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

0:00Welcome 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 Gillette. Dr. Gillette, great to have you back. Great to be back, thank you. 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? 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. What do you think are the key things to look for in blood work? I mean, testosterone is always the topic that comes up in the context of male hormone optimization,

1:16but certainly there are a lot of other hormones that are important as well. And with testosterone, you want to get either testosterone and SHBG or a free testosterone. Could you define SHBG for our listeners, please? 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. So assuming that there's no major intervention, how often do you recommend that people get their blood work done? Using shared decision-making with their physician, usually a good follow-up is about six months. 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? I'll briefly touch on some of the lifestyle pillars to start. Diet and exercise are the first two. In puberty, sleep

2:36is 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. And just again for our audience, maybe you just mentioned what having enough IGF-1 can do for us that's beneficial is? It helps you grow. It helps with genital development, secondary sexual characteristics, and long bone growth, skin growth, hair growth, a host of things. So getting an array of nutrients that include dairy, what other sorts of nutrients are important during development? 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

3:52to prevent a risk of osteoporosis or thin bones fractures when you're older. 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 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? 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. Are there any other micronutrients or macronutrients that people in their 20s and 30s should emphasize? 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 could 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 more detrimental.

5:08And would you say that the prebiotic fiber and getting essential fatty acids, that would be important to do throughout the lifespan or just for the people in their 20s and 30s? 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. In a previous discussion of ours, I asked you about caloric restriction in 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 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 that you'd like to give us now? 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.

6:24Another 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. What are some of the other pillars of creating the proper environment for hormone optimization? Stress is probably the next one. During both puberty, but also the twenties and thirties, 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 they 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. What would be some of the additional things that everybody should do? 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. The idea is not to pick the end goal, it's to pick a goal. And then

7:41once 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, you, you actually can change your, your, your goals and purpose over time. I'd like to take a quick break and acknowledge one of our sponsors element. Element is an electrolyte drink that has everything you need and nothing you don't. That means the electrolytes, sodium, magnesium, and potassium in the correct amounts, but no sugar. Proper hydration is critical for optimal brain and body function. Even a slight degree of dehydration can diminish cognitive and physical performance. It's also important that you get adequate electrolytes. The electrolytes, sodium, magnesium, and potassium are vital for functioning of all the cells in your body, especially your neurons or your nerve cells. Drinking Element dissolved in water makes it very easy to ensure that you're getting adequate hydration and adequate electrolytes. To make sure that I'm getting proper amounts of hydration and electrolytes, I dissolve one packet of Element in about 16 to 32 ounces of water when I first wake up in the morning, and I drink that basically first thing in the morning. I'll also drink Element dissolved in water during any kind of physical exercise that I'm doing, especially on hot days when I first wake up in the morning, and I drink that basically first thing in the morning. I'll also drink Element dissolved in water during any kind of physical exercise that I'm doing, especially on hot days when I'm sweating a lot and losing water and electrolytes. Element has a bunch of great tasting flavors. I love the raspberry. I love the citrus flavor.

8:57Right now, Element has a limited edition lemonade flavor that is absolutely delicious. I hate to say that I love one more than all the others, but this lemonade flavor is right up there with my favorite other one, which is raspberry or watermelon. Again, I can't pick just one flavor. I love them all. If you'd like to try Element, you can go to drinkelement.com slash Huberman, spelled drinkelement.com slash Huberman to claim a free Element sample pack with a purchase of any Element drink mix. Again, that's drinkelement.com slash Huberman to claim a free sample pack with a purchase of any element drink mix again that's drinkelement.com slash huberman to claim a free sample pack 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 what do you think is a healthy sustainable exercise regimen that anyone can follow that will also support their hormone status. 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, one area that's been studied 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

10:12perceived 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, it is not hormonally helpful to train, especially regularly train vigorously for longer than an hour. 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 twenties or even thirties whose blood levels of testosterone and estrogen are at the appropriate levels, meaning within the normal reference range, why would they 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 forties and

11:30fifties or even never. So is there ever a case for somebody in their twenties or thirties to take testosterone if their blood levels are within the 300 to 900 nanograms per deciliter reference range. You know, everyone has their different reason 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, you know, rare cases like Kalman syndrome and whatnot, but almost never if you're very young. Okay, so for people in their 20s, 30s and beyond, 40 almost never if you're very young. Okay. So for people in their twenties, thirties and beyond forties, et cetera, whose testosterone and estrogen levels are at the appropriate ratios and in the, within the normal reference range, libido, energy recovery, et cetera, are feeling, you know, at least 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? Let's mention creatine as the first one.

