Essentials: Tools for Hormone Optimization in Males | Dr. Kyle Gillett

1. 0:00 – 0:20

   Kyle Gillett

   1. AHAndrew Huberman0:00

      Welcome to Huberman Lab Essentials, where we revisit past episodes for the most potent and actionable science-based tools for mental health, physical health, and performance. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. And now for my discussion with Dr. Kyle Gillett.

2. 0:20 – 2:17

   Male Hormone Optimization, Testosterone, Tool: Blood Tests

   1. AHAndrew Huberman0:20

      Dr. Gillett, great to have you back.

   2. KGDr. Kyle Gillett0:22

      Great to be back. Thank you.

   3. AHAndrew Huberman0:24

      I'd like to begin with a question about what all males ought to do in order to optimize their hormones. What should they be doing? What should they avoid doing if the goal is to have a long arc of healthy hormone optimization throughout the lifespan?

   4. KGDr. Kyle Gillett0:38

      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, you know, obviously you're a functioning human, but, uh, I would say there's still development, and I think that the, the human always develops. I don't think development ever ends, but you want to monitor that progress across a person's h- lifespan.

   5. AHAndrew Huberman1:09

      What do you think are the key things to look for in blood work? I mean, ev- testosterone is always the topic that comes up in the context-

   6. KGDr. Kyle Gillett1:15

      Mm-hmm

   7. AHAndrew Huberman1:15

      ... of male hormone optimization, but certainly there are a lot of other hormones that are important as well.

   8. KGDr. Kyle Gillett1:19

      Mm-hmm. And with testosterone, you want to get either testosterone and a SHBG or a free testosterone.

   9. AHAndrew Huberman1:25

      Could you define SHBG for our listeners, please?

   10. KGDr. Kyle Gillett1:27

       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 a balance between, um, a high enough free DHT and a high enough total DHT.

   11. AHAndrew Huberman2:05

       So assuming that there's no major intervention, how often do you recommend that people get their blood work done?

   12. KGDr. Kyle Gillett2:11

       Using shared decision-making with their physician, usually a good follow-up is about six months.

   13. AHAndrew Huberman2:16

       So

3. 2:17 – 5:36

   Diet & Hormone Health, Diary, Vitamin D, Fiber

   1. AHAndrew Huberman2:17

      on a daily basis, uh, maybe you could just take us through the arc of a day and, um, 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.

   2. KGDr. Kyle Gillett2:29

      I'll briefly touch on some of the lifestyle pillars to start. Diet and exercise are the first two. Um, in puberty, sleep is particularly important, of course. Um, but with diet and exercise, uh, 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.

   3. AHAndrew Huberman2:56

      And w- and just-

   4. KGDr. Kyle Gillett2:57

      Which is-

   5. AHAndrew Huberman2:58

      ... again, for our audience, maybe you just mention what IG- what having enough IGF-1 can do for us that's beneficial is.

   6. KGDr. Kyle Gillett3:03

      It helps you grow. It, uh, helps with, uh, genital development, secondary sexual characteristics, and long bone growth, um, skin growth, hair growth, a host of things.

   7. AHAndrew Huberman3:14

      So getting an array of nutrients that include dairy. What other sorts of nutrients are important during development?

   8. KGDr. Kyle Gillett3:20

      You want to have adequate vitamin D. Vitamin D helps with testosterone production. It helps, again, with bone mineralization and stature. Um, 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, uh, from the dietary standpoint, you want to have enough free estrogen, not too much when you're growing, but you want to help, um, basically stockpile bone to prevent a risk of osteoporosis or thin bones, fractures when you're older.

   9. AHAndrew Huberman3:57

      I realize that some of this relates to ethics and food allergies and things of that sort, but would you say that on balance that most people would benefit from eating a combination of, you know, 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, uh, pure vegan diet in their 20s and 30s?

   10. KGDr. Kyle Gillett4:23

       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.

   11. AHAndrew Huberman4:37

       Are there any other micronutrients or macronutrients that people in their 20s and 30s should emphasize?

   12. KGDr. Kyle Gillett4:42

       Fiber is going to be paramount in kind of like 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. Any fiber or food that you're putting in your gut, it's either going to... it's going to skew your gut microbiome towards something that is more beneficial or, or more detrimental.

   13. AHAndrew Huberman5:08

       And would you say that the prebiotic fiber and the getting essential fatty acids, uh, that would be important to do throughout the lifespan or just for people in their 20s and 30s?

