Dr. Kyle Gillett: Tools for Hormone Optimization in Males | Huberman Lab Podcast 102

ANDREW HUBERMAN: Welcome to the Huberman Lab podcast

where we discuss science and science-based tools

for everyday life.

[MUSIC PLAYING]

I'm Andrew Huberman, and I'm a professor

of neurobiology and ophthalmology

at Stanford School of Medicine.

Today, my guest is Dr. Kyle Gillett.

Dr. Kyle Gillett is a dual board certified physician

in family medicine and obesity medicine and an expert

in hormone optimization.

He is an M.D--

that is, a medical doctor--

and he treats patients with a variety

of backgrounds, ages and goals.

Today, we discuss male hormone optimization.

We discuss behavioral tools, nutrition-based tools,

supplement-based tools, prescription-drug-based tools,

and their interactions in determining overall levels

of testosterone, free testosterone,

dihydrotestosterone, estrogen, growth hormone, thyroid

hormone, and many other hormones that impact mood,

libido, well-being, strength, cognition,

and various psychological factors.

We've covered hormone optimization

in both men and women in previous episodes

of the Huberman Lab podcast, but today's discussion

is different.

Dr. Kyle Gillett offers very specific recommendations

for people with different goals and of different ages.

And we get deep into the weeds of,

for instance, how does one know whether or not

their testosterone is optimized or not, how often to test

for specific hormones such as testosterone

and other hormones, and really, how to gauge

how good one should feel?

This is something that's often overlooked in discussions

about hormone optimization or health optimization

of any kind, for that matter.

For instance, people will talk about reduced libido

and discuss whether or not testosterone levels are

to blame, but how does one calibrate their libido

in the first place?

That is, how does one know whether or not their libido is

normal, too low, or too high?

We also discuss, for instance, whether or not

hormone optimization should be pursued continually

throughout the year-- for instance,

whether or not you should cycle on and off supplements

and/or prescription drugs geared towards hormone optimization.

And we discuss the behavioral foundations

of optimal hormone function.

These are things that every male should be doing

and various things they should actively

avoid if their goal is to have healthy hormones and to,

quote, unquote, optimize their levels of every hormone

from growth hormone to testosterone

at any stage of life.

And while today's discussion is about male hormone

optimization, I want to emphasize

that we discuss all the various ages for male hormone

optimization.

So for those of you that are parents, for those of you that

are young, those of you that are middle aged, or old,

or teenagers, we explore adolescent, puberty,

teen and late teens, early adulthood, adulthood,

and into the late geriatric ages.

So regardless of your age and whether

or not you are male or female, today's episode

ought to be of interest to you.

I should also point out that we will soon also

be hosting an expert guest on female hormone optimization.

One thing that I'm certain people of all ages

and biological sex will enjoy about today's conversation

is that we also get into descriptions

of how psychology and life events impact hormones

and how hormones impact our psychology and the way

that we show up to various life events.

So today is really a broad overview

that goes all the way down to fine details about male hormone

optimization.

And I'm certain that by the end of today's episode,

you will have an immense amount of new information about how

this endocrine-- that is, hormone system in your body

works--

and how it interacts with your brain and other tissues

and many, many actionable tools that you can pursue regardless

of stage of life.

Before we begin, I'd like to emphasize

that this podcast is separate from my teaching and research

roles at Stanford.

It is, however, part of my desire and effort

to bring zero cost to consumer information

about science and science-related tools

to the general public.

In keeping with that theme, I'd like

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And now, for my discussion with Dr. Kyle Gillett.

Dr. Gillett, great to have you back.

KYLE GILLETT: Great to be back.

Thank you.

ANDREW HUBERMAN: I'd like to begin with a question about one

of the most mysterious and important phases of life, which

is puberty.

I've long wondered whether or not how quickly somebody goes

into puberty-- so at what age--

and how long puberty takes-- so how

brief or protracted that puberty is

for them to acquire the so-called secondary sexual

characteristics, things like hair growth

on the face for males and changes in bone, and muscle

density, and growth, et cetera.

When I was in middle school and high school,

I noticed that some people transitioned into all that

very fast and some people took a long time to acquire

those characteristics.

Can we learn anything about ourselves, our hormones,

and maybe even how long we're going

to live based on the time in which we enter puberty

and how long it takes us to progress through puberty?

And I guess that also raises the question,

does puberty ever truly end?

KYLE GILLETT: There are many takeaways from puberty.

Some of the actionable items from it are, yes, it can

and does affect your adult height and also stature

and also body composition.

So puberty is a time--

and if we're talking specifically about males,

think of it as a time where, if you have obesity as a child,

you could potentially use that time

to change your lifestyle and habits and reset things,

and it is a bit easier.

It's almost like a free injection

of testosterone and metabolism and drive and effort

into your life.

There is a wide variation in how quickly puberty goes through.

So there are stages called Tanner stages, which we don't

necessarily need to get into.

But if you enter puberty very early,

then it can decrease your adult height or stature.

ANDREW HUBERMAN: So for a given male that enters puberty

at 13 versus a male that enters puberty at 15,

can we say that the guy that entered puberty at 13

is going to be shorter than the guy that entered puberty at 15,

or it's not quite that straightforward?

KYLE GILLETT: If they are identical twins

and the individual who entered puberty

at age 13 also finished puberty, went all the way

through the Tanner stages--

and if you do a bone scan, which I believe

is usually done on the left wrist,

and it says yes, your growth plates are mostly closed,

you're not going to grow more than a couple inches of height

after that.

ANDREW HUBERMAN: Just a related question.

When I was growing up, it was thought,

or at least people would say, that resistance training--

in particular, lifting heavy weights

could stunt one's growth.

Is that true or false?

KYLE GILLETT: It is false when you're

talking about just lifting heavy weights.

Dirty bulking certainly has the potential to stunt

one's growth for two main mechanisms.

ANDREW HUBERMAN: Could you define dirty bulking?

KYLE GILLETT: [CHUCKLES] So dirty bulking

is eating an excess of calories not just to acquire

lean metabolically active body mass or get stronger,

but purposely acquiring body fat.

ANDREW HUBERMAN: So purposely acquiring muscle

and fat by overeating and lifting weights

can stunt one's growth.

Do I have that correct?

KYLE GILLETT: Correct.

So it does two things.

If you're doing it as a very young child, it can--

that fat can become leptin resistant

and it can produce more leptin, and that leptin

can activate the hypothalamus, which

activates the pituitary, which releases gonadotropin, which

basically just increase testosterone

and estrogen earlier than it otherwise would have.

It's the same mechanism behind why childhood obesity causes

early puberty.

ANDREW HUBERMAN: Interesting.

I do remember a paper published in Science Magazine--

I believe it was focused mainly on females,

but showing that when enough body fat accumulates,

the hormone leptin is secreted, and that

triggers the onset of puberty.

KYLE GILLETT: Correct.

ANDREW HUBERMAN: Given the increase in childhood obesity

that we're observing now, are we seeing

an earlier onset of puberty in males and females?

KYLE GILLETT: Yes, in both males and females.

Not to get too technical, but there's

a G protein-coupled receptor on the hypothalamus

and leptin directly binds it, so it

does appear directly cause causatory and not

just correlation.

ANDREW HUBERMAN: And if I understand correctly,

what you're saying is for a young guy-- let's

say, 13, 14-- who wants to really bulk up

and deliberately-- deliberately, excuse me-- overeats, and is

doing their squats, and deadlifts, and bench presses

and really trying to get big, they will get big, but only

in the lateral dimension.

They're effectively limiting their total height

and it can shut down the long bone growth of their limbs.

Is that correct?

KYLE GILLETT: Correct.

The growth of the long bones is mostly related

to the estradiol alpha receptor, so basically,

one of the receptors for estrogen,

which can be secondary to early puberty and also

is related to body fat because you have that conversion

of testosterone to estrogen.

ANDREW HUBERMAN: So can we assume that if a young male

wants to get into resistance training that bodyweight

exercises are probably OK and maybe even some weight

training, kettlebells, et cetera,

but that they should avoid doing so-called dirty bulking--

trying to deliberately gain weight--

up until what age?

Until puberty is over?

KYLE GILLETT: I would say an individual should limit

the amount of abnormal body fat accumulation,

or dirty bulking, indefinitely throughout their entire life.

ANDREW HUBERMAN: So again, if I understand correctly,

that recommendation to avoid deliberate weight gain

or rapid weight gain is not just to allow an individual

to reach their maximum height, but also to avoid laying down

a lot of body fat cells.

Correct?

KYLE GILLETT: Correct.

The balance between that is, when

you are going through puberty, you

are able to add a lot of lean body mass--

not just muscle mass, but bone mass and other mass as well.

ANDREW HUBERMAN: I started lifting weights when I was 16,

and I confess I trained pretty heavy at times.

I don't know whether or not I would

have been taller than I am now, but when

I started that training, I had already

reached what was at least close to my predicted height.

I can't say that I deliberately waited until I had grown.

It just so happened that I stumbled into the weight room

and found that I liked it at age 16, at which point,

I was already the height that I am now.

So in any case, what I'm hearing is

that laying down a lot of excess body fat is not a good idea.

What if somebody grows up chubby or fat for whatever reason--

reasons related to the eating patterns in their family,

maybe even some genetic reasons.

Is it safe and/or wise for a young person--

so let's say somebody who's around the age of puberty,

or even younger, or in their late teens-- to be dieting

and actively trying to lose body fat.

Is that safe?

KYLE GILLETT: Under the supervision of a physician,

it is certainly safe to change your body composition.

In pediatric obesity medicine, you're

often talking about a recomposition

or a renormalization of the growth curve compared to peers.

ANDREW HUBERMAN: Great.

Thank you.

So as you may have sensed, we started chronologically

with puberty, and I know that there's

another puberty that even precedes the puberty that we're

all familiar with.

Maybe-- if you want to just briefly mention

that because I was talking with you about this

before we started.

The puberty that I'm most familiar with,

and I think most people are most familiar with,

the acquisition of deepening of the voice,

growth of muscle and bone, body hair, acquisition of libido

and things like that.

That's actually the second puberty that we all go through.

Maybe would just mention for us and educate us

on the first puberty.

I think most people will be hearing

this for the very first time.

KYLE GILLETT: The first puberty of everyone's life

is the first three months of their life.

You may notice that your baby has more acne the first three

months and that they also have, in general, just more changes

related to androgens and estrogens, perhaps oilier skin,

even more genitourinary--

genital growth during the first three months.

And this is mostly due to DHEA, which is an adrenal hormone.

The second puberty, or the puberty

that most people know of, actually starts that same way

as well.

It's called adrenarche, and it's when the adrenals kick in,

I guess, for the second time.

ANDREW HUBERMAN: Is there a standard age or age

range in which the testicles descend in males?

KYLE GILLETT: Usually before birth.

It is not uncommon to have one or even two undescended testes,

but there is a risk of testicular cancer,

especially if they are not fixed early and also

heat damage to the teste.

ANDREW HUBERMAN: Well, thank you for that coverage

of the two puberties.

So early in life.

I imagine some of our listeners probably

still in one or the-- well, one or the other puberty.

The ones that are in the first puberty,

obviously, aren't aware that they're

listening to this podcast, but maybe it'll

be embedded in their subconscious.

But some listeners probably are still in puberty.

But I think everyone can remember back to their puberty,

and roughly when they first entered puberty,

and how quickly they aggregated the secondary sex

characteristics.

I'd like to turn now to a general question about what

all males ought to do in order to optimize their hormones.

