot baths are terrible

What about the cold?

Paul doesn’t worry about the cold
He remembers Surfer Magazine called him and asked, “ Are surfers infertile? ” He’s a Northern California surfer, not an LA surfer California water is 60-degrees F Paul has never met an infertile surfer, so he doesn’t think it’s bad at all
He’s a Northern California surfer, not an LA surfer
California water is 60-degrees F
Paul has never met an infertile surfer, so he doesn’t think it’s bad at all

It’s not bad, especially a plunge where you’re talking seconds ‒ your muscles are going to go up and you’re going to be able to maintain that heat

If you did it all the time, it would probably be bad because enzymes in the testicle work optimally at that one temperature

How different levels of exercise—especially cycling—affect male fertility [1:41:45]

Earlier Paul mentioned one example of exercise that can be problematic: 2 hours a day, 5 days a week above 80% VO 2 max That was enough to put a dent in their fertility
That was enough to put a dent in their fertility

Tell me about riding a bicycle

Paul is a biker
He has old vintage bikes he used to race in Connecticut He had them rehabbed They’re all Italian, all steel, and they weigh a ton The seats are from Britain, they’ve got 10,000 miles on them, and they weigh 4 lbs. (Brooks leather saddles) A saddle nowadays is about half the weight of a carbon bike
It’s like golf clubs, Paul is going to be as bad a golfer with a $150 set of clubs as with a $1000 set of clubs
In San Francisco, Paul bikes into work
He had them rehabbed
They’re all Italian, all steel, and they weigh a ton
The seats are from Britain, they’ve got 10,000 miles on them, and they weigh 4 lbs. (Brooks leather saddles) A saddle nowadays is about half the weight of a carbon bike
A saddle nowadays is about half the weight of a carbon bike

The problems with the bike seat

It got started that biking was bad for reproductive health with a Spanish competitive cycling study Competitive Spanish cyclists, Tour de France caliber cyclists, their sperm counts were examined [the groups studied were: professional cyclists, elite triathletes, recreational marathon runners, and sedentary men]
Competitive Spanish cyclists, Tour de France caliber cyclists, their sperm counts were examined
[the groups studied were: professional cyclists, elite triathletes, recreational marathon runners, and sedentary men]

The cyclists sperm counts were low, their morphologies were off

And they’re extreme athletes
Maybe they were on drugs, it’s a big industry, they’re super fit
They’re certainly exercising 2 hours
The study said, “ Look at these guys who are really healthy and look at their sperm counts. ”
But this other data did come out
Paul wrote a blog called Cycling Towards Childlessness? He looked at a more comparable study of British commuting cyclists, everyday people bicycling the work in Britain on different saddles He looked at their fertility, and their fertility was far better than the average Brit
He looked at a more comparable study of British commuting cyclists, everyday people bicycling the work in Britain on different saddles
He looked at their fertility, and their fertility was far better than the average Brit

Peter’s takeaway ‒ even if they were taking some hit off the bike, it was more than compensated for by their healthy lifestyle (which included riding the bike)

Obviously there’s a healthy user bias because anybody who’s riding their bike to work is probably consuming less Guinness, fewer fish and chips, smoking less In other words, riding a bike is a proxy for being healthy, but in spite of that, it didn’t offset that health risk unless we found people who were equally healthy who didn’t ride a bike Paul doesn’t remember what they controlled for
In other words, riding a bike is a proxy for being healthy, but in spite of that, it didn’t offset that health risk unless we found people who were equally healthy who didn’t ride a bike
Paul doesn’t remember what they controlled for

Peter asks, “ Is this a myth? ”

Paul is worried about bicycles: he worries about sexual health, worries about the pudendal nerve , and worries about the seat anatom y

If you’re biking a lot, that’s good

⇒ If you’re biking and you’re getting pelvic numbness, that’s bad ‒ you need to get a better seat

The best seat was studied by Dr. Schrader at the NIOSH

Bicycle seats that come into the middle where the arteries and nerves are to the penis are bad Bad for your sit bones It’s an erection issue
Bad for your sit bones
It’s an erection issue

The saddles with the two little tongs that hold your iliac crest bones with no nose are perfect [a no-nose bike seat]

Figure 4. Example of a noseless bicycle seat . Image credit: Amazon

The pressure is outside leaning in
We gave those bike seats to police in Washington in the National Cathedral area, and they all gave the seats back a week later They said, “ We’re not doing this. We don’t know where the seat is. We go to sit down and it lands somewhere .”
You have to have the nose for bicyclists, because they use it to guide where they sit
They said, “ We’re not doing this. We don’t know where the seat is. We go to sit down and it lands somewhere .”

Paul’s advice on the best bike seats for men

The best saddle is flat or gel in the back, cut out in the middle, and some kind of lean in
So cut out saddles and then you should get your bones fit You can do this online, you can ask them to send you a pressure pad and you sit on it and then you send it back and then measure the distance There’s only a couple of different saddles, maybe 12 widths that you could do and you get it done
Or like Paul, he’ll use a saddle for 30 years and it’s perfect, but it weighs 4 lbs. It’s leather and it’s fit to him
You can do this online, you can ask them to send you a pressure pad and you sit on it and then you send it back and then measure the distance
There’s only a couple of different saddles, maybe 12 widths that you could do and you get it done
It’s leather and it’s fit to him

How alcohol, marijuana, and nicotine affect male fertility [1:46:00]

Let’s talk specifically about the effects of alcohol on fertility

For men, the government considers less than 2 glasses of alcohol a day to be okay 4 a day is binging
4 a day is binging

“ Now, alcohol is a small molecule, goes right into the brain, goes right into the testicle, it’s definitely a poison… I worry about it a lot. The effects I see are direct, when it’s abused .”‒ Paul Turek

⇒ Paul sees a direct effect of alcohol on sperm morphology, motility, and count issues

Alcohol is one of the few things that gets into the testicle

⇒ The hormonal effect of alcohol: it tends to cause the liver to rev up estrogenization, so you tend to get low testosterone from that