   14. KGDr. Kyle Gillett5:18

       Throughout the lifespan. Um, particularly important in the teenage, 20s, 30s because that helps with brain development. Um, you're certainly more of an expert than me when it comes to, um, brain development, but it does continue to de- develop throu- really throughout the lifespan, but certainly through the 20s and 30s as

4. 5:36 – 6:44

   Caloric Restriction & Testosterone

   1. KGDr. Kyle Gillett5:36

      well.

   2. AHAndrew Huberman5:36

      In a previous discussion of ours, I asked you about, um, caloric restriction and testosterone, and if I recall correctly, the idea was that if somebody is overweight, they have excess fat, adipose tissue, then getting rid of some of that adipose tissue by-- 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, um, addendums to that, that you'd like to, to give us now?

   3. KGDr. Kyle Gillett6:13

      That's correct. Um, 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 cat- 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.

5. 6:44 – 7:56

   Lifestyle Pillars: Stress, Life Purpose

   1. AHAndrew Huberman6:44

      Now, what are some of the other pillars of creating a, the proper environment for hormone optimization?

   2. KGDr. Kyle Gillett6:49

      Uh, stress is probably the next one. Um, during, uh, 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, uh, it can put all the other lifestyle pillars and then they stop dieting well, um, they stop exercising, and everything else can go askew.

   3. AHAndrew Huberman7:18

      What would the, be some of the additional things that everybody should do?

   4. KGDr. Kyle Gillett7:21

      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.

   5. AHAndrew Huberman7:36

      The idea is not to pick the end goal, 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.

   6. KGDr. Kyle Gillett7:50

      Yeah.

   7. AHAndrew Huberman7:50

      But you, you, you actually can change your, your, your goals and purpose over time. I'd like

6. 7:56 – 8:59

   Exercise & Hormone Health

   1. AHAndrew Huberman7:56

      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. What do you think is a healthy, sustainable exercise regimen that anyone can follow that will also support their hormone status?

   2. KGDr. Kyle Gillett8:12

      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 three or four more instances of less vigorous exercise. When they study the effect of exercise, specifically vigorous exercise, um, one area that's been studied is, uh, 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... I- it is not hormonally helpful to train, especially regularly train, uh, vigorously for longer than an hour.

7. 8:59 – 10:32

   Testosterone Replacement Therapy (TRT) & Young Adults

   1. AHAndrew Huberman8:59

      These days, for better or for worse, I think for worse, younger guys are asking about and using testosterone replacement therapy, so-called TRT. Why in the world would any male in his teens or 20s, or even 30s, whose blood levels of testosterone and estrogen are at the appropriate levels, meaning within the normal reference range, why would they u- take exogenous testosterone, i- given all the negative effects on fertility, um, 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.

   2. KGDr. Kyle Gillett9:43

      Yeah.

   3. AHAndrew Huberman9:43

      If they are playing a sport, chances are they're not allowed to do that anyway. It's, it's on the banned substances list. So to me, it just seems like a crazy idea. Um, 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, uh, or even never. So is there ever a case for somebody in their 20s or 30s to take testosterone, es- but if their blood levels are within the 300 to 900 nanograms per deciliter reference range?

   4. KGDr. Kyle Gillett10:12

      You know, everyone has their different reason, uh, as far as, like, when does the benefit outweigh the detriment? Not very often if you're, um, in your 20s, and certainly, uh, probably almost hardly never. There's always, you know, rare cases like Kallmann syndrome and whatnot, but, um, almost never if you're very young.

8. 10:32 – 14:16

   Supplements for Testosterone, Creatine & Hair Loss; Betaine, Doses

   1. AHAndrew Huberman10:32

      Okay, so for people in their 20s, 30s, and beyond, 40s, et cetera, whose, uh, testosterone and estrogen levels are at the appropriate ratios and in the, within the normal reference range, uh, libido, energy, recovery, et cetera, and are feeling, you know, at least, um, workable for, 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?

   2. KGDr. Kyle Gillett11:10

      Let's mention creatine as 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 kind of 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, um, men in their, even their teenage years and their 20s.

   3. AHAndrew Huberman11:41

      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. Uh, so the question therefore is, does creamine- creatine supplementation increase the rate of hair loss?

   4. KGDr. Kyle Gillett12:07

      In each individual Uh, 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, uh, you know, increase your androgens to an unnormal level of binding. So I feel like, um, this-- if that was a reason to not take creatine for hair loss, then that's-

   5. AHAndrew Huberman12:32

      You mean for-- sorry, you mean hair loss is not a reason to avoid taking creatine?