So if you could just list off the things

that all males should do on a daily basis, weekly basis.

I mean, should guys in their teens and 20s

be getting their bloodwork done, should they

be taking supplements?

We already talked about weight training.

What should they be doing and what should they

avoid doing if the goal is to have

a long arc of healthy hormone optimization

throughout the lifespan?

KYLE GILLETT: There's many things that you should do.

An analogy that I often make is when

there's a brand new car that comes off the assembly line,

you do a full scope of diagnostic workup--

hook it up to the computer.

And I think we should do the same thing with humans as well.

During puberty, obviously, you're a functioning human,

but I would say there's still development.

And I think that the human always develops.

I don't think development ever ends,

but you want to monitor that progress

across a person's lifespan.

[INTERPOSING VOICES]

ANDREW HUBERMAN: Oh, sorry.

So for bloodwork-- I mean, what would be the earliest--

let me put it this way.

If blood work didn't cost anything and everyone

could get it, when would you want

to see everybody get their bloodwork done

for the first time?

Obviously, individuals under the age of 18

should talk with their parents about this.

And as long as the parents and the child

agree and the parents are on board with this as well,

you can start getting bloodwork.

Often, a child will come in with complaints

of either precocious puberty or delayed puberty,

and this individual might be 9 or this individual might be 15.

For a healthy child, when they're

going through their later Tanner stages-- which

is 4 and 5, so they've developed several secondary sexual

characteristics-- they might have hair growth or starting

to notice more beard growth.

That's a good time to do it.

If you're concerned with stature or heighth,

or if you're not tracking along where most

members of your family have--

not just their height and stature, but also

the timing of their puberty, then that's time to get labs.

ANDREW HUBERMAN: So if I could travel back in time,

I would have gotten my bloodwork done for hormones, and lipids,

and everything else at 18.

I, unfortunately, didn't know where and how to get that,

and I didn't have any pressing clinical issues.

And so I think the first time that I got my bloodwork done,

I was in my late 20s, maybe even in my early 30s.

And I'm still dying to know what my bloodwork was

when, for instance, I was 17 and I felt a certain way.

And I confess that in many dimensions,

I actually feel better now at--

I'll be 47 soon-- at 47 than I did in my teens and 20s.

And I think it was more on the psychological side.

I think that-- but in terms of just understanding

why we felt great or why we felt or feel terrible or not so

great, I think bloodwork is extremely informative.

What do you think are the key things

to look for in bloodwork?

I mean, testosterone is always the topic that comes up

in the context of male hormone optimisation,

but certainly there are a lot of other hormones

that are important as well.

KYLE GILLETT: And with testosterone, you

want to get either testosterone and an SHBG

or a free testosterone.

ANDREW HUBERMAN: Could you define SHBG for our listeners,

please?

KYLE GILLETT: It is Sex Hormone Binding Globulin.

It is the protein that binds up all androgens

and estrogen in the body.

So the stronger the androgen, the stronger it binds.

During puberty, strong androgens,

especially DHT which is the strongest

bioidentical androgen, has a huge role--

a prominent role in secondary sexual characteristics.

And if your SHBG is very high, then your DHT

can run higher because it's not metabolized,

but there's not quite as much free DHT.

So you want to balance between a high enough free DHT

and a high enough total DHT.

ANDREW HUBERMAN: And obviously, these blood tests

are going to have to be read and interpreted

by a qualified physician.

Most people aren't going to be in a position to evaluate them

properly, or at least not with the full depth that they could

if they had an M.D like yourself looking at them.

So everyone should get bloodwork as early as possible

depending on their budget and availability.

What should everybody do in terms

of monitoring those markers?

So assuming that there's no major intervention,

how often do you recommend that people

get their bloodwork done?

KYLE GILLETT: Let's say--

let's take an individual who just turned 18,

they just got their first set of bloodwork.

They'll probably find something in it

that they may want to optimize using shared decision-making

with their physician.

Usually, a good follow-up is about six months.

ANDREW HUBERMAN: So twice a year, getting bloodwork done,

and then having a physician evaluate it.

That sounds reasonable to me.

And for those that didn't initiate this at 18,

such as myself, I guess the best time to start then

would be as soon as possible.

KYLE GILLETT: Yeah.

ANDREW HUBERMAN: In terms of the other things

that all males should do, meaning all males of all ages--

puberty and beyond-- what are some of those things?

So on a daily basis, maybe you could just

take us through the arc of a day and push out

some of the protocols that you use

or the things that you like to see your male patients

use in order to try and optimize their hormone status.

KYLE GILLETT: I'll briefly touch on some of the lifestyle

pillars to start.

Diet and exercise are the first to.

In puberty, sleep is particularly important,

of course.

But with diet and exercise, throughout a lifespan,

you want to not exclude things that are helping you.

For example, during puberty if you're

consuming dairy, and then all of a sudden you cut out all dairy,

dairy can help increase IGF-1 and free IGF-1.

ANDREW HUBERMAN: And just, again, for our audience,

maybe just mention what having enough IGF-1 can

do for us that's beneficial is?

KYLE GILLETT: It helps you grow.

It helps with genital development,

secondary sexual characteristics, and long bone

growth--

skin growth, hair growth, a host of things.

ANDREW HUBERMAN: So getting an array of nutrients

that include dairy.

What other sorts of nutrients are

important during development?

KYLE GILLETT: You want to have adequate vitamin D. Vitamin

D helps with testosterone production,

it helps, again, with bone mineralization and stature.

After an age of about 25--

and there's not a strict cutoff, but up to about an age of 25,

optimizing your growth hormone and IGF-1

helps with bone density and bone growth.

So from the dietary standpoint, you

want to have enough free estrogen-- not too much

when you're growing.

But you want to help basically stockpile bone

to prevent a risk of osteoporosis or thin bone

fractures when you're older.

ANDREW HUBERMAN: Well, as someone

who broke his left foot 5 times while in high school,

I can say that whatever young people can

do to optimize their bone density would be great.

That problem seems to have resolved itself over time,

but I don't know.

Back then, I did a short run as a vegetarian,

but I've always been an omnivore.

I realize that some of this relates

to ethics, and food allergies, and things of that sort.

But would you say that, on balance,

most people would benefit from eating a combination of quality

proteins from animal sources and non-animal sources--

fruits, vegetables, and starches?

I mean, what do you think, for instance,

about people following a pure carnivore or a very pure vegan

diet in their 20s and 30s?

KYLE GILLETT: In their late 20s, it

might be a reasonable option.

In early 20s and certainly teens,

it is a horrible idea because it is likely to significantly

decrease your free androgens.

So you will have less testosterone acting

on receptors through the body.

ANDREW HUBERMAN: Are there any other micronutrients

or macronutrients that people in their 20s and 30s

should emphasize?

KYLE GILLETT: We haven't really touched on fatty acids or fiber

too much.

Fiber is going to be paramount in kind

of setting your set point of your gut

microbiome the rest of your life.

There is prebiotic fiber, which you

can think of as fish food for your good gut microbiome.

Your gut microbiome is kind of like an aquarium or a fish

tank.

ANDREW HUBERMAN: Now, I'm just thinking

about goldfish swimming around in that-- the goldfish eating

people.

Don't eat goldfish, people--

[INTERPOSING VOICES]

ANDREW HUBERMAN: --live or dead.

KYLE GILLETT: Yeah, but any fiber or food

that you're putting in your gut, it's

either going to skew your gut microbiome toward something

that is more beneficial or more detrimental.

ANDREW HUBERMAN: And would you say

that the prebiotic fiber and getting essential fatty acids,

that would be important to do throughout the lifespan or just

for people in their 20s and 30s?

KYLE GILLETT: Throughout the lifespan,

particularly important in the teenage, '20s, '30s, because it

helps with brain development.

You're certainly more of an expert than me

when it comes to brain development,

but it does continue to develop, really,

throughout the lifespan, but certainly through the 20s

and 30s as well.

ANDREW HUBERMAN: What about taking a multivitamin

while you're growing up?

So many people do that.

Is it necessary, is it useful?

And if it's not necessary, is it safe to do anyway?

KYLE GILLETT: It's generally safe to do anyway.

I do not think everybody needs a multivitamin.

The more exclusionary your diet is--

for example, if you have celiac disease

or if you're planning on fertility soon, then perhaps

it's more reasonable to take a multivitamin.

ANDREW HUBERMAN: In a previous discussion of ours,

I asked you about caloric restriction and testosterone.

And if I recall correctly, the idea was that if somebody is

overweight-- they have an excess fat, adipose tissue--

then getting rid of some of that adipose tissue

through caloric restriction and exercise,

provided it's done not too fast in a healthy way,

is going to be beneficial for testosterone in the long-run.

But that for individuals who are not

carrying an excess of body fat, caloric restriction

is actually going to lower testosterone.

First of all, do I have that correct?

And second, are there any addendums to that

you'd like to give us now?

KYLE GILLETT: That's correct.

If you look at an individual in a caloric deficit,

several changes will happen.

One is that they'll have less building blocks for hormones.

Another is that they will be in a catabolic state

more often, so that balance of anabolism and catabolism

will be different.

They'll likely have less signaling from growth hormone

and IGF-1, and they'll also have the high SHBG

that we defined earlier as the binding protein,

so their free androgens and free estrogens will go down.

ANDREW HUBERMAN: Got it.

So we touched on sleep being critical.

I would say throughout the lifespan, trying

to get enough quality sleep at least 80%

of the nights of your life, and the other 20%

are just what happens when there's noise outside

or you're stressed.

It just-- you have an exam or you're

having a great time for whatever reason.

There are a lot of good reasons to lose some sleep

now and again as well.

So we have sleep, we've got nutrition.

We touched on that.

We'll get back into supplementation.

Now, what are some of the other pillars

of creating the proper environment for hormone

optimization?

KYLE GILLETT: Stress is probably the next one.

During both puberty, but also the 20s and 30s,

individuals are figuring out how they want to cope with stress

and also figuring out what they want to choose

to put their effort into.

So if someone is overstressed, then it can have--

it can put all the other lifestyle pillars--

and then they stop dieting well, they stop exercising,

and everything else can go askew.

There is also some degree of social component to this,

so perhaps I need to add a seventh pillar of social.

During your 20s and 30s, you may be forming a family as well.

Perhaps you have children, and the health of the family unit

is going to be vitally important not only-- not

necessarily directly for hormone optimisation,

but it's going to throw everything

else off if it's off.

ANDREW HUBERMAN: And for people that are not

starting their own families in their 20s and 30s,

can that social connection be extended to friendships

and work relationships as well?

KYLE GILLETT: Absolutely.

In fact, if someone's not starting a family,

it is just as concerning, but for other reasons.

Each individual is going to have their close group of family

and friends.

And if someone does not have one of those connections,

that's when things can potentially

get bad not just for them individually, but also society.

ANDREW HUBERMAN: So when you say stress,

you mean learn to manage your stress.

What does that look like?

I mean, if a patient has high blood pressure,

or even if they don't, you just sense that they're stressed.

They have a lot of pressured speech,

or they're not feeling well, or communicating

that they're not doing well.

What are some of the things that you

recommend in order to try and ameliorate that stress?

KYLE GILLETT: There's different mindfulness or relaxation

techniques.

Going outside can often help with this as well.

Dietary changes and exercise can help with this too.

Some people like prayer or meditation.

And a lot of people like counseling or therapy,

or even just talking openly with a family member or a friend.

ANDREW HUBERMAN: What would it be

some of the other pillars for hormone optimization?