Alcohol has both a hormonal effect and a direct effect

Peter asks, “ Any evidence that it’s having an epigenetic effect? ”

Probably
Paul doesn’t know about the evidence

Marijuana

Marijuana ( THC ) is the worst player for Paul
The same problems on sperm count, motility, and morphology
We know it has an effect on fragmentation, which is a quality measure of sperm Not only the way it looks, descriptively, but quality
It probably has an epigenetic effect
Some of the early studies on sperm epigenetics showed alterations with nicotine and with pot
Not only the way it looks, descriptively, but quality

Paul adds, “ What I don’t like about pot is, you ingest it (and however you ingest it), you get a peak, you feel it, it goes away, you feel it’s out of your system (like nicotine), but it sits your fat… ”

It sits in your fat for 3 weeks to a month, and it’s a depot effect (it keeps coming back)
So you get a low level of toxicity
Paul wrote a blog on this called Weed Worries : there’s compelling evidence from epidemiology that chronic use of pot is associated with testis cancer Paul doesn’t know if it’s causal but it worries him
Paul doesn’t know if it’s causal but it worries him

Peter replies, “ Interesting, given that it otherwise seems kind of benign. I personally can’t stand the stuff, but I know so many people that use it so frequently that seem to have relatively few effects .”

Medical marijuana means safe
Paul asked pot growers in the Emerald City up in Northern California who have the artisanal stuff that wins awards, “ Which is worse for driving, being stoned or being drunk? ” Being drunk They said, “ We tend to stop at stoplights and wait for them to turn when we’re stoned .”
There are probably far fewer people that die at the hands of a stoned driver than a drunk driver
Being drunk
They said, “ We tend to stop at stoplights and wait for them to turn when we’re stoned .”

What do you think is the mechanism of action by which THC is having these negative fertility impacts?

Paul is not sure
He thinks it might just be the chronic exposure

There is some evidence that THC acts like LH and bind the receptor so it blocks LH from binding; you can get low testosterone, but it’s not that profound

What are the effects of nicotine, either synthetic or in the form of tobacco?

It’s a bad actor at high doses (from either one)
It doesn’t last as long as THC

It does have effects on sperm count and motility and fertility

⇒ Both THC and nicotine are probably oxidants and it’s oxidizing things

Why Type 2 diabetes is a risk factor for male infertility [1:50:00]

Earlier Paul mentioned diabetes as part of the patient history and physical he collects

What is it about diabetes? Is it the high levels of glucose? Is it the microvascular damage? Is it the inflammation that typically travels in parallel with it?

Probably all of them
We don’t know exactly

⇒ Paul diagnoses diabetes in a lot of infertile men

What’s the physical finding you’re seeing in the testes that tells you, like you know how an ophthalmologist will often make the diagnosis because they’re looking into the eye?

It’s usually their weight and low motility count
Paul looks for a chronic exposure and then they have polyuria or polydipsia Or something like that, where they’re drinking a lot and they’re peeing a lot, because the sugar is dragging it out You check their UA and it’s full of sugar
Some of them have an A1C that’s a little pre-diabetic
A lot of it is neurogenic too They can develop an ED A third of type 2 diabetics have low testosterone, and that’s secondary, so you can bend them right back
Or something like that, where they’re drinking a lot and they’re peeing a lot, because the sugar is dragging it out
You check their UA and it’s full of sugar
They can develop an ED
A third of type 2 diabetics have low testosterone, and that’s secondary, so you can bend them right back

Common indications of type 2 diabetes: the sugars and then the low T and the low sperm count

How varicoceles—a common cause of male infertility—are diagnosed and treated [1:51:15]

What are some of the other modifiable things that you see?

The most common is a varicocele

You could develop varicose veins in your leg and need treatment, and this is the same thing in the scrotum, but it’s not related
It happens, typically at puberty
You’ll develop this, you won’t know it sometimes, unless it hurts

⇒ Varicocele is a reflux of blood in the wrong direction

So the testicle drains to the kidney, which is uphill and it wants to drain back down The reason why it drains back down is because as a species, we stood up a half a million years ago, maybe three quarters of a million years ago And when you’re an animal, your kidney and your testicle drains this way, there’s no gravity But when you stand up, you’re now draining uphill The system was never made for valves
If you asked Paul what’s the reason our sperm counts are falling, he would say we stood up as a species That’s probably not a good idea for male fertility, because that blood that’s supposed to be staying up there, comes back down to the testicle, pulls around it like a hot bath It is warmer and usually the first sign is the left testicle usually is smaller than the right
The reason why it drains back down is because as a species, we stood up a half a million years ago, maybe three quarters of a million years ago
And when you’re an animal, your kidney and your testicle drains this way, there’s no gravity
But when you stand up, you’re now draining uphill
The system was never made for valves
That’s probably not a good idea for male fertility, because that blood that’s supposed to be staying up there, comes back down to the testicle, pulls around it like a hot bath
It is warmer and usually the first sign is the left testicle usually is smaller than the right

Diagnosis : the physical exam will be a testicular discrepancy in size, that’s the first thing you see; and then you feel above it, and you feel a bag of worms

Peter asks, “ There are no valves in that vein? ”

Correct
The blood has to climb 30 cm
That’s a pretty big distance to travel without a valve
They think it does it at night, Paul doesn’t know
The growth spurt in puberty blows the angle of the renal vein (there’s a right angle) The right side has a natural valve off the vena cava, so it kind of has to go around 270 degrees, so you don’t reflux on the right
The right side has a natural valve off the vena cava, so it kind of has to go around 270 degrees, so you don’t reflux on the right

Usual presentation : left-sided lesion, and you can be perfectly fertile with it

If you look at statistically: 85% of men conceive naturally, without varicocele 80% will conceive naturally in about a year [with varicocele] The curves are very similar, clinically, maybe insignificant, but there is a difference and it’s statistical
But if you multiply that by millions of people, it becomes important
The best way to figure that out is a physical exam Paul doesn’t order an ultrasound If he can palpate it, then it’s clinical
85% of men conceive naturally, without varicocele
80% will conceive naturally in about a year [with varicocele]
The curves are very similar, clinically, maybe insignificant, but there is a difference and it’s statistical
Paul doesn’t order an ultrasound
If he can palpate it, then it’s clinical