12:48Creatine 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 men in even their teenage years and their 20s. 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? In each individual, preventing hair loss is a very poor reason to take creatine because it's not going to take you to a supra-physiologic level. It's not going to increase your androgens to an unnormal level of binding. So I feel like if that was a reason to not take creatine for hair loss,

14:03then that's... Sorry, you mean hair loss is not a reason to not take creatine for hair loss, then that's... Sorry, you mean hair loss is not a reason to avoid taking creatine? 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 to DHT. So it's not gonna 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. So what other supplement-based tools can people consider? Another one we can loop in with creatine is betaine. Some people are non-responders 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. Beta-ene, do you recall what dosage people typically would take if they're a creatine non-responder? One to three grams. In fact,

15:20several versions of creatine have beta-ene mixed in because it helps with the processing of methionine and homocysteine. So if somebody is already taking creatine and likes it in response to it, I'll raise my hand, such as myself, would adding beta-ene help or is it redundant with creatine? 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. How would I know? Just a blood test. So L-carnitine, 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? Correct. You need a prescription for the injectables, or you should really get a prescription for the injectables or you should really get a prescription for the injectables. 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 like an oil or a carrier oil in it like testosterone esters do. However, if you inject it too superficially, it's not going to make or rake 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

16:38low bioavailability, maybe only 10%. 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? Usually I recommend for oral L-carnitine between 1,000 milligrams and up to four or 5,000 milligrams. So one to four, maybe even five grams. Correct, 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. Is it true that I can offset any negative effects of alpha-GPC choline, that is NL-carnitine, that I take by ingesting garlic? Is that right? 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,

17:57but it's something that you should certainly consider if you were on a high dose. 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. 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. Okay. And what we did not talk about is what L-carnitine does. It's a shuttle. So I think it's named carnitine palmatyl 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 in the cytoplasm of your cells. So even if your 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. Does one need to cycle L-carnitine, creatine, betaine? No reason to cycle any of those. 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?

19:12And 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? Are they going to have more optimized recovery from exercise, right? 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, right? 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 five 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. 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

20:31that'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, five to 12 milligrams per day, right? And then what are some of the other things to optimize testosterone that are in supplement form? 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. Yeah, but I'm guessing a number of people probably haven't heard that conversation. 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 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 Tonkat 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

21:47as 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. What sorts of dosages of Tongkat do you recommend to your patients? Anywhere from 300 to 1200 milligrams a day. With Tongkat, you need to be careful with the standardization because if you're thinking about a general Tongkat supplement, which is by far the most well-studied, then you're looking at the uricomonone 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 uricomonone very, very high, then theoretically you're having more effect at a lower dose. 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 blood work of your patients, taking Tongkat Ali? Tongkat can also slightly increase DHEA. And if you have a very high SHBG,

23:02again, 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. 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? Yes. It'll increase theirotics and adaptogens. I discovered AG1 way back in 2012, long before I ever had a podcast, and I've been taking it every day since. The reason I started taking AG1 and the reason I still take it every day is because AG1 is, to my knowledge, the highest quality and most comprehensive of the foundational nutritional supplements on the market. AG1 is designed to support things like gut health, immune health, and overall energy, and it does so by helping to fill any gaps that you might have in your daily nutrition. I get asked pretty much all the time, if I could only take one supplement, what should that supplement be? And my answer is always AG1. It has just been so helpful for supporting all aspects

24:19of physical health, mental health, and performance. If you would like to try AG1, you can go to drinkag1.com slash Huberman to get a special offer. For a limited time, AG1 is giving away a free bottle of their new Omega-3 Coenzyme Q10 product. Omega-3 and Coenzyme Q10 are known to support cardiovascular health, cellular health and energy generally, brain health, and much more. I personally take them both every day. Again, go to drinkag1.com slash Huberman to get a free bottle of the new omega-3 coenzyme Q10 with your first AG1 subscription. 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? We can talk about Fidoja next. Fidoja is interesting because it's a genus of plants. Fidoja 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 memetic. 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 latic cell, to the LH receptor, kind of like HCG does, and it will increase the release of testosterone.

25:36What dosages do you have patients take? I've heard of some potential toxicity to the testicular cells. 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 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 ALKFOS, again, coming 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. So that would be 300 milligrams a day in humans is the dosage that did not have toxicity, correct? 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. My understanding is that nowadays, a lot of people are using testosterone. Let's not even call it replacement therapy because some of these

26:54people 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, you know, a hundred 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, their blood work and they have 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 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? 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,

28:09if 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. So 260 milligram injections of testosterone cypionate per week. Yeah, very common dosing. To hit that 120 milligrams per week as kind of the typical average. 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 a testosterone therapy, then you're going to have a steady state. So your testosterone level is gonna be pretty much the same even in the evening. In your experience, when patients do that, I'm guessing they report the normal

29:29constellation of positive effects, you know, improved mood, improved energy, improved sleep, recovery, et cetera. What are some of the hazards or things that can crop up in blood work 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. So this is when you really have to be at least well-versed in every organ system, not just the genital system. You need to have dermatology prowess, acne is a 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. 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 fertility concerns as well, and lipid concerns too. So you really have to be, you know, hematologist, dermatologist, cardiologist, lipidologist, the whole nine yards.