Here, I feel like we're not just talking about people

in their 20s and 30s, but again, we're

wrapping our arms around basically puberty onward.

I mean, gosh, looking back, I started

meditating pretty early, I started weight training

and running early.

I gave some thought to my diet in high school,

but it really was in college that I

started thinking more about what I was ingesting and why

and trying to do better there.

But people are coming to the table

at different stages of life and trying

to optimize for hormones.

So what would be some of the additional things

that everybody should do?

KYLE GILLETT: Everyone should get outside and find a movement

pastime to last a lifetime.

You're going to get sunlight, you're

going to get some degree of heat and cold exposure,

and you're also just going to move more.

Being in an artificial environment, where there's

artificial lights artificial air conditioning,

is going to have many effects on your body.

So that's vital.

Another one is finding what your purpose is in life.

So I call this spirit, but it's really

just the self-actualization component of Maslow's hierarchy

of needs, which is basically your physical needs,

your mental needs, and then your purpose in life-- what

you really like to do.

ANDREW HUBERMAN: Yeah, picking some goal or target.

And I always say that you don't have to stick

to the same goal over time.

Certainly, I haven't although I got

started early in the science game and I'm still in it.

The idea is not to pick the end goal, it is to pick a goal.

And then once you reach that goal to assess, and then

pick another goal, and so on.

I think sometimes, when people hear about picking a purpose,

they're like, oh, my goodness, I have to define--

sort of like naming oneself--

that you actually can change your goals and purpose

over time.

This is terrific.

Would you suggest that people actively use

or avoid supplementation prior to doing

all these other things?

I'm somebody that likes to throw the kitchen sink at things,

but I also like to do things pretty systematically.

So I would say behavior is first, then nutrition, then

supplementation, and then maybe if, and only if, there's

a real need--

and of course, working with a doctor-- prescription drugs.

But there are probably people in their 20s or 30s--

maybe even in their 50s--

that aren't feeling great, and they

want to do something in order to be able to train more

or to feel more confident to seek out social connection.

They just try and go about the whole business

from the other side as well.

What are your thoughts on that?

KYLE GILLETT: I see supplements and medications

as very similar--

one is prescribed and one is not.

In general, medications have more side effects

or potentially stronger therapeutic with more efficacy.

But they are just tools to reach an end goal.

So depending on the goal, if there's

an individual that's an athlete, then

certainly they should consider supplementation.

Or if someone desires optimal or a very high level

of cognitive performance, they should also

consider supplementation.

At the same time, food is medicine,

and a lot of the benefits you can get in supplements,

you can get in food as well.

ANDREW HUBERMAN: I guess it depends

on how much time and energy you're willing to spend

and also finances.

I know that when I was in college,

I could afford just a few supplements,

and they were basically whey protein and some fish oil--

I was fortunate that I was pointed

in the direction of those things-- and some creatine.

I couldn't afford much else.

Over time, of course, I could afford more.

But it really does often depend on finances.

Before we get into some specific recommendations

to optimize testosterone, estrogen, thyroid,

growth hormone, et cetera, I want to ask you

a question I've been wondering about for a long time.

So often in the discussion about male hormone optimization,

people will say, well, if your libido is suffering,

you might want to be concerned about testosterone--

or even estrogen because we know that estrogen can impact libido

as well.

Sometimes, having estrogen too low is detrimental for libido.

Or that people will say, you're not recovering from workouts

or you're just you're feeling kind of depressed.

The problem is, it's all subjective.

[CHUCKLES] So how does one know whether or not

their recovery from workouts, their energy, their confidence,

their libido is within a healthy range?

I mean, obviously, for people in a relationship

they can know whether or not their libido matches

the sort of cadence of the relationship and their partner.

But how should people think about this

and maybe then start to talk about it?

Because one of the big differences, I think,

between males and females is that, because females

have a monthly cycle, they are familiar with the changes that

occur in their hormones over time because every 28 days,

those hormones are changing dramatically

in ways that impact their physiology and psychology.

But for males, I feel like there's

a dearth of language to get into the more subtle aspects

of this.

It also has to do with privacy issues and people

feeling like they don't want to overshare too much--

not knowing what's appropriate to share.

But when you talk to a patient who's in their 30s,

or maybe even their 70s or 60s-- it

doesn't matter-- a male patient, what are you listening for?

And I know you're not a psychiatrist,

but what are your ears tuned to in order to try and figure out

whether or not this person could really

use some help with hormone optimization

or whether or not something else--

or maybe they're just doing great

and they don't realize it because they're

placing demands on themselves that are excessive?

KYLE GILLETT: You want to use a lot of open-ended questions.

This process is called motivational interviewing.

And your goal is to listen to the patient

and not plant an idea in their mind

that they can follow because everybody is

going to have a different goal.

Some people are better at reading their biofeedback

or telling how they feel on a daily basis.

There is screening questionnaires designed--

for example, an ADAM questionnaire

to look at men's men's health and hormone-related health.

ANDREW HUBERMAN: It's called ADAM questionnaire?

KYLE GILLETT: ADAM questionnaire.

ANDREW HUBERMAN: A-D-A-M?

KYLE GILLETT: Correct.

ANDREW HUBERMAN: Is it available online

that people could administer it to themselves.

Although we don't want people making

clinical diagnoses of themselves or anyone else,

is it that sort of exam?

KYLE GILLETT: It is.

ANDREW HUBERMAN: Interesting.

KYLE GILLETT: I don't believe it is a clinically-validated tool

like an ASCVD, which is like a risk of heart attack and stroke

tool or many other tools.

There's one for depression, there's one for anxiety.

They're called PHQ9 and GAD7 respectively.

But anyway, there is often an in--

the ADAM questionnaire-- and what you hear from the patient,

if you are a very careful listener, is often different.

ANDREW HUBERMAN: Can you give me an example

of some of the questions on this ADAM questionnaire

or the sorts of motivational interviewing that you might do?

So let's say I'm your patient.

I sit down.

What sorts of questions would you

ask to probe these kinds of dimensions of hormones?

KYLE GILLETT: Questions about libido,

questions about athletic performance,

questions about motivation.

And often, the patient will answer one thing,

but what you hear from them subjectively is far different.

ANDREW HUBERMAN: Interesting.

Can you give me an example of a question?

I'm happy to be the guinea pig here.

KYLE GILLETT: A classic one is, a guy comes in--

and a lot of times, they say, oh, no,

the wife made me go to the doctor.

I go once a year, that's it.

I don't want anything, I don't want any medications.

Their screening questionnaires might be zeros

across the board, so nothing.

No issues.

They're apparently in perfect health.

They talk to you for a while, they get some rapport,

they like you, and then right as you're finishing up the visit

and about to go out the room, they

mention that their libido isn't quite there,

and they're having a little bit of ED as well,

and perhaps they're even having some chest

pressure or tightness.

ANDREW HUBERMAN: I see.

So right as you're leaving the room,

a patient will tell you that they're having some sexual side

effects-- or not side effects.

They're having some sexual challenges,

and then they'll mention chest pressure.

Is the chest pressure a general decoy

for, it's got to be my heart, or is it

related to the other things that they're reporting?

KYLE GILLETT: It can be related.

In fact, erectile dysfunction is known

as the canary in the coal mine.

So coal miners would take the canary down, and it would--

the canary would die before the coal miners would

of, I believe, carbon monoxide poisoning.

And often, one of the causes of ED

is plaque buildup, which can happen in the coronaries

as well.

But sometimes, they notice the symptom in the genitals

before they do in the coronaries.

ANDREW HUBERMAN: So for such a patient,

let's say that patient was a young person where

plaque buildup in the arteries and veins

is not all that likely if they're, let's say,

in their 20s or 30s, what would be

your next step of the interview at that point, and what would

you consider?

Would you immediately order labs for that person

to try and rule out any kind of actual hormone level

deficiency?

KYLE GILLETT: I certainly would order labs.

There are some individuals that are very similar,

and they come in, and they have the same symptoms,

and one individual might have a very, very high testosterone,

and one individual might be severely hypogonadal.

So there's a big difference between the subjective

and what the labs look like.

So I certainly order labs.

You also ask them about if it's situational or not,

you ask them if they have ED if they're--

you ask them about their habits.

You even ask about porn, and masturbation,

and all these issues.

And of course, that's between the doctor and the patient.

And depending on what they tell you,

you can often determine if there is a situational component--

some people call it psychogenic ED,

but I don't love the term psychogenic ED,

because it kind of puts some blame on the patient's mind.

But a lot of the time, that is the case.

There is even a test.

And this is very rarely ordered, but it's called

a nocturnal penile tumescence.

ANDREW HUBERMAN: Now, is it true that there

are periodic erections during sleep-- correct?

KYLE GILLETT: Yes.

So you basically put a cuff to see

if you were having a normal sized erection during sleep.

And I believe about 90% of the time they do that test,

they are indeed having erections.

ANDREW HUBERMAN: Which would point

to this psychogenic origin of whatever

challenges they're having in terms of sexual interactions.

You mentioned porn and masturbation.

This topic has come up a bunch of times on this podcast

and on other podcasts I've gone on

because of the relationship between dopamine sexual

motivation and sexual behavior.

And I've been of the pretty strong stance

that, while I'm not judging porn or masturbation,

it can create a brain wiring situation where

males in particular essentially teach their brain

to be aroused by watching other people have sex as opposed

to being the first person actor in sexual interactions.

So in that sense, that's more about the brain wiring,

and neuroplasticity, and dopamine.

But what are your thoughts on porn and masturbation

as they relate to hormones?

I mean, this is a big debate on the internet.

In fact, one of the most common debates

is whether or not masturbation increases or decreases

testosterone in males.

Certainly, it will decrease motivation

to go find sexual partners.

We know this.

KYLE GILLETT: Yes.

ANDREW HUBERMAN: And there are more and more data on this

all the time.

In terms of the effects of pornography and masturbation--

and here, I suppose we need to be somewhat specific

and operationally define what we're talking about.

We're talking about porn and masturbation

to the point of ejaculation, because my understanding

is that the ejaculation and orgasm associated with

causes an increase in prolactin, which blunts

libido for some period of time.

The duration of that will vary from person to person

and circumstance to circumstance.

But basically, all of this points to the fact

that porn and masturbation can really

limit libido in the real world.

And to me, pornography and the screen is not the real world.

Although screens exist in the real world,

the real world doesn't exist in the screen.

KYLE GILLETT: That's an accurate statement,

and prolactin does have a significant acute increase

after ejaculation.

It does to some degree after orgasm as well,

but prolactin acts on the pituitary

to inhibit the release of the hormones LH and FSH,

of which LH can increase testosterone.

So this may be one of the cases where

the dose makes the poison.

And if it is a very frequent habit,

certainly daily or more than once a day

would be very detrimental from a hormonal component not even

taking into account the neural wiring.

ANDREW HUBERMAN: Listen, I think it's terrific

that you've actually defined frequency,

because this is the problem on the internet or even

in the doctor's office.

You'll see descriptions about pornography

being dangerous for certain things

or detrimental to hormones.

People say frequent, but what's frequent?

So you're saying daily or multiple times per day

would be potentially detrimental to the hormone

profile of a male of essentially any age.

KYLE GILLETT: And that's just for masturbation.

With pornography-- with porn use as well,

it would likely be worse.

ANDREW HUBERMAN: And why is that?

Just the sort of dopaminergic drive

of the stimulus-- just the really intense visual stimulus?

KYLE GILLETT: Dopamine sensitivity.

I think that using the analogy of a dopamine wave pool,

it would deepen the pool, but not increase

your supply of dopamine.