Treatment : it’s an outpatient microsurgery; it takes an hour

Peter asks, “ Is it more involved than a vasectomy? ”

Yes, and you’re doing microsurgery at the level where you don’t cut muscle, you want to recover quicker
It’s an involved area with lots of veins
Paul uses twilight sedation (that’s the most common)

⇒ 40% of men have a varicocele

And most men are fertile
Again, you look at the semen analysis as a “poker hand” and you see count motility being down, nothing else going on, and you see a varicocele and it’s implicated

The major modifiable factors that affect fertility are the varicocele and hormonal issues

Varicocele is maybe 40 [% of men]
Hormononal
Maybe 10-15 genetics (so they’re non-modifiable now)

Genetic factors that affect fertility [1:54:00]

What are some factors on the genetic side that affect male fertility?

The most common one for zero sperm is Klinefelter This is an extra X chromosome
The most common one for low sperm count is Y chromosome deletions This is an interesting area There’s no phenotype; they look normal Because it’s only on the long arm of the chromosome Analogy: it’s only a couple of floors on the building There’s regions that are missing
Reijo found at MIT, 20, 30 years ago now, that the Y chromosome is a hall of mirrors In meiosis, every chromosome has a partner, except the Y in the X in a man The Y plays with itself, it combines with itself Instead of finding a partner, it has to do the dance too And so it changes a lot, so it’s very adaptable
The Y chromosome actually comes from the X, through evolution So there’s a lot of X genes that are on the Y and the Y
We thought the Y chromosome was sort of a wasteland, maybe hairy ears and tooth decay and things like that, but now it’s probably more important regions on the long arm of the Y
The short arm of the Y is very important, it has a gene called SRY , which makes you male The SRY is a male sex determining gene If you have that gene, your phenotype will be male If you don’t have that gene, you’re probably going to be female It’s complicated now, but that’s sort of what it is
But the long arm has these genes that control fertility Typically Paul ordered [analysis] in men with a low sperm count or below 5 million That would be a pretty common cause of a sperm count lower than 5 million [the figure below shows a genetic map of the Y chromosome]
This is an extra X chromosome
This is an interesting area
There’s no phenotype; they look normal
Because it’s only on the long arm of the chromosome Analogy: it’s only a couple of floors on the building There’s regions that are missing
Analogy: it’s only a couple of floors on the building
There’s regions that are missing
In meiosis, every chromosome has a partner, except the Y in the X in a man
The Y plays with itself, it combines with itself
Instead of finding a partner, it has to do the dance too
And so it changes a lot, so it’s very adaptable
So there’s a lot of X genes that are on the Y and the Y
The SRY is a male sex determining gene
If you have that gene, your phenotype will be male
If you don’t have that gene, you’re probably going to be female
It’s complicated now, but that’s sort of what it is
Typically Paul ordered [analysis] in men with a low sperm count or below 5 million
That would be a pretty common cause of a sperm count lower than 5 million
[the figure below shows a genetic map of the Y chromosome]

Figure 5. Structure of the Y chromosome . Image credit: Reproductive Biology and Endocrinology 2018

Paul published a study that if you have a Y chromosome deletion and you have a varicocele (and they both cause low sperm counts) and you fix the varicocele, you’re not going to improve Because it’s non-modifiable in all ways, it’s who you are
But if you didn’t have the Y chromosome deletion and you fix the varicocele, you’ll expect a good response ⅔ will improve, 1/3 or more will conceive naturally
Because it’s non-modifiable in all ways, it’s who you are
⅔ will improve, 1/3 or more will conceive naturally

So you could take guys with low sperm counts and you can fix them or not, but the driver [of infertility] is genetics

The phenotype in offspring is simply inherited as a Y chromosome deletion
Paul just had a couple from Texas and he had a Y chromosome deletion He conceived with help of a technology, with a low sperm count
Sons have it, they have no sperm
So you can inherit the deletion, but it might increase You’re going to get what your dad had or it might be worse, because mutations tend to get larger
You would never know until you try to conceive because everything else is normal
He conceived with help of a technology, with a low sperm count
You’re going to get what your dad had or it might be worse, because mutations tend to get larger

The impact of lifestyle and environmental exposures on fertility [1:56:30]

For environmental/lifestyle things that affect fertility, obesity is the big one

Do you think that that’s mostly propagated through the endocrine system then?

Yeah, that’s a big one, in terms of the percent of sperm with the lifestyle issues
Lousy diet is probably something

Obesity and diet, lifestyle, recreational drugs impact fertility

Toxic exposures at work

Any smelly solvents are really worrisome Airport fuels, airline stuff, machine shop oils, anything, benzene, derivatives, used to be pesticides and stuff like that But they’re pretty well controlled
Environmental exposures are kind of an unknown
Airport fuels, airline stuff, machine shop oils, anything, benzene, derivatives, used to be pesticides and stuff like that
But they’re pretty well controlled