   6. KGDr. Kyle Gillett12:36

      Correct. Hair loss is not a reason to avoid taking creatine. Um, it-- think of it as just bringing you to what you are, um, 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 five alpha reduced DHT. So it's not gonna speed up hair loss more than, um, 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 five alpha reductase activity, it will return them to natural or normal.

   7. AHAndrew Huberman13:17

      Uh, so what other supplement-based tools, uh, can people consider?

   8. KGDr. Kyle Gillett13:21

      Another one we can loop in with creatine is betaine. Some people are non-responders to creatine, so you can increase that to ten 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.

   9. AHAndrew Huberman13:38

      Betaine, uh, do you recall, uh, what dosage people typically would take if they're a creatine non-responder?

   10. KGDr. Kyle Gillett13:45

       One to three grams.

   11. AHAndrew Huberman13:47

       Per day?

   12. KGDr. Kyle Gillett13:47

       In fact, s- yeah. Several versions of creatine have betaine mixed in because it helps with the processing of methionine and homocysteine.

   13. AHAndrew Huberman13:55

       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?

   14. KGDr. Kyle Gillett14:05

       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 downstream.

   15. AHAndrew Huberman14:14

       How would I know?

   16. KGDr. Kyle Gillett14:15

       Uh, just a

9. 14:16 – 17:29

   L-Carnitine, Forms, Dose, TMAO, Garlic & Berberine

   1. KGDr. Kyle Gillett14:16

      blood test.

   2. AHAndrew Huberman14:16

      So L-carnitine, uh, what are the ways to take L-carnitine? I know that there's an oral form, so capsules, and there's injectables. The injectables, I think you need a prescription. Is that right?

   3. KGDr. Kyle Gillett14:26

      Correct. You need a prescription for the injectables, or you should really get a prescription for the injectables. For when you inject it, um, of course, at the supervision of your doctor, it's usually done intramuscularly. It's an aqueous solution, so it does not have, like, an oil or a carrier oil in it like TR-- like testosterone esters do. Um, however, if you inject it too superficially, it's not gonna make or break anything. Often it just burns if you inject it subcutaneously, and it does not, um, 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 ten percent.

   4. AHAndrew Huberman15:09

      So what are the dosages of L-carnitine that one needs to ingest then if they want to get a benefit? Because if only ten percent is being absorbed, uh, it's probably a lot of L-carnitine.

   5. KGDr. Kyle Gillett15:18

      Mm-hmm.

   6. AHAndrew Huberman15:19

      How much should people take per day?

   7. KGDr. Kyle Gillett15:20

      Usually I recommend, uh, for oral L-carnitine between one thousand milligrams and up to four or five thousand milligrams.

   8. AHAndrew Huberman15:28

      Okay, so one to four, maybe even five grams.

   9. KGDr. Kyle Gillett15:31

      Correct.

   10. AHAndrew Huberman15:31

       Okay.

   11. KGDr. Kyle Gillett15:32

       Up to five 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.

   12. AHAndrew Huberman15:49

       Is it true that I can offset any negative effects of alpha-GPC, uh, choline, that is, and L-carnitine, um, that I take by ingesting garlic? Is that right?

   13. KGDr. Kyle Gillett15:59

       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, um, probably through alteration of the gut microbiome, and then just, um, optimizing your gut microbiome can decrease conversion. So not everyone needs allicin, but it's something that you should certainly consider if you are on a high dose.

   14. AHAndrew Huberman16:28

       I'm going to continue to take the six hundred 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.

   15. KGDr. Kyle Gillett16:40

       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.

   16. AHAndrew Huberman16:46

       Okay, and what we did not talk about is what L-carnitine does.

   17. KGDr. Kyle Gillett16:50

       It's a shuttle. So I think it's named carnitine palmitoyl coenzyme A. Basically, it's-- 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 in the cytoplasm of your cells. So even if your androgen receptor sensitivity doesn't change and even if your does-- testosterone does not change, you will have more testosterone binding to that increased number of receptors.

   18. AHAndrew Huberman17:23

       Does one need to cycle L-carnitine, creatine, betaine?

   19. KGDr. Kyle Gillett17:27

       No reason to cycle any of those.