30:45So 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 blood work is what I'm hearing. 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? 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, supinate, 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

32:02good strategy? I'm hearing that it's being done quite a lot now. 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 it blocks the oxygen of estrogen so it crowds out estrogen from the estrogen receptor on the hypothalamus and the pituitary 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 the main rationale behind taking a CIRM 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 anyway. So most of the time it is not clinically useful and CIRM should not be prescribed very often, certainly not as long-term testosterone replacement or testosterone optimization in most individuals. There's always exceptions to everything, but there's five different estrogen

33:20and estrogen-related receptors. There's two main estrogen receptors, and Clomid and every CIRM has a very unique profile because they selectively inhibit some receptors in some tissues, but not other receptors in other tissues. For example, Clomid can inhibit receptors that are in the eye, and it can cause visual changes, blurry vision, 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. I'd like to take a quick break to acknowledge one of our sponsors, David. David makes protein bars unlike any other. Their newest bar, the Bronze Bar, has 20 grams of protein, only 150 calories, and zero grams of sugar. I have to say, these are the best tasting protein bars I've ever had, and I've tried a lot of protein bars over the years. These new David bars have a marshmallow base, and they're covered in chocolate coating, and they're absolutely incredible. I of course eat regular whole foods. I eat meat, chicken, fish, eggs, fruits, vegetables, et cetera. But I also make it a point to eat one or two David bars per day as a snack, which makes it easy to hit my protein goal of one gram of protein per pound of body weight. And that allows me to take in the

34:39protein I need without consuming excess calories. I love all the David Bronze Bar flavors, including cookie dough, caramel chocolate, double chocolate, peanut butter chocolate. They all actually taste like candy bars. Again, they're amazing. But again, they have no sugar and they have 20 grams of protein with just 150 calories. If you'd like to try David, you can go to davidprotein.com slash Huberman. Right now, David is offering a deal where if you buy four cartons, you get the fifth carton for free. You can also find David on Amazon or in stores such as Target, Walmart, and Kroger. Again, to get the fifth carton for free, go to Davidprotein.com slash Huberman. Alcohol, does it increase aromatase, the enzyme that converts testosterone into estrogen or not? And is there a dose dependence there? It significantly does. There is a dose dependence. In general, I would not recommend more than three to four standard drinks. 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 can activate inhibitory neurotransmission.

35:54And that can also affect how many, how much LH and FSH is released. So that can also decrease testosterone, almost kind of similar to how opiates can decrease testosterone. 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 you've talked a little bit about this in previous podcasts, 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 five 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 to the genitalia as well. But again, not specifically a deal with erectile dysfunction, but to deal with prostate health and blood flow to the genitalia as well. But again, not specifically a deal with 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? Tadalafil is a very underrated medication. 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 at theory a high dose would be 20 milligrams not

37:122.5 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 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. Interesting. So you said 2.5 to 5 milligrams per day is kind of typical for these prostate enhancing effects. Yes. 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 dihydrocystosterone system, for the reasons we talked about before, DHT receptors being on the scalp and causing beard growth on the face. Is it the case that a number of people taking things like Propecia and other things to block the DHT

38:31or disrupt the DHT pathway are going to experience diminished sex drive, diminished kind of motivation and general vigor? And if so, are there alternatives like topical DHT antagonists that they might use if they want to keep their hair but not have those negative effects? Many people that have just a bit of predisposition, they can use things that are topical antiandrogens. Ketoconazole is one of them. Caffeine is actually another one. Wait, you have to explain how this works. How do people get caffeine into the hair follicle? 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 it is absorbed systemically because of 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 also systemically absorbed, but it is not extremely

39:46well 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. On behalf of the audience 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. My pleasure. Hey, it's Ryan Reynolds here from Mint Mobile. Now, I was looking for fun ways to tell you that Mint's offer of unlimited premium wireless for $15 a month is back. So I thought it would be fun if we made $15 bills. But it turns out that's very illegal. So there goes my big idea for the commercial. Give it a try at mintmobile.com slash switch. Upfront payment of $45 for three months, $90 for six months, or $180 for a 12-month plan required. $15 per month equivalent. Taxes and fees extra. Initial plan term only. Greater than 50 gigabytes. May slow when network is busy. See terms.