Paul thinks viruses have a role

He saw that Peter recently wrote about HPV, and he’s been thinking about that for years
With lifestyle issues and stuff like that, you can pretty much sort it out
But there are men who we’re like, what is going on here? He’s a perfectly healthy guy When there’s obesity it’s always the elephant in the room, but everyone is so healthy Paul pokes around places where no one else goes, because he has to explain it and there’s nowhere to go
Paul wrote about STD’s: HPV is the most common ‒ it’s hard to know if that’s the link Herpes is very common We know more about chlamydia and gonorrhea and syphilis , and they’re pretty obvious Some like trichomonas are pretty subtle
20 years ago, when Paul was a professor at UCSF, a guy sent him a picture of an electron photograph of a sperm with a hexagonal herpes virus in it and asked, “ Is this virus in a sperm? ” Yeah, it looked like it He didn’t know what was causing it
Normally when you see infections (viral or bacterial) as a cause of semen analysis, you’ll see pus cells So you’ll see what’s called pyospermia or leukocytospermia , the round cells This will show up in higher numbers in the semen analysis They tend to be destructive and they tend to lower motility, so you tend to see a certain look to the semen analysis volume, normal count motility is really low A lot of the sperm are dead, ’cause they’ve been wiped out by these cytokines and all the white cells
Maybe you’ll find the pathogen somewhere or may not
But culturing mycoplasma, CMV, all these viruses
Joe Derisi at UCSF analyzed semen from Paul’s patient in the 2000s He had 2,000 mammalian viruses on his chip They tested sperm from fertile guys and infertile guys 99% of the infertiles were positive for something, and 98% of the normals were positive for something
He’s a perfectly healthy guy
When there’s obesity it’s always the elephant in the room, but everyone is so healthy
Paul pokes around places where no one else goes, because he has to explain it and there’s nowhere to go
Herpes is very common
We know more about chlamydia and gonorrhea and syphilis , and they’re pretty obvious
Some like trichomonas are pretty subtle
Yeah, it looked like it
He didn’t know what was causing it
So you’ll see what’s called pyospermia or leukocytospermia , the round cells
This will show up in higher numbers in the semen analysis
They tend to be destructive and they tend to lower motility, so you tend to see a certain look to the semen analysis volume, normal count motility is really low
A lot of the sperm are dead, ’cause they’ve been wiped out by these cytokines and all the white cells
He had 2,000 mammalian viruses on his chip
They tested sperm from fertile guys and infertile guys
99% of the infertiles were positive for something, and 98% of the normals were positive for something

The presence of viruses in sperm is ubiquitous, and you can’t really do much with that

“ I do agree with your assessment, that the pathologic phenotypes, the worst ones are probably doing something. The question is, how do we measure it? ”‒ Paul Turek

Semen analysis is a blunt instrument It varies a lot It’s tough to do
Would you do genotyping on sperm? Probably not
When you look at HPV, it’s probably one of those things that might be in the ejaculate It might be coming from another fluid source and not in the sperm itself So its effect would be post ejaculation, which could still have a fertility effect, but it won’t be probably as deep
It varies a lot
It’s tough to do
It might be coming from another fluid source and not in the sperm itself
So its effect would be post ejaculation, which could still have a fertility effect, but it won’t be probably as deep

What if a guy has prostatitis and the prosthetic fluid has pus in it?

That could sabotage the whole thing
The problem with the male system is it’s all through the same tube, so urine comes through that tube and semen comes through that tube
So you have to look for infections in the urinary tract in anything like that when you’re doing fertility, because pus cells kill whatever they see
If your urine’s infected, that’s a big deal

The evidence (or lack thereof) behind stem cell and PRP therapies for male infertility, and how lifestyle and non-invasive interventions often lead to successful conception [2:00:30]

Have you done work with intratesticular PRP, and stem cells?

Just stem cells, but not PRP

Paul adds, “ Not a big fan, as a trained stem cell biologist and someone trying to make sperm from skin and working with some of the best stem cell scientists in the world, I have a lot of respect for them. But it’s not that simple. ”

There’s 560 offshore stem cell companies in the world that will take your money and do things like stick PRP in there, they’ll stick bone marrow aspirates, fat in your testicle
Paul’s experience has not been favorable, some of the toughest cases in the world They come to Paul after that and Paul uses techniques and doesn’t find anything
The trials aren’t really real Come here, we’re going to do this, and then we’re going to do a microdissection on your testicle But they didn’t have one beforehand, so the chance of finding it even without that, is X, and they’re finding X So it’s just not well done
Paul has his patients investigate all that
Then he will call them and ask, “ Hi, I’m just wondering about, do you have any papers or what’s the science behind it? ”
They usually hang up
They come to Paul after that and Paul uses techniques and doesn’t find anything
Come here, we’re going to do this, and then we’re going to do a microdissection on your testicle
But they didn’t have one beforehand, so the chance of finding it even without that, is X, and they’re finding X
So it’s just not well done

So far, the claims around stem cells are unfounded

Peter’s experience has been very similar with a few friends and patients who have wanted him to talk with their stem cell docs He accepts the fact that they’re not going to have remarkable peer-reviewed data, but it is amazing, at how few individuals can provide even one cell layer of scientific reasoning
It’s a topic Peter would like to explore more deeply on the podcast
His guess is there are some indications for where it makes sense He would like to figure it out with people wasting so much money
He accepts the fact that they’re not going to have remarkable peer-reviewed data, but it is amazing, at how few individuals can provide even one cell layer of scientific reasoning
He would like to figure it out with people wasting so much money

For every 100 guys that walk into your office, who are struggling with infertility, what percentage of them will be able to conceive?

Assuming they are able to fully comply with the prescriptions that you provide, be it lifestyle or pharmaceutical, for example, hormone modulation, etc.
Let’s exclude the 40% varicoceles, because you’re going to fix those guys and they’re fine
So 100 people who don’t have a varicocele, who don’t have a genetic condition Presumably they showed up with some iatrogenic reason for infertility
Presumably they showed up with some iatrogenic reason for infertility

How many of those guys are going to be able to conceive without resorting to IVF?