10. 17:29 – 19:10

    Vitamin D, Boron

    1. AHAndrew Huberman17:29

       What other supplements can one use to try and improve hormone profiles? And, 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, I think about the subjective, um, stuff. You know, do people feel like they are going to have more energy as a consequence of doing these things? Are they gonna have the, uh, more optimized libido? Are they gonna have more optimized, uh, recovery from exercise, right? Because, I mean, it- it's not clear to me that taking one's testosterone from six hundred to eight hundred 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, right?

    2. KGDr. Kyle Gillett18:09

       Let's briefly mention vitamin D, which is also a hormone. It's actually a sterol hormone. And have-- 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, uh, 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 me- might be one of the reasons why the reference range for testosterone is much higher in those countries than other countries.

    3. AHAndrew Huberman18:51

       And just to remind people, the 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. Okay, 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, right?

11. 19:10 – 23:56

    Tongkat Ali (Longjack); Fadogia Agrestis

    1. AHAndrew Huberman19:10

       Um, and then what are some of the other things to optimize, uh, testosterone that are in supplement form?

    2. KGDr. Kyle Gillett19:15

       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. It's also known as-

    3. AHAndrew Huberman19:22

       Yeah, but I'm guessing a number of people probably haven't heard that conversation

    4. KGDr. Kyle Gillett19:25

       ... also known as longjack, and that upregulates several different enzymes in the steroidogenesis cascade. And by that w- um, what you mean if-- and this is another good thing to Google. I think anybody interested in hormone optimization should understand where hor- where sterol 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 progestogens quite easily as well. But tongkat helps with the conversion of multiple key steps where you synthesize testosterone. Another, um, 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.

    5. AHAndrew Huberman20:29

       What sorts of dosages of tongkat do you recommend to your patients?

    6. KGDr. Kyle Gillett20:33

       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, um, you're looking at the eurycomanone content, which is a plant compound that is likely the main, um, 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.

    7. AHAndrew Huberman21:10

       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. Um, what are some of the other effects on various hormones that you've observed in the blood work of your patients taking tongkat ali?

    8. KGDr. Kyle Gillett21:24

       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. Uh, the higher your SHBG, the more it helps decrease it. So they've studied tongkat in, uh, populations with very normal SHBGs, and it does nothing for SHBG.

    9. AHAndrew Huberman21:47

       Interesting. Does that mean it does nothing for somebody overall? So if somebody has SHBG that's in the normal range, will taking tongkat benefit them in any other way?

    10. KGDr. Kyle Gillett21:57

        Yes. It- it'll increase their total and free testosterone.

    11. AHAndrew Huberman22:01

        What are some of the other hormones that you, uh, prescribe to your patients, uh, who do not want to go on testosterone replacement therapy or take exogenous DHEA or anything like that?

    12. KGDr. Kyle Gillett22:12

        We can talk about Fadogia next. Uh, Fadogia is interesting because it's a genus of plants. Fadogia Agrestis is one of them. There's many others that are very interesting. Um, that species is likely the most well-studied, and it will increase LH. So, um-

    13. AHAndrew Huberman22:27

        Luteinizing hormone

    14. KGDr. Kyle Gillett22:28

        ... I would not consider it an LH mimetic, so it doesn't really mimic it, 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.

    15. AHAndrew Huberman22:44

        What dosages, uh, do you have patients take? I've heard of, uh, some potential toxicity to the testicular cells.

    16. KGDr. Kyle Gillett22:52

        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 different, um, like pro-inflammatory markers. One is GGT or gamma-glutamyl transferase, comes from both the testes and the liver, and one is alkaline phosphatase, also known as alk phos, 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.

    17. AHAndrew Huberman23:31

        So that would be 300 milligrams a day in humans is the dosage that did not have toxicity, correct?

    18. KGDr. Kyle Gillett23:37

        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, um, another regimen that I have people take is 600 milligrams every other day or 600 milligrams three times a week, often Monday, Wednesday, Friday.

12. 23:56 – 28:32

    Testosterone Therapy, Dose; Side Effects

    1. AHAndrew Huberman23:56

       My understanding is that nowadays a lot of people are using testosterone, let's not even call it replacement therapy, 'cause some of these people have 600, 700, or even, you know, 800 nanogram per deciliter reads. 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 gonna be more beneficial than the kind of old school way of giving, you know, 100 or even 200 milligrams in a single injection once every two weeks. Is that right? And, and what do you do with your patients? So let me give you a hypothetical. Somebody comes into your office, they're [lips smack] um, do their blood work and they have, um, blood levels of, let's say, 600 nanograms per deciliter testosterone. Their estrogen is also in normal range. Everything else checks out, but they're complaining of, you know, slightly diminished libido, slightly poor recovery from workouts, maybe, um, you know, 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, uh, range and frequency of administration range that you might consider exploring?