ANDREW HUBERMAN: Maybe you could describe the dopamine wave pool

because I think it's such a powerful way of thinking

about dopamine and what dopamine does.

In fact, I've always credited you when I've done it,

but I've generally stolen your analogy of the dopamine wave

pool because it's so astute.

KYLE GILLETT: The dopamine wave pool

describes the natural variation of ups and downs

in your dopamine or your motivation.

And in the wave pool, depending on how high the peak is,

you often have a deeper trough.

So you do not want to high of a peak.

In addition, if your peak is very, very high--

for example, when you're using many substances like cocaine

or like amphetamines, your dopamine

can go so high that you lose almost all

the water from the wave pool, and then

when you crash from that, not only is the trough low,

you have less dopamine in the pool to begin with.

The dopamine receptor is extremely

sensitive, as is the Gaba receptor, which

is an inhibitory receptor, whereas dopamine is technically

a stimulant more related to adrenaline and noradrenaline.

The depth of the pool can change very quick.

So you want to have that happy medium where you're

fairly near the top, but you're not so near the top

that the depth of the pool is going to go down.

ANDREW HUBERMAN: So if I interpret that in the context

of this discussion about libido, sex, porn, and masturbation,

if somebody has a very intense sexual experience-- and here,

we're not necessarily talking about an intense orgasm--

we're talking about just a lot of intense visual, so very--

a lot of intense imagery, or auditory input, or both--

that is going to lead to a situation

where dopamine is going to be depleted afterwards.

A guest on this podcast before-- my colleague at Stanford, Dr.

Anna Lembke, who's an expert in addiction,

talked a bit about this-- the sort of seesawing.

Like, here, we're talking about a wave and a crashing

out of the water from the wave pool.

There, it was a seesawing from pleasure and pain.

There's going to be a longer and deeper period of lack

of pleasure following that.

And I think a lot of people think, oh, well, that's great.

They want the intense experience.

But if that intense experience is coming from pornography

and masturbation-- or I suppose coming from high adrenaline

activities, like life-risking parkour hanging off the side

of a building-- it inevitably is going to lead to depressive

episodes, low libido episodes that follow.

Is that right?

KYLE GILLETT: Correct-- in a similar physiologic way

to withdrawal from stimulants, like amphetamines.

ANDREW HUBERMAN: Now, is sex with a partner different?

Because there are many people who

are chasing more and more intense

experiences with a partner as opposed to through pornography

and masturbation.

Again, here, we're talking about all ages.

And I should always say, anytime we're talking about sex

with a partner, we're talking--

the four conditions that I always lay out on the Huberman

Lab podcast are that we're talking about consensual,

age appropriate, context appropriate, species

appropriate interactions.

KYLE GILLETT: Yeah, and this is also

a case where the dose makes the poison.

So if there's-- obviously, meeting all those criteria,

if they have one preference that, for both of them,

is a positive experience, then that is likely OK.

You're not going to be able to maintain dopamine

over a certain threshold for a long period of time,

so there very well may be a crash

from that experience as well.

And that crash may be different in one partner than the other.

ANDREW HUBERMAN: Interesting.

So I'll draw an analogy to food.

It would be like you don't have to serve the banquet meal seven

nights of the week, maybe just two.

Is that right?

And there are other delicious foods out there?

Can--

KYLE GILLETT: Yes--

ANDREW HUBERMAN: --we use that analogy?

KYLE GILLETT: --that is very reasonable.

I'm not trying to be PG-13.

I'm just trying to parsimony Occam's razor the ability

to describe a lot of things in a few words.

I'd like to return to the key things that people should do--

or I should say, the key things that men should

do to optimize their hormones.

So we talked about getting some movement,

getting some sunlight, getting quality social connection one

way or the other, avoid excessively frequent

masturbation and viewing pornography.

And for some people, zero might be the optimal number.

And I keep coming back to this--

KYLE GILLETT: For most people.

ANDREW HUBERMAN: --for most people.

Interesting.

I feel so fortunate to have grown

up prior to the availability of internet pornography.

I've never been a big consumer of pornography.

It's just not been my thing, but I

hear so often from males of all ages about their addiction

to it, their affliction by it.

It's really a serious issue, and that's

one of the reasons why I'm grateful that you're

willing to talk about this and your clinical experience

with these patients.

I'd like to take a quick break and acknowledge

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In terms of exercise, here's-- again,

it's a double-edged sword.

On the one hand, it's great to get exercise,

but I'm familiar with--

if I train an hour a day--

10 minutes of warm-up in 50 minutes

to an hour of weight training or 50 minutes

to an hour of cardio, I feel great,

especially if, once a week, I take a complete day off.

That's sort of my general schedule.

I'm also familiar with when I go out

for runs that are excessively long-- two hour runs or I spend

90 minutes in the gym to frequently,

I start to feel like garbage.

Everything suffers.

My sleep starts to suffer.

It doesn't matter how much I eat--

I don't seem to recover.

I don't feel well.

So I realize that recovery ability varies

between individuals, but what do you

think is a healthy, sustainable exercise regimen that anyone

can follow that will also support their hormone status?

KYLE GILLETT: For really vigorous exercise,

around three to four times a week

is very sustainable over a long period of time.

On top of that, you could add in 3 or four more instances

of less vigorous exercise.

ANDREW HUBERMAN: So for less vigorous,

would you mean zone two cardio where you can hold

a conversation, but beyond which you can't?

And for more vigorous you're thinking

weight training or high intensity interval type

training?

Is that right?

KYLE GILLETT: Correct.

You can also weight train and have some benefit even

at a low to moderate intensity.

If you think about weight training

where you have-- and it's not necessarily related

to the incidence of DOMS, which is Delayed Onset Muscle

soreness.

But if you weight train lazy or easy

from time to time-- obviously, you

want to weight train very heavy from time

to time as well because of more lean body mass growth.

But if you weight train lighter, you're

going to be able to do it more often,

and it can still help with the hypertrophy of collagen--

for example, in tendons and ligaments.

ANDREW HUBERMAN: So here, again, I'd

like to perhaps drill into this notion of intensity

and light weights because for me, some of the most

brutal workouts I've ever done were

in what I would consider a high repetition range--

15 to 50.

Actually, I went up to Oregon to watch the International Track

and Field Championships.

We went by to Cameron Haynes's place--

the Cameron Haynes-- and he and his trainer

put us through a workout that was

25 to 50 repetitions per set, and it was done in circuit,

and it was brutal.

So it was light--

I mean, those weights were nothing.

In some cases, it was body weight.

But the number of repetitions was brutal.

So when you say limiting intensity,

are you talking about limiting the number of sets to failure,

are you talking about really being

kind of a lazy bear in the gym?

I like to do that every once-- so a long rest,

that sort of thing.

What are your thoughts on that as it relates

to hormone optimization?

So I'll just mention-- and then I'll let you answer--

I feel best overall when I'm training for 10 minute warm-ups

and about 45 or 50 minutes of weight training,

where I'm pretty lazy between sets.

Two to three minute rests, training somewhere

in the 6 to 10 rep range, going to failure every once

in a while, but mostly getting that sort

of last rep before what I would think is failure.

No forced reps, that kind of thing.

And then jogging on the other days, nice and easy.

When I do that, I feel fantastic in all other dimensions

of life.

When I train more intensely than that,

even with lightweight, so faster cadence and lower rest,

I feel like garbage.

I get a headache, I'm kind of ornery, everything suffers.

So what are your thoughts on defining a optimal exercise

strategy for hormones.

I've never measured my hormones in those two

different contexts, but I have to imagine

that it's cortisol related.

KYLE GILLETT: When they study the effect of exercise,

specifically vigorous exercise, one area that's been studied

is vigorous exercise-- episodes lasting longer than an hour.

And they usually track it by a rating of perceived exertion,

which isn't perfect, and it's not extremely actionable,

but it's helpful for clinical science.

But the takeaway from that is, basically, do not--

it is not hormonally helpful to train, especially regularly

train, vigorously for longer than an hour.

ANDREW HUBERMAN: So I'm happy to hear that because it sounds

like for most people, that hour of work

is really the threshold.

I think this is important for people to hear,

especially males because I think with all

of the incredible examples out there of people like Cam,

like David Goggins, people who are training

for very long periods of time--

and leaving aside all issues of what people are doing in order

to optimize the recovery, I think an hour a day of exercise

is just a great program that most anyone can follow.

And beyond an hour, you start running into challenges.

And the occasional 90-minute or two hour workout

is no big deal.

But if you start doing that more than once every two months,

I think you're headed for trouble.

Have you seen that in people's blood work

and in their hormones?

Do you ever see people that are just

badly overtrained because they're just training

too hard and too often?

KYLE GILLETT: Yes.

When the blood work is particularly bad,

they're often in a large caloric deficit as well.

There's a synergistic effect between a caloric deficit.

Even if you're maintaining adequate protein intake,

you might not be maintaining adequate iron intake

or adequate vitamin D. And you're also just literally

in a caloric deficit.

Perhaps low carbs as well, very low free testosterone.

And they're simultaneously doing a lot of vigorous exercise.

ANDREW HUBERMAN: Interesting.

I often hear, and I'm starting to wonder whether or not,

some of the quicker-to-results nutrition tactics--

things like dropping all carbohydrates,

or the quicker-to-results exercise habits,

like starting to do six day a week really intense

workouts-- whether or not, in the short run,

they work because they cause the cosmetic changes that people

are seeking, but that they really undermine

the overall goal, which is, at least to me,

to have your hormones Maybe. not optimized to 100%,

but to always be aiming for 100% and be close to it

at every stage of life.

KYLE GILLETT: Consistency is key here.

If you are not consistent, then the law

of diminishing returns certainly applies.

So 80% or 90% of the benefit over many, many months

is far better than 100%, but only half the time.

ANDREW HUBERMAN: Yeah.

One thing that I found to be tremendously useful

is to finish the workout while I still have energy, to not take

myself to exhaustion.

And then I'm able to talk about the dopamine wave pool.

I'm able to sort of ride that into the rest

of the day feeling great.

I sort of save or bank some of the vigor from the training

to bring it into my work.

But then again, I'm not an athlete.

I get paid to think and to speak, not to lift weights

or to run.

KYLE GILLETT: Another component of that

is the balance between your sympathetic,

which is your fight or flight nervous system,

and your parasympathetic, which is your rest or digest

nervous system.

There is an anecdote, which is likely true,

that many elite bodybuilders are very

parasympathetic besides while they're lifting weights.

ANDREW HUBERMAN: You mean they're lazy

and they like to eat a lot.

KYLE GILLETT: Yeah.

ANDREW HUBERMAN: The lazy bear in the gym kind of phenomenon.

KYLE GILLETT: Absolutely.

But that being said, after a very, very vigorous workout--

for example, one where you're trained to failure,

which bodybuilders and power lifters do all the time--

you feel the tiredness-- or you feel the strain

from that heavy sympathetic activity

when you are lifting a heavy weight,

and it can potentially affect how

you feel the rest of the day.

So many people who have a job where that is highly cognitive

do not like to have an extremely vigorous workout

in the morning, which is when a lot of people

are able to exercise.

ANDREW HUBERMAN: When I exercise early in the morning-- that is,

before 9:00 AM--

I have more energy all day long.

If I do it mid-morning, I have experienced

more of an afternoon crash.

There's probably some circadian biology in there.

I also noticed-- and I've actually seen in my bloodwork--

that if I don't get out for a 45-minute jog

at least once a week, all of my blood profiles

suffer in a direction that I don't want them to go.