Most men will be able to conceive without IVF, and that is the goal of Paul’s practice

But the caveat is, you got to tell me about the woman
The only data he can provide is a paper where he saw men for their infertility evaluation, got it done, and he thought they were fine They had varicoceles and stuff, but their semen analysis was normal and my investigation of their risk lifestyle, everything was good They were fine/cleared, and no one’s ever said that before They went home and they said, “ Turek, couldn’t figure out what was wrong with us .” And Paul said, “ That’s not what I said, I don’t do women .” Most people would say, I’m not sure why you’re not conceiving Paul said, “ I’m pretty sure you’re not the problem .” Didn’t get interpreted like that, that got him a little angry
Paul did a study with USC of the men he cleared and he called them up a year later 65% had conceived naturally [shown in the figure below] Another 15 to 20% conceived with IOI or IVF These women were 35 years old, year and a half infertility, they weren’t going to wait around Most conceptions occurred within 6 months
They had varicoceles and stuff, but their semen analysis was normal and my investigation of their risk lifestyle, everything was good
They were fine/cleared, and no one’s ever said that before
They went home and they said, “ Turek, couldn’t figure out what was wrong with us .”
And Paul said, “ That’s not what I said, I don’t do women .”
Most people would say, I’m not sure why you’re not conceiving
Paul said, “ I’m pretty sure you’re not the problem .” Didn’t get interpreted like that, that got him a little angry
65% had conceived naturally [shown in the figure below]
Another 15 to 20% conceived with IOI or IVF
These women were 35 years old, year and a half infertility, they weren’t going to wait around
Most conceptions occurred within 6 months

Paul didn’t do anything for them, he didn’t fix their varicoceles, he didn’t give them medication “ You’re fine.”

Figure 6. Mode of conception after a “cleared” male factor evaluation . Image credit: Translational Andrology and Urology 2021

He published it as a lifestyle study The idea was they probably made changes, they probably took a nutritional supplement, they probably timed their sex better, they probably got out of hot tubs and all that stuff Paul has a list of what they did A figure in that paper [reproduced above] reported a 65% natural pregnancy rate ‒ that is higher than anything he can offer as a treatment that we have published on So if you fix their varicocele or, you rarely get a 65% natural conception rate
This paper also included a table of all the published conception rates for the technologies that work [reproduced below] Paul is saying, this is even better
The idea was they probably made changes, they probably took a nutritional supplement, they probably timed their sex better, they probably got out of hot tubs and all that stuff
Paul has a list of what they did
A figure in that paper [reproduced above] reported a 65% natural pregnancy rate ‒ that is higher than anything he can offer as a treatment that we have published on So if you fix their varicocele or, you rarely get a 65% natural conception rate
So if you fix their varicocele or, you rarely get a 65% natural conception rate
Paul is saying, this is even better

Figure 7. Male fertility treatments and associated pregnancy rates . Image credit: Translational Andrology and Urology 2021

Considerations for sperm banking, and how paternal age impacts fertility planning and offspring health [2:05:00]

What advice do you give a guy who comes to your practice and says he wants to bank/freeze his sperm?

Presumably he’ll get a lot of that if a guy is undergoing therapy for cancer or something like that

Is there anything a guy needs to know ?

And would you recommend a guy do that if he’s 40, doesn’t have a partner but says, “Look, I want to have kids,” and isn’t there something to the idea that my sperm are better today than they will be in a decade?

Paternal age and fertility is a huge issue
Paul doesn’t place value judgements; he says, “ Good idea. ”

Disclosure: Paul is on the board of Legacy

He loves that they’re mission-driven and they’re going for military and exposed patients

Paul thinks sperm banking is the lowest hanging fruit in the field for cancer survivors and things

Disclosure: Paul started a nonprofit called Banking on the Future

To help 16-year-olds to 21-year-olds with cancer They’ll pay for it [sperm banking] for 5 years
They’ll pay for it [sperm banking] for 5 years

Would you advise any male that hasn’t reproduced who might want to, who’s undergoing any chemotherapy for any cancer to play it safe and bank their sperm?

For cancer, yes
Should anyone do it for any reason? Probably not But again, Paul doesn’t pass judgement If they’re worried about something, then they should
But again, Paul doesn’t pass judgement
If they’re worried about something, then they should

What paternal age do you worry about?

National guidelines for sperm donation consider 40 as older paternal age 50 for sure
If you look at risks to offspring, miscarriages, stillborns, birth defects, things immediately related to conception, prematurity, those go up with paternal age
Then you look at birth defects when they’re born, those go up 1-2-fold
The worrisome ones, are the single gene defects and the epigenetics like psychiatric morbidity Autism, schizophrenia, dyslexia, bipolar disorder, potentially Alzheimer’s in offspring and they’re not detectable young
Paul has published on it He was actually having my second child at 50 when he was writing this thing with Alex Yatsenko from University of Pittsburgh
50 for sure
Autism, schizophrenia, dyslexia, bipolar disorder, potentially Alzheimer’s in offspring and they’re not detectable young
He was actually having my second child at 50 when he was writing this thing with Alex Yatsenko from University of Pittsburgh

“ I think it’s a hockey stick curve for risk to offspring .”‒ Paul Turek

Do you think the inflection is 40 or 50?

Paul thinks it’s more like 60
There’s a slow linear increase in risk to offspring from 25 to 50 or 60, and then there’s an inflection and then there’s the blade at the stick
Paul thinks that’s logarithmic, same curve as women with chromosomal [abnormalities], but they’re shifted For women, it’s a shorter curve: age 38-40 is the point where things really ramp up with chromosomes
In men it’s not chromosomal
If you take the curves together, they’re different spans, same shape
Paul thinks the female curve is on top of the male curve
This is not the same relative risk, so women, you go from 25 to 40, your chance of a miscarriage (it’s chromosomal) goes up quite significantly after that
And the consequence of women’s issues with offspring-related health, is basically miscarriage In many ways, it’s almost easier to detect They’ve been doing it for years Now it’s prevented with preimplantation genetic testing
For women, it’s a shorter curve: age 38-40 is the point where things really ramp up with chromosomes
In many ways, it’s almost easier to detect
They’ve been doing it for years
Now it’s prevented with preimplantation genetic testing

⇒ Men are different, you can’t detect these things, there’s single gene mutations

In men, the machinery is constantly working, it’s getting old, the quality control of the process goes down and little gene mutations get in there that are always being spun off in the heat of the engine So the machinery’s not doing a good job. So they’re getting through and they’re not going to be lethal, they’re going to be deleterious
Autism is a classic one ‒ looks like paternal age is the biggest risk factor for That worries Paul a lot
So the machinery’s not doing a good job. So they’re getting through and they’re not going to be lethal, they’re going to be deleterious
That worries Paul a lot

Paul explains, “ The facts are that human evolution is entirely driven by sperm .”