    2. KGDr. Kyle Gillett25:07

       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, um, 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.

    3. AHAndrew Huberman25:55

       So two 60 milligram injections of testosterone cypionate per week.

    4. KGDr. Kyle Gillett25:59

       Yeah, very common dosing.

    5. AHAndrew Huberman26:01

       To hit that 120 milligrams per week as kind of the typical average.

    6. KGDr. Kyle Gillett26:04

       Correct. And I would consider this, um, a, 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 nor- normally released in a pulsatile manner. So it's high in the morning, low in the evening, whereas if you're on, uh, testosterone therapy, then, um, you're going to have a steady state, so your testosterone level is gonna be pretty much the same even in the evening.

    7. AHAndrew Huberman26:33

       In your experience, when patients do that, they, I'm guessing they report the normal constellation of positive effects, you know, improved mood, improved energy, improved sleep, uh, recovery, et cetera. Uh, what are some of the hazards or things that, um, can crop up in blood work or just subjectively that, um, can be warning signs that even a dosage of 120 milligrams divided into these two or three dosages per week can, is too high?

    8. KGDr. Kyle Gillett26:56

       So this is when you really have to be, uh, at least well-versed in every organ system, not just the gonadal, um, like, you know, genital system. You need to have, uh, you know, dermatology prowess. Acne is a very common change. Lots of different, uh, skin pathologies or even bruising can be related to hormone replacement. Hair loss is very common to see as well. Um, mental status changes. It could inc- occasionally it even induces a manic or a bipolar episode because testosterone is also dopaminergic. And then cardiovascularly, not just in the heart, but also concerns for like microvascular ischemic disease, ferritin buildup because the estrogen also increases, and then, uh, fertility concerns as well, and lipid concerns too. So you really have to be, you know, hematologist, dermatologist, cardiologist, um, a lipidologist, the whole nine yards.

    9. AHAndrew Huberman27:54

       So another reason or set of reasons rather to, uh, if one is considering using testosterone therapy to really do this in close communication with a really good physician [chuckles] 'cause 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 blood work is what I'm hearing.

    10. KGDr. Kyle Gillett28:16

        Correct. And if your physician that is managing or prescribing your, uh, 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.

13. 28:32 – 31:06

    Clomiphene, SERM & Testosterone

    1. AHAndrew Huberman28:32

       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, no, um, pill, no injectable cypionate, but decide to take clomiphene a couple 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, I'm hearing that it's being done quite a lot now.

    2. KGDr. Kyle Gillett29:14

       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, uh, does what's called negative feedback inhibition, um, or it, it blocks the action of estrogen. So it crowds out estrogen from the estrogen receptor on the hypothalamus and the pituitary.

    3. AHAndrew Huberman29:43

       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.

    4. KGDr. Kyle Gillett29:51

       The main rationale behind taking a SERM is as a very temporary measure that is not going to suppress pituitary or hypothalamic function if your testosterone is just so drastically low that it is unlikely to recover anywi- any way. So most of the time it is not clinically useful and, um, SERM should not be prescribed very often, certainly not as long-term testosterone replacement, um, or testosterone optimization in most individuals. There's always exceptions to everything, but, um, there's five different estrogen and estrogen-related receptors There's two main estrogen receptors, and Clomid and every SERM has a very unique profile because they selectively inhibit some receptors in some tissues, but not other receptors in other tissues. For example, um, Clomid can inhibit receptors that are in the eye, and it can cause, um, visual changes, blurry vision, um, especially at higher doses, and it also acts in every other tissue of the body. So side effects from Clomid and other selective estrogen receptor modifiers are very common.

14. 31:06 – 31:58

    Alcohol, Aromatase & Testosterone

    1. AHAndrew Huberman31:06

       Alcohol, does it increase aromatase, the enzyme that converts testosterone into estrogen or not? And, um, is there a dose dependence there?

    2. KGDr. Kyle Gillett31:15

       It significantly does. There is a dose dependence. In general, I would not recommend more than, uh, three to four, you know, standard drinks. Uh, one huge glass of wine is probably five standard drinks. Every two weeks. The other thing to keep in mind with alcohol is it has a lot of calories, seven kilocalories per gram, almost as much as fat, which is nine, and then it's also very GABAergic, so it, it, it can activate inhibitory neurotransmission, um, and that can also affect how many, how much, uh, LH and FSH is released, so that can also decrease testosterone, almost kind of, uh, similar to how opiates can decrease testosterone.