In particular, testosterone and estrogen move in directions

that are not conducive to my goals.

I'd like to talk about some of the approaches

that people can use in order to optimize hormones.

And these days, for better or for worse--

I think for worse--

younger guys are asking about and using

testosterone replacement therapy-- so-called TRT.

And I just want to frame this up by saying

there is no strict cutoff for what is TRT.

There are plenty of people whose blood levels of testosterone

and estrogen are within the normal reference range

and decide to start doing these things.

Of course, they can limit fertility.

There are a bunch of issues even at non, quote,

unquote, steroidal performance enhancing dosages.

I'd love to frame this up by first defining our terms,

because one of the challenges on the internet

is people talk about TRT, then they'll

talk about performance enhancing drugs,

they'll talk about steroids.

They're all steroids.

I mean, testosterone, estrogen are both steroid hormones.

But what one considers replacement therapy

versus what one considers performance enhancing

is going to depend.

So here's my question.

Why in the world--

[EMPHASIS] why in the world--

would any male in his teens or twenties, or even 30s,

whose blood levels of testosterone and estrogen

are at the appropriate levels, meaning

within the normal reference range,

take exogenous testosterone given all the negative effects

on fertility, some of the challenges that it

can present if the dosages aren't quite right, et cetera.

Why would they do that, certainly

if they are not being paid for a particular endeavor,

like they're not making money?

If they are playing a sport, chances

are they're not allowed to do that anyway.

It's on the banned substances list.

So to me, it just seems like a crazy idea.

But then again, I'm of a generation

that really hasn't thought about doing that stuff until people

were in their 40s and 50s or even never.

So is there ever a case for somebody in their 20s or 30s

to take testosterone if their blood levels are

within the 300 to 900 nanograms per deciliter reference range?

KYLE GILLETT: Not many cases.

The reason for any performance enhancing drug, whether or not

it is a steroid, synthetic, bioidentical, or otherwise,

varies a lot.

Some individuals do it only for cosmetic reasons

even if it can have deleterious effects

on the cosmetic appearance, for example,

of your skin in the long run.

But everyone has their different reasons.

As far as like when does the benefit

outweigh the detriment, not very often if you're in your 20s

and certainly--

probably-- almost hardly never.

There's always rare cases, like Coleman syndrome and whatnot,

but almost never if you're very young.

ANDREW HUBERMAN: So for people in their 20s, 30s, and beyond--

40s, et cetera-- whose testosterone and estrogen

levels are at the appropriate ratios,

and then within the normal reference range,

and they feel pretty good--

[CHUCKLES] we talked about the ADAMs exam-- or this sort

of like feel-pretty-good is code for libido, energy, recovery,

et cetera, and are feeling at least

workable for their lifestyle.

For those people, what can they do

besides get great sleep, train, but not too hard or too often,

et cetera, et cetera?

What are some of the things in the realm of supplementation

that can help them optimize their testosterone and estrogen

without suppressing their own endogenous production

of testosterone and estrogen?

KYLE GILLETT: Let's mention creatine is the first one.

Creatine is interesting because it

has multiple different effects.

It helps with amino acid synthesis.

It also helps with oxidative stress.

It can also serve as the backup fuel

tank for your mitochondria, so holding backup ATP.

And it does slightly increase total testosterone,

and it also increases the conversion of testosterone

to dihydrotestosterone, so potentially it's

especially useful in men in even their teenage years

and their 20s.

ANDREW HUBERMAN: You mentioned the conversion of testosterone

to dihydrotestosterone, and there is mythology out there

that creatine can increase hair loss,

I'm guessing because there's at least one study showing

that creatine can increase DHT--

dihydrotestosterone.

And DHT is one of the primary hormones that can

promote male pattern baldness.

So the question therefore is, does creatine supplementation

increase the rate of hair loss?

KYLE GILLETT: Theoretically, it can, but in each individual,

preventing hair loss is a very poor reason

to take creatine, because it's not

going to take you to a supraphysiologic level,

it's not going to increase your androgens

to a unnormal level of binding.

So I feel like this--

if that was a reason to not take creatine for hair loss,

then that's--

ANDREW HUBERMAN: You mean-- sorry--

hair loss is not a reason to avoid taking creatine?

KYLE GILLETT: Correct.

Hair loss is not a reason to avoid taking creatine.

Think of it as just bringing you to what you

are naturally inclined to have.

If your conversion of testosterone to DHT

is already high, then often, creatine does not affect this.

It just kind of resets your balance

between testosterone being aromatized to estrogen

or being 5-alpha reduced DHT.

So it's not going to speed up hair loss more than just

naturally being a male does.

So in some individuals, it will have no effect.

In some individuals-- for whatever reason,

they have almost no 5-alpha reductase activity--

it will return them to natural or normal.

ANDREW HUBERMAN: I see.

Well, I take 5 grams a day of creatine monohydrate.

I do it for the tissue volumizing

effects, so for exercise benefits,

but also for the cognitive effects.

I don't know if it's increasing my hair loss.

I mean, I've got a little bit of widow's peak type hair loss.

That's where it is for me.

I suppose beard growth is associated with DHT too.

Is that right?

KYLE GILLETT: Yes

ANDREW HUBERMAN: What I learned--

but then again I haven't been into those literature

in a long time-- is that because of differences in receptors,

that DHT causes hair growth on the face and hair

loss on the head.

Is that right?

KYLE GILLETT: Yes, and the amount,

and the sensitivity, and density of those receptors

is genetically determined.

ANDREW HUBERMAN: And is it true that if your mother's father

was bald that you will be bald in the same pattern,

and if he wasn't, you won't?

KYLE GILLETT: That is a decent correlation.

Part of the proposed mechanism of this-- well,

there are several genes, and you can actually

test your genes for hair loss.

You do get a decent amount of them from your mother.

The unique thing you get from your mother

that she may have gotten from her father--

that she got one of the copies from her father--

is your X chromosome.

And the androgen receptor gene is on your X chromosome,

so all men got their androgen receptor

gene from their mother.

ANDREW HUBERMAN: It's on their X chromosome,

not on the Y chromosome.

KYLE GILLETT: Correct.

ANDREW HUBERMAN: Interesting.

Even though all of the, quote, unquote,

male promoting genes are on the Y chromosome, like malaria,

and inhibiting, et cetera.

Interesting.

So 5 grams a day of creatine for most people should be fine.

Beneficial for tissue volumizing-- so strength,

bringing water into the muscles--

and for the cognitive effects.

And the clinical support for creatine, I think,

is quite strong at the 5 gram per day dosage.

What other sorts of supplements can people benefit from?

We already talked about the omegas

and making sure that people are getting enough prebiotic fiber

to support the gut microbiome and vitamin D.

So what other supplement-based tools can people consider?

KYLE GILLETT: Another one we can loop in with creatine

is betaine.

Some people are nonresponders to creatine,

so you can increase that to 10 grams,

or you can use its cousin betaine

to help with amino acid synthesis

and shunting of energy.

Along with that, I would put l-carnitine which is actually

the smallest peptide hormone.

It's just two amino acids that are put together, so it's a--

ANDREW HUBERMAN: It's a hormone?

Interesting.

I'm not challenging it.

KYLE GILLETT: Well, peptide.

ANDREW HUBERMAN: I'm just--

I'm not challenging it.

KYLE GILLETT: I would call it a peptide more than a hormone.

So I would not call l-carnitine a hormone,

but I would call dopamine a hormone.

ANDREW HUBERMAN: Yeah, I could-- a neurohormone.

It's so hard to define things as transmitters or hormones

at some level.

I agree.

So l-carnitine-- actually, I should backtrack.

Betaine-- do you recall what dosage people typically

would take if they're a creatine non-responder?

KYLE GILLETT: 1 to 3 grams.

ANDREW HUBERMAN: Per day?

KYLE GILLETT: In fact--

yeah-- several versions of creatine

have betaine mixed in because it helps with the processing

of methionine and homocysteine.

ANDREW HUBERMAN: So if somebody is already taking creatine

and likes it and responds to it--

I'll raise my hand-- such as myself,

would adding betaine help or is it redundant with creatine?

KYLE GILLETT: Only if their homocysteine

is persistently elevated.

And homocysteine is kind of like an inflammatory marker that

can build up if you're not converting enough of it

down stream.

ANDREW HUBERMAN: How would I know?

KYLE GILLETT: Just a blood test or if you

knew your MTHFR polymorphism, which

is basically how you add methyl groups

to many things in the body.

ANDREW HUBERMAN: Great.

Any side effects of betaine that people should be aware of?

KYLE GILLETT: Not that I know of.

ANDREW HUBERMAN: People can look it up on-- examine.com

is a great site for that.

They'll surely list it.

They just revamped their site by the way,

and it was awesome before, and it's platinum now.

So l-carnitine-- what are the ways to take l-carnitine?

I know that there is oral forms in capsules

and there's injectables.

The injectables, I think you need a prescription.

Is that right?

KYLE GILLETT: Correct.

You need a prescription for the injectables,

or you should really get a prescription

for the injectables.

For when you inject it--

of course, at the supervision of your doctor--

it's usually done intramuscularly.

It's an aqueous solution, so it does not

have an oil or a carrier oil in it

like TR-- like testosterone esters do.

However, if you inject it too superficially,

it's not going to make or break anything.

Often, it just burns if you inject it subcutaneously

and it does not disseminate throughout the body as well.

L-carnitine potentially has localized effects

if you inject it.

If you ingest it orally, then it has a very low

bioavailability-- maybe only 10%.

ANDREW HUBERMAN: Well, I think most people are

going to be able to get l-carnitine only--

or in its capsule form.

So what are the dosages of l-carnitine

that one needs to ingest then if they

want to get a benefit because if only 10% is being absorbed,

it's probably a lot of l-carnitine.

How much should people take per day?

KYLE GILLETT: Usually, I recommend

for oral l-carnitine between 1,000 milligrams

and up to 4,000 or 5,000 milligrams.

ANDREW HUBERMAN: So 1 to 4-- maybe even 5 grams.

KYLE GILLETT: Correct.

Up to 5 grams a day.

If you're on that much, especially

if you have a dysregulated gut microbiome,

you should be concerned with TMAO

which is a potential carcinogen that both carnitine

and choline can convert into.

And your gut microbiota determine

how much that happens.

ANDREW HUBERMAN: Is it true that I

can offset any negative effects of alpha GPC--

choline that is-- and l-carnitine that I

take by ingesting garlic?

Is that right?

KYLE GILLETT: There's a compound in garlic called allicin--

I believe it's A-L-L-I-C-I-N. It's also part

of the scientific name-- the genus of types of garlic.

And this can help decrease the conversion to TMAO.

Berberine actually slightly decreases the conversion

to TMAO as well probably through alteration

of the gut microbiome.

And then just optimizing your gut microbiome

can decrease conversion.

So not everyone needs allicin, but it's something

that you should certainly consider

if you were on a high dose.

ANDREW HUBERMAN: I'm going to continue

to take the 600 milligrams of garlic every time

I take my l-carnitine, but I'm going

to skip the berberine because berberine gives me

brutal headaches and it makes me crave carbohydrates because it

drops my blood sugar.

KYLE GILLETT: It has many other effects, including the dawn

phenomenon where it drops your blood

sugar when you're sleeping and you can't even realize it.

ANDREW HUBERMAN: I am not a fan of berberine,

and I'm sorry for those of you that are.

I'm not trying to offend anyone, although frankly,

if you're being offended by my stance on berberine,

then maybe we should have another discussion.