50 mutations a generation get spit out ( Nature paper )
There’s always mutations occurring in 14-year-old fathers, but it goes way up with 60-year-old fathers

⇒ So the rate of mutations goes way up with age, but it averages 50 over a human reproductive life

Half of the mutations that we are throwing off as a species, are not ears or hands or feet or height, about half are neurodevelopmental When you think about what we’re seeing, the Martians from the ‘50s in the movies with big heads? That’s kind of where we’re headed It’s autism, dyslexia, bipolar disorder, these are neurodevelopmental or neurodegenerative issues Why is that? That’s where we’re being asked to evolve
Look at the last 30 years
One of the biggest investors in Salesforce said to Paul, “ I realized I was dyslexic when my son was born… but you know what? It helped me be the man I am to realize that Salesforce is going to fly… It let me focus .”
When you think about what we’re seeing, the Martians from the ‘50s in the movies with big heads?
That’s kind of where we’re headed
It’s autism, dyslexia, bipolar disorder, these are neurodevelopmental or neurodegenerative issues
Why is that? That’s where we’re being asked to evolve

Paul’s thoughts on autism

Autism is one of the diseases where you ignore a lot of input and you find the gift and it’s amazing
If you go down the rabbit hole of what they’re good at, it’s like their whole brain trust is there
So is that a disease or is that where we’re headed?
Peter thinks it exists on a spectrum
Use ASD as an example, it has 3 categories now in the DSM-V, and the mildest version probably comes with more superpowers than limitations (or maybe equal amounts)
But the more severe it gets, it’s pretty debiliting

Paul adds, “ Maybe it’s not disease, maybe it’s where we’re headed, maybe it’s the future. Maybe the non-sequiturs that come out of those brains. Look at who’s changing the world right now, at least in Silicon Valley .”

For class I not class III

Back to sperm banking, what is the probability of thawing correctly?

If a guy is 40 and he freezes and banks his sperm, assuming he was good to go
Freezing sperm is about a 200-year-old process, regularly used for about 75 Paul forgot who the Italian scientist was who froze sperm in snow and then thawed it, and it was alive (and moving) a couple of hundred years later after Leeuwenhoek came up with the microscope
Egg freezing and thawing is very new
Everyone is thinking about sperm now because eggs are being frozen left and right
Paul forgot who the Italian scientist was who froze sperm in snow and then thawed it, and it was alive (and moving) a couple of hundred years later after Leeuwenhoek came up with the microscope

This is much older technology and the [sperm] cell is much heartier than an egg, so it does a lot better typically

It’s the freezing process that kills sperm, be it from icicles on the inside
And then while it’s frozen, there’s usually no issue
There’s another problem when you thaw it, the rapid temperature shifts is where the kill rate comes from

In a good sample, half of it should survive

How much sperm would you tell a guy to bank?

It depends on what technology you’re going to use
If your sperm count is normal, 3 ejaculates is 1 kid’s worth of sperm with insemination technology Where you would thaw it and then turkey baster it
Where you would thaw it and then turkey baster it

Paul jokes, “ 10 ejaculates will give you most of China with IVF. ”

Meaning IUI or something like that
There are 3 levels of technology: sex (no technology), IVF (high-tech), and IUI (is in the middle)

3 ejaculates per kid would be more than enough if you’re normal

Cancer survivors, half of those will not be normal, and they’re looking at IVF So they don’t need that many But 3 is a good number, it’s an insurance policy
So they don’t need that many
But 3 is a good number, it’s an insurance policy

Paul started his podcast last year, Talk With Turek

It’s Paul and his associate Rob Clyde, who’s a director in Hollywood

Paul explains, “We’re going to be the anti-verdain of men’s health. We’re going to just take on the topics, testosterone, et cetera, penis myths, and just talk about stuff that everyone is asking questions about, but no one’s talking about. And, like you, data-driven answers. ”

⇒ Paul has a clinic that he runs up and down the coast of California

Advice for men

“ I think we’ve given folks a roadmap for their local urologist as well, if they’re getting the work up .”‒ Peter Attia

Basically, it sounds like if you’re being worked up for fertility with your urologist and they’re not going through the steps that we’ve described, maybe you should find somebody else
That’s the first step

Semen quality as a biomarker: linking male fertility, longevity, and preventative health through Medicine 3.0 and epigenetics [2:14:45]

There’s a lot going on now that the biomarker concept relates a lot to Peter’s views on Medicine 3.0

A paper came out two days ago, looking at longevity based on the semen analysis Danish in the Rigshospitalet in Copenhagen looked at 74,000 men over 50 years and found that those guys with, say, normal semen quality, live 3 years longer (all causes) than men with low sperm counts when they were younger This was a single-payer system, so they have all the data on it It’s very much a landmark study
Paul shares what excites him about the field, “ I would say, as the author of the biomarker concept early in my career, I would say I’m really happy that we’re scaring couples to realize that their fertility is a measure of their health .”
Danish in the Rigshospitalet in Copenhagen looked at 74,000 men over 50 years and found that those guys with, say, normal semen quality, live 3 years longer (all causes) than men with low sperm counts when they were younger
This was a single-payer system, so they have all the data on it
It’s very much a landmark study
Now we have our food in the door
If we can get a sperm count and get men in the office, we can actually tell them a little bit about their trajectory And that’s becoming more and more every day
We’ve never had a chance to do preventative medicine with young men
So it’s a men’s health play in a big way, because their partners are bringing them in But who cares? They’re in the office
There’s metabolic stuff, you can pick up diabetes This is the work of Paul’s nurse practitioner, Molly Jessup
And that’s becoming more and more every day
But who cares? They’re in the office
This is the work of Paul’s nurse practitioner, Molly Jessup

We have an opportunity here we’ve never had ever: to get men at younger ages

Paul was a professor at UCSF for 15 years, an endowed chair
He left and went to Yo San University of Traditional Chinese Medicine He lectures there now
He likes it because he thinks western medicine is too reactive
He lectures there now