15. 31:58 – 33:59

    Prostate Health & Tadalafil, Nighttime Urination

    1. AHAndrew Huberman31:58

       I want to go back to the prostate and talk to you about something that's kind of a newer emerging trend. I know that, um, you've talked a little bit about this in a previous podcast, that a number of men, or I should say a number of physicians are prescribing low dose Tadalafil, also known as Cialis, to their male patients, so in dosage ranges of like 2.5 milligrams to 5 milligrams per day, but not for erectile dysfunction, but rather for improving prostate health, and presumably they get sort of a boost in terms of blood flow, um, to the genitalia as well. But again, not specifically to deal with, uh, erectile dysfunction, but to deal with prostate health and blood flow to the prostate. Is that something that you sometimes often prescribe to your patients, and of what age?

    2. KGDr. Kyle Gillett32:44

       Tadalafil is a very underrated medication. Um, the age would kind of depend on the indication. So Tadalafil is also a blood pressure medication. It can very slightly decrease blood pressure, especially at higher doses. At higher doses it theore- a high, a high dose would be 20 milligrams, not 2.5 milligrams. But consistently it can somewhat affect with the cones in the eye that have to do with red and green sight. Although if you remove it, that effect is reversed. So basically if you don't need really, really good red green discrimination, you can take higher doses. But in general, I recommend no higher than 10 milligrams a day, usually just two or five milligrams. One, uh, other benefit or other use of Tadalafil is that it increases the density of the androgen receptor similarly to L-carnitine. So that's an interesting benefit. Another benefit is that if you give it to people with nocturia, which is urinating at night, in general, it will cut the episodes in half. So it could go from two to one, which can make a big difference for your sleep, which will secondarily make a big difference for your growth hormone and testosterone optimization.

    3. AHAndrew Huberman33:52

       Interesting. So you said 2.5 to 5 milligrams per day is kind of typical for these prostate enhancing effects.

    4. KGDr. Kyle Gillett33:58

       Yes.

16. 33:59 – 36:02

    Hair Loss, Caffeine, Finasteride, Dutasteride

    1. AHAndrew Huberman33:59

       I get a lot of questions about drugs to offset hair loss. Most of those drugs are going to operate through the DHT system, the dihydrotestosterone system, for the reasons we talked about before, DHT receptors being on the scalp and, uh, causing beard growth on the face. Is it the case that a number of people taking, um, things like Propecia and other things to block the DHT or disrupt the DHT pathway are going to experience diminished, um, sex drive, diminished, um, you know, kind of motivation and general vigor? And if so, are there alternatives like topical DHT antagonists that they might use, um, if they want to keep their hair but not have those negative effects?

    2. KGDr. Kyle Gillett34:39

       Many people that have just a bit of predisposition, they can use things that are topical antiandrogens. Uh, ketoconazole is one of them. Caffeine is actually another one.

    3. AHAndrew Huberman34:50

       Wait, you have to explain how this works. How do people get caffeine into the hair follicle?

    4. KGDr. Kyle Gillett34:55

       Topically, the caffeine enters the scalp and crowds out, like somewhat crowds out the androgen. It is a weak effect. It's likely just strong enough to be clinically significant. Usually caffeine is put into formulations with other things like ketoconazole that are also weak antiandrogens. Of note, spironolactone can be prescribed topically, but is, it is absorbed systemically because the size of the molecule. So unless your doctor specifically prescribes that for you, especially as a male, do not use topical spironolactone. Topical finasteride is also a smaller molecule, so it is also systemically absorbed, but it is not extremely well systemically absorbed. If you take topical finasteride, then usually your systemic DHT will decrease by about 30%. Topical dutasteride is likely a tiny bit systemically absorbed, but it's unique because its half-life is much faster at a lower dose. So topical dutasteride will not affect your systemic DHT at all, and I've seen this anecdotally on many people on topical dutasteride therapy.

    5. AHAndrew Huberman36:01

       On behalf

17. 36:02 – 36:17

    Acknowledgements

    1. AHAndrew Huberman36:02

       of the audience and, and just for myself, thank you so much. You have an immense amount of knowledge and you're exquisitely good at sharing it with people in an actionable way. So thank you.

    2. KGDr. Kyle Gillett36:11

       My pleasure. [outro music]

Episode duration: 36:17