In any case injectable l-carnitine,

if one can get that through a doctor, how much is absorbed

and how much should one take?

KYLE GILLETT: Almost all of it's absorbed.

In general you're taking between 500 milligrams up to--

you can take a pretty high dose up to 2,000 milligrams.

ANDREW HUBERMAN: And what we did not talk about

is what l-carnitine does?

So why should why should someone go through all of this?

Is it to optimize testosterone, is it

working on the receptor side?

What's l-carnitine doing?

KYLE GILLETT: It's a shuttle.

So I think it's named carnitine palmitoyl coenzyme

A. Basically, it just takes nutrients

from outside your mitochondria and puts them in.

It also has a unique effect--

well, not too unique because tadalafil actually

has this effect as well--

is that it increases the density of the androgen receptor

and the cytoplasm of your cells.

So even if your androgen receptor sensitivity

doesn't change and even if your testosterone does not change,

you will have more testosterone binding to that increased

number of receptors.

ANDREW HUBERMAN: Does one need to cycle

l-carnitine, creatine, betaine?

KYLE GILLETT: No reason to cycle any of those.

ANDREW HUBERMAN: What other supplements

can one use to try and improve hormone profiles?

And here, I realize we're using a very broad brush

because when we say improve hormone profiles,

what are we really talking about?

And for me, at least, I think about the subjective stuff.

Do people feel like they are going

to have more energy as a consequence of doing

these things, are they going to have the more optimized libido,

or are they going to have more optimized recovery

from exercise?

Because, I mean, it's not clear to me

that taking one's testosterone from 600 to 800

is always going to be a good thing, especially if estrogen

is increasing in parallel.

That could cause issues.

It could certainly make things better.

It could certainly make things worse.

So with that backdrop, what are some of the other things

people can take?

And then we'll go back to this issue

of what really is optimization.

KYLE GILLETT: Let's briefly mention vitamin D,

which is also a hormone.

It's actually a sterile hormone.

And if you have deficient vitamin D and you replace it,

then you will optimize your testosterone.

Let's also mention boron.

So if you have a very high SHBG, boron

can acutely help lower it usually in a dose

of 5 to 12 milligrams per day.

It's not really a sustained effect,

but boron is depleted in soils in many countries.

I believe it's very high in soils in Greece and Turkey.

So eating dates or raisins that are from those areas

potentially have more boron.

Boron also might be one of the reasons

why the reference range for testosterone

is much higher in those countries than other countries.

ANDREW HUBERMAN: And just to remind people,

that SHBG sex hormone binding globulin

is attaching to the testosterone molecule

and limiting the amount of so-called free testosterone

that's available to have its impact on cells.

When Dr. Peter Attia was on this podcast--

in fact, sitting in that very chair--

he said that the ideal level of free testosterone in males

should be about 2% of one's total testosterone.

Would you agree with that number or disagree?

I'm sure Peter would be fine if you said either.

[CHUCKLES]

KYLE GILLETT: 2% is a good rule of thumb.

Usually, the reference range is between about 1% and 4%.

Some people do have genetic polymorphisms

in SHBG, a specific gene mutation where

they have very low SHBGs.

Also men that have varicose veins in their testes,

also known as varicoceles, tend to have very high SHBGs,

so that percentage would likely be less than 2%.

So just because your percentage of free T to total T

is a little bit above or below 2%, that's OK.

We just need to figure out the reason why it is.

ANDREW HUBERMAN: How would somebody

know if they have varicose veins in their testicles,

especially if their testicles are still in--

attached to their body?

KYLE GILLETT: Sometimes, it's hard to tell.

There are several grades.

If you have a grade 3 or a grade 4 varicocele,

it has what's called a bag of worms appearance.

So think about if you've just resistance trained,

or it's a really hot day, or you're

wearing very tight fitting clothing,

then if you feel it and almost feels like there's

worms in the scrotum.

The other way is to do--

ANDREW HUBERMAN: That's a scary visual.

KYLE GILLETT: --yeah, bag of worms.

ANDREW HUBERMAN: Well, it was just that-- yeah, anyway.

I think parasites when I hear that,

but that's not what you're referring to.

You're talking about just the texture.

KYLE GILLETT: The best way for most people to check

is to valsalva for a long period of time.

When you valsalva, venous return will decrease.

ANDREW HUBERMAN: Can you explain valsalva for people?

KYLE GILLETT: It's bearing down like you're lifting a weight

or having a bowel movement, where you swallow.

And a lot of times, you can almost

see build up of blood in you're jugular veins as well.

So you have decreased blood return

to the heart and increased blood in the veins themselves.

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So vitamin D3--

I'm guessing you're talking about vitamin D3

specifically when you say vitamin D--

and then boron, 5 to 12 milligrams per day.

And then what are some of the other things

to optimize testosterone that are in supplement form?

KYLE GILLETT: We can talk about things that affect

the steroidogenesis cascade.

So we could touch on tongkat ali.

I know we've talked about that a little bit before--

ANDREW HUBERMAN: But I'm guessing a number of people

probably haven't heard that conversation.

KYLE GILLETT: Also known as Long Jack.

And that upregulates several different enzymes

in the steroidogenesis cascade.

And by that, what you mean if-- and this is another good thing

to Google--

I think anybody interested in hormone optimization

should understand where sterile hormones come from.

They come usually from cholesterol

and they can be shunted off to vitamin D very easily,

they can be shunted off to testosterone,

or estrogens, or progestins quite easily as well.

But tongkat helps with the conversion

of multiple key steps where you synthesize testosterone.

Another-- think of it as like a coenzyme or a cofactor--

an upregulator of these steps is insulin and IGF-1.

So a good rule of thumb is if you are not expecting as much

growth hormone, insulin, and IGF-1--

for example, lower carb diets, caloric deficits,

you're trying to cut body fat or body weight--

then tongkat is going to be theoretically especially

powerful.

ANDREW HUBERMAN: What sorts of dosages of tongkat

do you recommend to your patients?

KYLE GILLETT: Anywhere from 300 to 1,200 milligrams a day.

With tongkat, you need to be careful with

the standardization because--

and if you're thinking about a general tongkat supplement,

which is by far the most well-studied--

then you're looking at the eurycomanone content, which

is a plant compound that is likely

the main active pharmacologic effect.

So that's the compound that's having the effect on the body.

And if you standardize the eurycomanone very, very high,

then theoretically you're having more effect at a lower dose.

ANDREW HUBERMAN: I take 400 milligrams

of tongkat ali per day.

I take it early in the day because it

has a bit of a stimulant effect, and if I take it after 2:00 PM,

it starts to inhibit my sleep.

I've been taking it for years.

And I rather like that the effects.

It seems subtle but consistent.

I've never cycled it.

Do you recommend cycling it?

KYLE GILLETT: I don't see any reason to cycle it.

There is a reason to cycle some supplements,

but no reason to cycle tongkat.

ANDREW HUBERMAN: My blood work tells me

that it causes an increase in free testosterone for me

and also a slight increase in luteinizing hormone for me.

What are some of the other effects on various hormones

that you've observed in the bloodwork of your patients

taking tongkat ali?

KYLE GILLETT: Tongkat can also slightly increase DHEA.

And if you have a very high SHBG--

again, that's the protein that binds up your androgens

and estrogens-- an extremely important protein--

the higher your SHBG, the more it helps decrease it.

So they've studied tongkat in populations

with very normal SHBGs and it does nothing for SHBG.

ANDREW HUBERMAN: Interesting.

Does that mean it does nothing for somebody overall?

So if somebody has an SHBG that's in the normal range,

will taking tongkat benefit them in any other way?

KYLE GILLETT: Yes, it'll increase their total and free

testosterone.

ANDREW HUBERMAN: Got it.

Does it-- is it known to have effects on anything

else like thyroid hormone, growth hormone,

or is it purely in these steroid synthesis pathways?

Or steroid-- I should say synthesis, and receptor,

and modulation pathways.

KYLE GILLETT: There's no direct effect on those pathways.

However, any time you alter your free androgen or free estrogen,

particularly one without altering the other,

it will alter the binding protein

that binds thyroid hormones.

So any change you make, whether it's

natural optimization or hormone replacement,

you're going to slightly skew your thyroid hormone profile.

One common actionable example of this that I see often

clinically is someone starts, let's say,

estrogen replacement or testosterone replacement--

maybe they're taking an AI with their testosterone

replacement--

ANDREW HUBERMAN: Aromatase inhibitor?

KYLE GILLETT: Correct, an aromatase inhibitor,

which blocks the conversion to estrogen.

If they're taking testosterone and they have

very little estrogen, then you're

going to decrease the binding protein, also known

as thyroxine binding globulin, which binds active thyroid

hormones.

So if you start TRT and you either

have low aromatase activity or no aromatase activity--

no conversion to estrogen-- then your free thyroid hormones

will go up.

Even just acutely, usually feedback inhibition,

which is how the body talks to itself and says,

we need to make more of this or less of this.

But acutely, there's not always enough time.

You're going to have very high thyroid hormones

and you can have tachycardia, which is a fast heart rate

or you can feel kind of like overly fight

or flight due to increased thyroid hormone

activity in the in tissue.

ANDREW HUBERMAN: Interesting.

So tongkat ali-- just a broad range--

300 to 1,200 milligrams per day.

And I realize that the source matters there.

What are some of the other hormones

that you prescribe to your patients who do not

want to go on testosterone replacement therapy

or take exogenous DHEA or anything like that?

KYLE GILLETT: We can talk about fadogia next.

Fadogia is interesting because-- it's a genus of plants.

Fadogia agrestis is one of them.

There's many others that are very interesting.

That species is likely the most well-studied,

and it will increase LH, so I would not

consider it an LH mimetic, so it doesn't really mimetic.

But it increases the release of luteinizing hormone

from the pituitary.

That's a hormone that binds to the Leydig cell

to the LH receptor kind of like hCG does.

And it will increase the release of testosterone.

ANDREW HUBERMAN: I see.

So I think for people who aren't familiar with hCG--

so human chorionic gonadotropin--

is basically synthetic luteinizing hormone

and luteinizing hormone is the hormone

released from the pituitary that is

going to travel down to the testes

to stimulate the production of sperm and testosterone,

but mainly testosterone.

Is that correct?

KYLE GILLETT: Mostly correct.

Technically, synthetic LH is also

known as little r LH, or recombinant LH.

And hCG can be synthetic, but often, it

is just refined from the urine of pregnant ladies

since the placenta makes it.

That's why it's called chorionic gonadotropin.

ANDREW HUBERMAN: So where are they

getting all this pregnant women's urine?

I mean, there a location?

I mean, not that I want to go there, I just--

KYLE GILLETT: Donation?

ANDREW HUBERMAN: --really-- so there are women that--

KYLE GILLETT: First trimester pregnant ladies.

It's very high.

ANDREW HUBERMAN: Donating their urine,

and then they're purifying it, and then men are injecting it?

KYLE GILLETT: Yes.

ANDREW HUBERMAN: Wow.

KYLE GILLETT: And that's actually

the same for menopausal ladies.

So first trimester pregnant ladies,

that's how you can make non-synthetic hCG.

And then for menotropins which are also known--

there's a couple of different names for it, like menopur.

You have menopausal ladies that have very high LH and FSH,

and then you refine the FSH and LH.

ANDREW HUBERMAN: So moving away from the sources

and from urine, Fadogia agrestis, what dosages

do you have patients take?

I've heard of some potential toxicity

to the testicular cells.