“ We’re always trying to get men out of trouble or get patients out of trouble, but we’re not thinking about getting them from unhealthy to healthy, which is the preventative aspect .”‒ Paul Turek

We’re just not very good at prevention

In general surgery, a guy is going to do something bad, and you get him back
But you’ve got to think about the next step
Like kidney stones, great urologists treat them all day It’s fun, it’s endoscopic, it’s lasers, it’s shock waves
But what are we doing about that stone?
How come we’re not preventing these more? It’s not on the radar
It’s fun, it’s endoscopic, it’s lasers, it’s shock waves
It’s not on the radar

Yo San University of traditional Chinese medicine is a fabulous place, and it’s all holistic

Paul sees patients who get referred by acupuncturists, and they come in, their diet’s under control, their stress is under control, they’re doing acupuncture, they’re sorted out
What does Paul find? Varicoceles Because they don’t find those But the phenotype is totally different from the western referral
Paul loves that, because that’s medicine 3.0, which they’re doing
They’ve been doing it for 4,000 years
Because they don’t find those
But the phenotype is totally different from the western referral

The impact of epigenetics on fertility

It’s interesting how we don’t give a lot of street cred to it, but in Paul’s view, much of we don’t understand about fertility (certainly in men, possibly women) is epigenetic
Epigenetics are marks on the DNA, not DNA mutations 50 DNA mutations a generation doesn’t explain it There’s other stuff going on
50 DNA mutations a generation doesn’t explain it
There’s other stuff going on

⇒ Epigenetics is all lifestyle and diet driven, it’s all lifestyle and diet driven. It’s everything in Peter’s book

Selected Links / Related Material

The Turek Clinic : The Turek Clinic (2025) | [1:30, 2:14:15]

Paul’s podcast : Talk With Turek | Host Paul Turek (2025) | [1:30, 2:13:45]

Paul’s blog : Dr. Turek’s Blog | TheTurekClinic.com (2025) | [2:13:45]

Arex Life Sciences : Arex Life Sciences (2025) | [6:45]

Characterization of spermatogonial stem cells : Isolation and characterization of pluripotent human spermatogonial stem cell-derived cells | Stem Cells (N Kossack et al, 2009) | [14:00]

Textbook on reproductive physiology : The Netter Collection of Medical Illustrations: Reproductive System by P Turek and R Smith (2024) | [22:15]

Receptor on sperm that detects follicular fluid : Natriuretic peptide type C induces sperm attraction for fertilization in mouse | Scientific Reports (N Kong et al. 2017) | [25:00]

Diaries of sex and pregnancy : Timing of sexual intercourse in relation to ovulation. Effects on the probability of conception, survival of the pregnancy, and sex of the baby | NEJM (A Wilcox, C Weinberg, D Baird 1995) | [28:30]

1960s study of spermatogenesis : Spermatogenesis in man: an estimate of its duration | Science (C Heller, Y Clermont 1963) | [31:45]

Study of spermatogenesis on men who drank deuterated water : A stable isotope-mass spectrometric method for measuring human spermatogenesis kinetics in vivo | Journal of Urology (L Misell et al. 2006) | [32:00]

Paul’s study of fixing varicocele : Can varicocelectomy significantly change the way couples use assisted reproductive technologies? | Journal of Urology (S Cayan et al. 2002) | [33:15]

Infection with Zika virus causes male infertility (in mice) : Zika virus infection damages the testes in mice | Nature (J Govero et al. 2016) | [43:30]

Study of COVID infecting the testicle out of China : Does COVID-19 affect sperm quality in males? the answer may be yes, but only temporarily | Virology Journal (Q Zhang et al. 2024) | [44:15]

Review on the impact of COVID-19 on fertility : COVID-19 and human reproduction: A pandemic that packs a serious punch | Systems Biology in Reproductive Medicine (G Anifandis et al. 2021)

Autopsy of men who died from COVID and detection of virus in the testicle of 1 man : Case series – COVID-19 is unlikely to affect male fertility: Results of histopathological and reverse transcriptase polymerase chain reaction analysis | Canadian Urological Association Journal (J Masterson et al. 2022) | [44:30]

Kruger morphology and IVF outcomes : Sperm morphologic features as a prognostic factor in in vitro fertilization | Fertility and Sterility (T Kruger et al 1986) | [49:00]

Episode of The Drive on microplastics : #332 – AMA #67: Microplastics, PFAS, and phthalates: understanding health risks and a framework for minimizing exposure and mitigating risk (January 20, 2025) | [1:00:15]

Consumption of estrogenized beef by pregnant women linked to lower sperm counts in sons : Semen quality of fertile US males in relation to their mothers’ beef consumption during pregnancy | Human Reproduction (S Swan et al. 2007) | [1:02:00]

Paul’s review on avoiding medications toxic to sperm : Avoiding toxins including spermatotoxic medications | Seminars in Reproductive Medicine (G Stearns, P Turek 2013)

Paul’s blog on exercise and fertility : Can You Be Too Fit to Be Fertile? | Dr. Turek’s Blog (2019) | [1:05:15]

Effect of extreme exercise on fertility : The Impact of Intense Exercise on Semen Quality | American Journal of Men’s Health (P. Jozkow, M Rossato 2017) | [1:05:15, 1:41:45]

Metabolism of oral testosterone : Reexamination of Pharmacokinetics of Oral Testosterone Undecanoate in Hypogonadal Men With a New Self-Emulsifying Formulation | Journal of Andrology (A Yin et al. 2012) | [1:09:45]

Blood thickening in men on testosterone therapy : Secondary Polycythemia in Men Receiving Testosterone Therapy Increases Risk of Major Adverse Cardiovascular Events and Venous Thromboembolism in the First Year of Therapy | Journal of Urology (J Ory et al. 2022) | [1:13:45]

ADAM questionnaire : ADAM screening questionnaire | The Men’s Health Clinic (2025) | [1:19:15]

Paul’s blog about getting off testosterone : Getting Off the Juice | Dr. Turek’s Blog (2012)| [1:27:45]

Case study of a guy who took testosterone for 25 years : The reversibility of anabolic steroid-induced azoospermia | Journal of Urology (P Turek et al. 1995) | [1:29:00]

hCG preserves fertility in men taking testosterone : Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression | The Journal of Clinical Endocrinology and Metabolism (A Coviello et al. 2005) | [1:33:30]

Paul’s study on the effects of heat on sperm motility : Wet heat exposure: a potentially reversible cause of low semen quality in infertile men | International Brazilian Journal of Urology (S Shefi et al. 2007) | [1:38:00]

Paul’s blog on the effect of hot tubs on sperm : Toxic Tubbing: Hot Tubs‘ Effects on Male Fertility | Dr. Turek’s Blog (2011)

Study of sperm counts in Spanish competitive cyclists : Reproductive function in male endurance athletes: sperm analysis and hormonal profile | Journal of Applied Physiology (A Lucia et al. 1985) | [1:43:00]

Paul’s blog on the effects of cycling on sperm : Cycling Toward Childlessness ? | Dr. Paul Turek’s Blog (2014) | [1:43:45]

Fertility of British who cycled to work : An Observational Study of Erectile Dysfunction, Infertility, and Prostate Cancer in Regular Cyclists: Cycling for Health UK Study | Journal of Men’s Health (M Hollingworth, A Harper, M Hamer 2014) | [1:43:45]

NIOSH findings on bicycle seats and men’s sexual health : NIOSH Research Demonstrates the Effectiveness of No-Nose Bicycle Seats in Reducing Groin Pressure and Improving Sexual Health | NIOSH (2010) | [1:45:00]

Paul’s blog on marijuana : Weed Worries | Dr. Paul Turek’s Blog (2010) | [1:48:00]

Reijo Pera’s study of the Y chromosome : Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene | Nature Genetics (R Reijo et al. 1995) | [1:54:45]

Y chromosome deletions drives infertility more than varicocele : Response to varicocelectomy in oligospermic men with and without defined genetic infertility | Urology (S Cayan et al. 2001) [1:55:30]

Paul’s review on the genetics of male infertility : The genetics of male infertility | Seminars in Reproductive Medicine (T Walsh, R Reijo Pera, P Turek 2009)

Peter’s newsletter on HPV and invertility : Concerning links between human papillomavirus (HPV) infection and male infertility | PeterAttiaMD.com (K Birkenbach, P Attia 2025) | [1:57:15]

Paul’s blog on STI’s : The Skinny on STIs and Male Infertility | Dr. Turek’s blog (2019) | [1:57:45]

Conception rates among men “cleared” of infertility : A study of pregnancy rates in “cleared” male factor couples | Translational Andrology and Urology (E Godart et al. 2021) | [2:03:30]

Paul’s review of male fertility treatment : Practical approaches to the diagnosis and management of male infertility | Nature Clinical Practices Urology (P Turek 2005)

Impact of paternal age : Reproductive genetics and the aging male | Journal of Assisted Reproduction and Genetics (A Yatsenko, P Turek 2018) | [2:07:15]

Semen analysis and longevity : Semen quality and lifespan: a study of 78 284 men followed for up to 50 years | Human Reproduction (L Priskorn et al. 2025) | [2:14:45]

Yo San University of Traditional Chinese Medicine : Yo San University of Traditional Chinese Medicine (2025) | [2:16:15]

People Mentioned

Harvey Cushing (1869-1939, American neurosurgeon, pathologist, and writer) [23:00]
Keith Jarvi (Professor of Surgery, Division of Urology, Department of Surgery at the University of Toronto where he established the fertility program in Urology) [34:00]
Thinus Kruger (Professor of Obstetrics and Gynaecology at Stellenbosch University; expert on sperm) [49:00]
Shanna Swan (Environmental and reproductive epidemiologist, Professor of Environmental Medicine and Public Health at the Icahn School of Medicine at Mount Sinai) [1:02:00]
Ranjith Ramasamy (Urologist and former Director of the Reproductive Urology Fellowship program at the University of Miami Miller School of Medicine) [1:13:45]
John Amor y (Professor of Medicine, Director of the Institute for Translational Health Sciences, and Associate Dean of Translational Science at UW Medicine) [1:33:30]
Steven Schrader (Research Biologist at NIOSH) [1:45:00]
Renee Reijo Pera (President of the McLaughlin Research Institute for Biomedical Sciences and Professor at the Touro College of Osteopathic Medicine, Montana) [1:54:45]
Joe Derisi (Professor of Biochemistry and Biophysics and Howard Hughes Investigator at UCSF) [1:59:00]
Alexander N Yatsenko (Associate Professor of Obstetrics, Gynecology & Reproductive Sciences and Director of the Pittsburgh Clinical Genomic Laboratory at the University of Pittsburgh) [2:07:15]
Molly Jessup (Nurse Practitioner specializing in male fertility and reproductive health at the Turek Clinic) [2:15:45]

Paul Turek earned his undergraduate degree from Yale and medical degree from Stanford. He completed his residency in urology at the Hospital of the University of Pennsylvania. He also did a fellowship in male reproductive medicine and microsurgery at Baylor. He is a board-certified urologist and former Full Professor and Endowed Chair in Urology at the University of California San Francisco. As the inventor of sperm mapping , he is recognized as one of the world’s top male reproductive health and fertility physicians and surgeons. His research focuses on low sperm count, poor sperm motility, and hormonal imbalances related to infertility. He has published hundreds of papers in leading medical journals. Dr. Turek is the founder and Medical Director of The Turek Clinic , which has offices in everly Hills and San Francisco. He is also the Co-Founder and Chief Scientist of Alpha Sperm , a company that developed the first prenatal vitamin and micronutrition supplement for men. [ AlphaSperm ]

Blog: Dr. Turek’s Blog

Instagram: @drpaulturek

Podcast: Talk with Turek

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