KYLE GILLETT: There is one study--

and this is a rat study, but you can equate the dose of toxicity

in rats and humans.

They did not give these rats any antioxidants,

but it increases a couple of different proinflammatory

markers.

One is GGT, or gamma glutamate transferase.

It comes from both the testes and the liver,

and one is alkaline phosphatase, also known as Alkphos, again,

coming from both areas.

There are several different ways that you

can attenuate this increase.

And you can also just check to see if you have increased.

In the rat dose that equates with humans that had no

effect-- so the safe dose--

was an average of 300 milligrams a day.

ANDREW HUBERMAN: So that would be 300 milligrams a day

in humans is the dosage that did not have toxicity.

Correct?

KYLE GILLETT: Correct.

And often, even if there is toxicity in rats,

there is not toxicity in humans.

So it's not directly equitable, but to be safe,

another regimen that I have people take is 600 milligrams

every other day or 600 milligrams

three times a week-- often Monday, Wednesday, Friday.

ANDREW HUBERMAN: This is very interesting and relevant,

because I've been taking fadogia for some period of time.

All my markers and tests indicate

that there's no toxicity.

But I've been taking 600 milligrams per day,

but I've been cycling it for about 8 to 12 weeks on and then

a few weeks off.

But based on what you're saying, I'm

thinking maybe three times per week or every other day

might be better.

Is that right?

KYLE GILLETT: If you weren't going to get any labs,

that is certainly the regimen that you want.

If you're going to check your GGT and ALK phos,

or even take other things to prevent those from increasing,

then you can certainly be more aggressive with your fadogia

dosing.

You can increase it quite a bit, and it

has a dose dependent response in both the activities associated

with high testosterone and also just LH and testosterone.

So the more aggressive regimen would

be 600 milligrams daily for a month

and then take one to two weeks off.

ANDREW HUBERMAN: Great.

I think that's more or less what I've been doing.

Terrific.

In terms of other hormones, what are

some of the supplements that can support growth hormone--

a hormone that's associated with tissue

repair and, in some cases, metabolism and fat loss?

What are some of the tools, nutritional and/or

supplement-based, one can do to tap on the growth hormone

pathway?

And let's lump IGF-1 in there too

since they're essentially working

along the same dimensions.

KYLE GILLETT: A quick synopsis-- growth hormone

is a peptide hormone, and it is released by the pituitary.

There's growth hormone releasing hormone and ghrelin

that stimulate the release.

So there's also peptides that are very analogous to these two

things.

You have that pulsatile secretion

of growth hormone in a very fast half life of just minutes,

and then it increases IGF-1.

There is both peripheral IGF-1 and central IGF-1 and IGF2,

but no need to get into the specifics.

There is a happy medium to where your growth hormone is

at an adequate level and your IGF-1 is an adequate level.

Usually, those two are congruent.

So in most cases, we just check an IGF-1 and, occasionally,

the binding peptides for IGF-1 kind

of like SHBG that we talked about earlier,

but you're estimating a free IGF-1.

It's kind of confusing because all hormone--

almost all hormones have binding proteins to help regulate them.

But often, you want to look at free testosterone,

free estradiol, free IGF-1--

or at least estimate it-- free cortisol even,

and free thyroid hormone.

But when you're talking about growth hormone and IGF-1,

usually you don't need to do anything to optimize it.

If you are diabetic, then-- and depending

on the type of diabetes, your IGF-1 and growth hormone

can be too high.

Specifically, in type 1 diabetes,

your growth hormone is extremely high, but your IGF-1 is low.

So if you're in a dysregulated state or have pathology,

I would just talk to your doctor about IGF-1 or growth hormone.

Taking amino acids before you go to bed

could potentially help with growth hormone release

just because most growth hormone is released while you sleep.

ANDREW HUBERMAN: I've heard that fasting

can increase growth hormone.

And I know there are certain patterns of weight training

that can increase growth hormone.

Some of those regimens in the weight room

that increase growth hormone have been covered by Dr. Duncan

French, who was a guest on this podcast,

and so maybe we'll refer people to that episode

for the specific protocols-- these high volume training.

KYLE GILLETT: During those training exercises,

it usually does it transiently for a period of a few hours.

And a lot of this IGF-1 is released by the muscle itself.

So it's not necessarily released by the liver.

IGF-1 that is released directly due to growth hormone

signaling-- usually, the growth hormone comes from

the pituitary and binds to the liver where usually,

it has a half life of about a week,

where the paracrine or autocrine--

think of it as like the peripherally acting or acting

in the muscles itself, which is also helpful--

is released and is not as concerning because it's not

related to insulin resistance, but it is

related to the training itself.

ANDREW HUBERMAN: So fasting and growth hormone--

is it true that fasting can increase growth hormone?

And maybe as a little related tangent,

I've heard that limiting food intake for the two hours

before going to sleep can increase

the pulse of growth hormone that one experiences during sleep.

Of course, everyone gets a pulse of growth hormone during sleep,

but especially carbohydrate-laden meals

can blunt that peak that occurs during sleep quite

substantially.

So two questions-- does avoiding food intake in the two hours

prior to sleep help increase growth hormone release?

Maybe it's being overly neurotic.

Maybe people need to avoid food in the four hours before sleep.

But regardless, what is the relationship between fasting

and growth hormone release?

I find this really interesting.

KYLE GILLETT: Fasting certainly potently increases

growth hormone release.

However, the IND binding to the receptor is less sensitive.

So although fasting does increase growth hormone,

the genes that are downstream to it--

both the growth hormone genes and IGF-1

related gene transcription activity-- will not

be significantly higher.

However, if you are optimizing the growth hormone that

is released as a pulsatile secretion,

it is helpful to avoid eating for two hours.

So the general rule of thumb is avoid eating about two hours

before bed.

I think that's clinically significant and helpful.

But fasting otherwise specifically for growth hormone

optimization in someone who already

has normal growth hormone signaling is not helpful.

ANDREW HUBERMAN: That's extremely useful

to hear because one of the major reasons

why people fast is to get that growth hormone increase.

But if they're adjusting things on the backend that negate

that, well, then, no such luck.

Not that I have anything against fasting.

I do a pseudointermittent fasting mostly

because I prefer to eat at fairly regular times of day.

So it doesn't sound like there's a lot

that people can take in supplement form

to improve growth hormone.

What about thyroid hormone?

What are some of the things that people can take or do in order

to make sure that their thyroid hormone levels are appropriate?

KYLE GILLETT: You want to have a balance of iodine

and you want to have a good source of iodine.

So there are some camps that say you

should use a huge high dose of iodine

and there's protocols for it.

And there are some that say you should use just barely enough

iodine--

I believe it's like 200 micrograms per day.

But you want to balance.

One of the things that I see that many people do not

talk about when it comes to iodine and thyroid

is there's compounds known as goitrogens.

And these goitrogens are neither good nor evil,

but they're actually kind of a nice check and balance.

You need more iodine if you consume more goitrogens.

And some examples of these are some of my favorite foods--

cruciferous vegetables.

Boron is also a goitrogen. So higher goitrogens,

higher iodine.

ANDREW HUBERMAN: So ingesting iodine

containing salt is useful?

Yes or no?

KYLE GILLETT: Iodized salt does prevent goiter,

but it is not necessarily the ideal form of iodine.

Good forms of iodine often come from the ocean.

If you look at a chart of hypothyroidism,

there is a tendency to have more hypothyroidism the more

inland you go.

ANDREW HUBERMAN: So trying to eat some cruciferous vegetables

each day would be the best way to improve thyroid hormone.

KYLE GILLETT: Along with plenty of iodine.

You don't want too much iodine signaling.

Many people are familiar with radioactive iodine tablets,

and that's basically an extremely high amount of iodine

to block out the radioactive iodine that

comes from after like a nuclear meltdown or whatnot.

ANDREW HUBERMAN: So we've got creatine, betaine, l-carnitine,

with allicin garlic to offset the TMAO.

Vitamin D3, boron, tongkat ali, fadogia, some fasting.

I'd love to talk to you about peptides.

So I can imagine a hierarchy.

A hierarchy starts with behaviors and nutrition.

Behaviors, of course, includes training,

and limiting stress, and all the things we talked about before--

sunshine et cetera-- and optimize nutrition.

Then, we talked about supplements--

all the things we just listed off to optimize testosterone.

And we can get into this, but estrogen

as well, which is important for libido, and brain

function, and tissue function, and joints feeling good, et

cetera.

But then we get into the realm where one might, or could

consider, exogenous hormones.

Get-- taking a small dose of testosterone

or taking a small dose of GH even if that were appropriate

and certainly only working with a doctor.

But in between, there's a step of so-called peptides.

And of course, there are many peptides.

We've already talked about some of them.

But when people talk about taking peptides,

the ones that I hear most often about

is a category that increases GH and IGF-1,

and those to my knowledge go by the things like sermorelin sort

of a kit of things that are taken separately

or in combination to increase GH and IGF-1.

But then other people, for instance,

are taking peptides like BPC 157 to try and improve

tissue healing and recovery.

There's a lot of interest in peptides.

Please, if you would, tell us about what

you know about the safety of peptides

in terms of their sourcing and the utility of peptides.

Is this something that people should consider before thinking

about hormone replacement?

Should people be wary of these things?

I am very wary of particular sources that are

sold online that are not clean.

They contain contaminants and that could be dangerous.

I really would love your thoughts on peptides.

So I'm just going to sit back and let you riff on peptides,

but if you could touch on some of the ones that I mentioned,

I'd be most grateful.

KYLE GILLETT: A peptide is just a chain

of amino acids between two and a couple hundred in length.

So I think of peptides as several different categories.

And the GHRPs that you mentioned,

I would consider those--

and that stands for Growth Hormone Releasing Peptide.

You have two main types--

the ghrelin agonist that are-- or they hit the ghrelin

receptor, and it helps release growth hormone because of that.

And then also the GHRH-like peptides.

So they're very similar to growth hormone releasing

hormone.

Often, they just change a couple amino acids,

and it acts like that.

Tesamorelin is one of them, sermorelin is another one,

and CJC is another common one.

I believe those are all in the class of GHRH-like peptides,

whereas ipamorelin or ibutamoren, which is also

known as MK-677, those two are in the class of ghrelin

agonist.

So they're more like they hit the receptor

that ghrelin does whereas the other ones hit the GHRH

receptor.

ANDREW HUBERMAN: I think of ghrelin as making me hungry.

KYLE GILLETT: Hungry and angry.

ANDREW HUBERMAN: Why would I want

to take something that would increase ghrelin signaling?

KYLE GILLETT: Some people are trying to gain weight.

It also does increase your growth hormone.

So if your growth hormone is very low, you can consider it.

Ibutamoren is a long-acting-- so it has a long half life, also

known as MK-677.

It was well-- it was studied mostly

in growth hormone deficiency.

ANDREW HUBERMAN: And do these people get angry also?

KYLE GILLETT: They can.

Many people report a side effect of anxiety

or significant hunger.

Most people take it in the evening

so they don't notice that hunger as much.

It can also greatly increase your blood glucose.

So if you're insulin resistant or pre-diabetic,

it gets especially concerning.

ANDREW HUBERMAN: This is one of those rare moments where I hear

something and I think, even though there is this kit

of compounds that can increase GH and IGF-1,

based on everything you're telling me,

maybe just taking GH is the better option for those people,

because growth hormone, at least it's--

synthetic growth hormone is mimicking

an endogenous hormone.

I mean, certainly not taking anything might be the ideal.

But for those that want to increase growth hormone

and they want to use pharmacology

to do that, it sounds like these peptides are pretty precarious.

KYLE GILLETT: Yeah, it kind of depends on the situation.

If there's an individual that struggles with hunger

and not eating enough--

for example, someone who has a very small stomach or they

just have a very low hunger drive,

sometimes you want more of that orexigenic signaling.

The hypothalamus, you have anorexia signaling, which

is kind of like anorexia, and orexigenic signaling,

which is--

I call it the hangry center of the hypothalamus

or the hangry center.

And if there's an imbalance between those two, then

perhaps it'd be helpful.

Potentially theoretically helpful in anorexics, of which,

the incidence of anorexia in men is increasing significantly.

ANDREW HUBERMAN: As you're telling me this,

I'm remembering being 14 or 15 years old,

and I would go into the kitchen sometimes,

and I was so hungry I would just obliterate all the food.

And I do remember being--

I've always been a pretty high energy guy,

but having an immense amount of energy.

I can't recall if it was a hangry feeling or not,

but I'm guessing that was growth hormone.

I grew one foot in a single academic year,

so I imagine that was at least in part due to growth hormone.

In any case, sermorelin is the peptide

that I hear most often about.

I admittedly tried a run of it.

I was researching a book, and decided

to take it before sleep on an empty stomach.

It gave me a tremendous depth of sleep,

but that sleep was really truncated,

which is just nerd speak for saying deep but short sleep.

I would wake up after very intense dreams.

I can't say that it helped me recover from exercise that

much.

I didn't notice any additional fat loss or anything.

Sort of abandoned it except for occasional use.

Again, this was prescribed by a doctor.

I'm starting to get the sense that these peptides

and their effects are somewhat vague, and distributed,

and highly individual.

Is that a fair way to describe them?

KYLE GILLETT: Part of the problem

with the effect of peptides is many people take them

and levels that are far above the physiologic range.

Even individuals who are checking their IGF-1 while they

take these different GHRPs, most of them

do not check the binding peptides-- for example,

IGF binding peptide 1, 2, or 3.

And their free IGF-1 level might be significantly different.

So common doses that people will take these off-label

for as a supplement are often much greater

than the therapeutic or physiologic range.

ANDREW HUBERMAN: Which, for me, just underscores the fact

that it's pretty precarious.

I mean, I'm not coming in here as the referee of what

anyone should or shouldn't do.

I'm just trying to gather and distribute information.

But I've heard, for instance, that some companies where

people can acquire these things without prescription,

those companies are not good at cleaning out

the lipopolysaccharide-- the LPS--

which can cause an inflammatory response.

In other words, these are dirty compounds.

And that just sounds risky.

It just sounds-- frankly, it just

sounds really dangerous to me.

KYLE GILLETT: LPS is a common additive in many companies

that are not pharmacies, but they're

selling things that people often use as human consumption.

One interesting note about lipopolysaccharide

is your gut microbiome actually makes a lot of it as well,

especially prevotella which is a specific species, that

can have to do with your baseline body temperature.

So your baseline body temperature

might also change depending on if you're on a peptide that

has LPS in it.

ANDREW HUBERMAN: Yikes, yikes, and yikes.

[CHUCKLES] But I tend to be pretty conservative

when it comes to taking anything exogenous.

But I do rely on many of the supplements

that we talked about earlier and I do try and optimize

the behavioral things and nutritional things

for a long time.

So then leaving peptides behind, we

are now I suppose in the territory of exogenous hormone.

So let's say that somebody decides

they're not concerned with fertility,

or they're going to bank sperm, or they already have kids,

or they're going to defer on this issue of wanting

to have kids, my understanding is

that nowadays, a lot of people are using testosterone--

let's not even call it replacement

therapy, because some of these people have 600, 700,

or even 800 nanogram per deciliter read.

So they're not replacing anything that is diminished.

They're just trying to augment what's already there--

increase what's already there.

My understanding is that taking a low dose more frequently

is going to be more beneficial than the kind of old school

way of giving 100 or even 200 milligrams

in a single injection once every two weeks.

Is that right?

And what do you do with your patients?

So let me give you a hypothetical.

Somebody comes into your office, they do their blood work,

and they have blood levels of, let's say,

600 nanogram per deciliter testosterone.

Their estrogen is also in normal range.

Everything else checks out, but they're

complaining of slightly diminished libido, slightly

poor recovery from workouts, maybe reduced motivation

and drive, although no major depression.

And you come to the conclusion that testosterone therapy--

not replacement, but testosterone therapy

might be a good option to explore.

What's a typical dosage range and frequency

of administration range that you might consider exploring?

KYLE GILLETT: And some of this depends on the SHBG

and free testosterone as well.

So if that same individual had a very high SHBG which, again,

is the binding protein that binds up

the testosterone and all androgens and estrogens,

if it is extremely high and they have

a free testosterone of two, then they

might need a different dose because they

need enough testosterone in order

to have a normal eugonadal free testosterone.

But a general normal dosing range, especially for someone

starting, is around 100 to 120 milligrams

divided over the course of a week, usually

either every other day or three times a week-- occasionally,

twice a week.

Many people with SHBG a bit higher

can get away pretty easily with twice a week.

This is assuming that the ester is cypionate or enanthate.

ANDREW HUBERMAN: So two 60 milligram injections

of testosterone cypionate per week.

KYLE GILLETT: Yeah, very common dosing.

ANDREW HUBERMAN: To hit that 120 milligrams per week

is kind of the typical average.

KYLE GILLETT: Correct.

And I would consider this like a physiologic eugonadal dose.

For many people, even 200 milligrams a week

is far above the reference range.

All of this is said with the caveat

that testosterone is normally released in a pulsatile manner.

So it's high in the morning, low in the evening.

Whereas if you're on testosterone therapy,

then you're going to have a steady state.

So your testosterone level is going

to be pretty much the same even in the evening.

ANDREW HUBERMAN: And in your experience,

when patients do that, I'm guessing

they report that normal constellation

of positive effects--

improved mood, improved energy, improve sleep, recovery,

et cetera.

What are some of the hazards or things that

can crop up in bloodwork or just subjectively

that can be warning signs that even a dosage of 120

milligrams divided into these two or three dosages per week

is too high?

KYLE GILLETT: Every organ system in the body.

So this is when you really have to be

at least well-versed in every organ system, not just

the gonadal genital system.

You need to have dermatology prowess.

Acne is very common change.

Lots of different skin pathologies or even bruising

can be related to hormone replacement.

Hair loss is very common to see as well.

Mental status changes.

It could occasionally even induce

as a manic or a bipolar episode because testosterone is also

dopaminergic.

And then a cardiovascularly not just in the heart,

but also concerns for like microvascular ischemic disease.

Ferritin buildup because the estrogen also increases.

And then fertility concerns as well and lipid concerns too.

So you really have to be hematologist, dermatologist,

cardiologist, lipidologist, the whole 9 yards.

ANDREW HUBERMAN: So another reason--

or set of reasons rather to, if one

is considering using testosterone therapy,

to really do this in close communication

with a really good physician because that's

a lot to monitor.

Knowing whether or not you have acne or not is one thing,

but knowing whether or not your LDL is going up,

your ApoB is going up, that's a whole other biz

and that needs to be done through bloodwork

is what I'm hearing.

KYLE GILLETT: Correct.

And if your physician that is managing or prescribing

your testosterone therapy or your HRT

is not well-versed in these systems,

you would want him or her to be part

of an interdisciplinary team where

they have other experts that can monitor those systems.

ANDREW HUBERMAN: I skipped over a sort

of still intermediate set of things-- prescription drugs--

but maybe talking about testosterone

first was a bit of a mistake on my part

because I'm aware that there are-- actually,

I think there are companies, but certainly groups out there

that say, no, wait-- don't go straight from nothing

to supplements to testosterone.

Once you're doing behaviors and optimizing

nutrition supplements--

let's forget peptides-- instead of going straight

to testosterone therapy, one idea that many people are

pursuing is to take the prescription drugs that trigger

luteinizing hormones-- so taking hCG--

human chorionic gonadotropin, which my understanding is

will increase testosterone, but also estrogen.

Or they'll take things like clomiphene.

In fact, I think there are a bunch of companies out there

now that are saying don't take testosterone-- it shuts down

spermatogenesis, it shuts down testosterone production--

clomiphene is the way to go.

Maybe you could educate us about the hCG monotherapy,

I think it's called, where you're just mono-- one--

just taking hCG and clomiphene as a--

and/or clomiphene as a tool to ratchet up hormones.

KYLE GILLETT: So a quick points on hCG--

human chorionic gonadotropin-- made

during especially the first trimester of pregnancy,

it has effects other than binding to the LH receptor.

It also binds to the TSH receptor in the thyroid.

ANDREW HUBERMAN: So it's thyroid stimulating hormone?

KYLE GILLETT: Yes.

In fact, if you look at a molecule of hCG and thyroid

stimulating hormone, they are extremely similar.

However, you need a relatively high dose of hCG

to bind to the TSH receptor.

This is the normal mechanism in pregnancy

that accounts for the increased need of thyroid hormone--

usually, about 30% to 40%.

So that's why if someone has hypothyroidism,

you increase their dose of thyroid,

because the hCG is not going to be doing it for you.

The Clomid, or clomiphene, there's two main--

I believe it's diastereomers.

And one of them is enclomiphene and one of them

is zuclomiphene.

And these two work slightly differently.

Enclomiphene, I believe, has a faster half life

and it is potentially slightly better tolerated.

However, they were studying it--

Clomid is a very commonly prescribed drug,

and obviously, there is plenty of enclomiphene in Clomid.

However, the drug which was Andrew androxal--

A-N-D-R-O-X-A-L-- did not go all the way through the FDA

approval process despite Clomid being FDA approved.

ANDREW HUBERMAN: So there's Clomid

which contains clomiphene, but there are also--

because we're talking about male hormone optimization

this episode-- there are males out there

who want to increase their testosterone and other

hormones-- maybe growth hormone, et cetera-- who opt to not take

exogenous testosterone-- so no cream, no pellet, no pill,

no injectable cypionate-- but decide to take clomiphene

a couple of times a week.

My understanding-- I've never done this.

I would say if I had.

My understanding is that taking clomiphene--

maybe two 50 milligram tablets a week

is what I hear people are doing--

will increase what-- luteinizing hormone,

the various estrogen receptor subunits?

Could you explain how clomiphene would benefit anyone,

and is this a good strategy?

I'm hearing that it's being done quite a lot now.

KYLE GILLETT: It will increase testosterone

in a dose dependent manner, but it

has many other pharmacodynamic effects, which

is the effect of the drug on the body

other than its effect on the hypothalamus and the pituitary.

So in the hypothalamus and the pituitary,

it does what's called negative feedback inhibition or it

blocks the action of estrogen. So it crowds out estrogen

from the estrogen receptor on the hypothalamus

and the pituitary.

ANDREW HUBERMAN: And what's this objective effect

that would cause?

So to my understanding and experience of estrogen

is that if I ever took-- and I did

take a very low dose of an aromatase inhibitor once

and I felt terrible.

Actually reduced libido, joints felt achy.

That's when I discovered that, wow, estrogen is actually

really important for your brain function, for joint function,

and for libido.

And suppressing estrogen, for me, it just

turned out to be the wrong idea.

But my levels indicate that it's within reference range.

So why would I want to take something

that would increase the activity of an estrogen receptor?

I just can't find the rationale for that.

KYLE GILLETT: The main rationale behind taking

a serm is as a very temporary measure that is not