Andrew Huberman interviews Dr Kyle Gillett on male hormone optimization tools and strategies
Andrew Huberman speaks with Dr Kyle Gillett about practical, evidence-based approaches to optimizing male hormones across the lifespan.
Summary
Andrew Huberman hosts Dr Kyle Gillett, a physician specializing in hormone optimization, for a wide-ranging discussion on how males can support healthy hormone levels from puberty through adulthood. Dr. Gillett argues that lifestyle pillars — diet, exercise, sleep, stress management, and sense of purpose — form the foundation of hormone health, and that most young men have no valid reason to use exogenous testosterone if their levels are within the normal reference range. He presents a detailed hierarchy of supplementation options, from creatine and L-carnitine through to tongkat ali and fadogia agrestis, explaining mechanisms and dosages for each. The conversation also covers the risks of testosterone therapy, the hazards of Clomiphene (Clomid) as a long-term strategy, the prostate and libido benefits of low-dose tadalafil, and topical approaches to managing hair loss without systemic hormonal disruption.
Key Takeaways
FULL TRANSCRIPT
Introduction and the Case for Lifelong Hormone Monitoring
Andrew Huberman: 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.
Dr. Gillett, great to have you back.
Dr Kyle Gillett: Great to be back. Thank you.
Andrew Huberman: 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?
Dr Kyle Gillett: There are 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're obviously a functioning human, but there's still development happening. And I think development never ends. But you want to monitor that progress across a person's lifespan.
Andrew Huberman: What do you think are the key things to look for in blood work? Testosterone is always the topic that comes up in the context of male hormone optimization, but certainly there are a lot of other hormones that are important as well.
Dr Kyle Gillett: With testosterone, you want to get either testosterone and SHBG, or a free testosterone measurement.
Andrew Huberman: Could you define SHBG for our listeners, please?
Dr Kyle Gillett: It is sex hormone binding globulin. It is the protein that binds up all androgens and estrogens in the body. The stronger the androgen, the stronger it binds. During puberty, strong androgens — especially DHT, which is the strongest bioidentical androgen — have a huge, 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: So assuming that there's no major intervention, how often do you recommend that people get their blood work done?
Dr Kyle Gillett: Using shared decision-making with their physician, usually a good follow-up is about six months.
Daily Lifestyle Pillars for Hormone Health
Andrew Huberman: 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.
Dr Kyle Gillett: I'll briefly touch on some of the lifestyle pillars to start. Diet and exercise are the first two. 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: Just for our audience, maybe you could mention what having enough IGF-1 can do for us that's beneficial.
Dr Kyle Gillett: It helps you grow. It helps with genital development, secondary sexual characteristics, 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?
Dr Kyle Gillett: You want to have adequate vitamin D. Vitamin D helps with testosterone production and again with bone mineralization and stature. After an age of about 25 — and there's not a strict cutoff, but up to about age 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 basically stockpile bone to prevent a risk of osteoporosis, thin bones, and fractures when you're older.
Andrew Huberman: 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? What do you think, for instance, about people following a pure carnivore or a very pure vegan diet in their 20s and 30s?
Dr Kyle Gillett: In their late 20s, it might be a reasonable option. In early 20s, and certainly in 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 throughout the body.
Andrew Huberman: Are there any other micronutrients or macronutrients that people in their 20s and 30s should emphasize?
Dr Kyle Gillett: Fiber is going to be paramount in setting your gut microbiome's set point for 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 is going to skew your gut microbiome towards something that is either more beneficial or more detrimental.
Andrew Huberman: Would you say that prebiotic fiber and getting essential fatty acids are important to do throughout the lifespan, or just for people in their 20s and 30s?
Dr Kyle Gillett: Throughout the lifespan. Particularly important in the teenage years, 20s, and 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 throughout the lifespan — certainly through the 20s and 30s as well.
Caloric Restriction, Body Fat, and Testosterone
Andrew Huberman: In a previous discussion of ours, I asked you about caloric restriction and testosterone. If I recall correctly, the idea was that if somebody is overweight and has excess adipose tissue, then getting rid of some of that adipose tissue through caloric restriction and exercise — provided it's done not too fast and in a healthy way — is going to be beneficial for testosterone in the long run. But 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 you'd like to give us now?
Dr 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 fewer building blocks for hormones. Another is that they will be in a catabolic state more often — so that balance of anabolism and catabolism will shift. They'll likely have less signaling from growth hormone and IGF-1. And they'll also have higher SHBG, which as we defined earlier is the binding protein. So their free androgens and free estrogens will go down.
Stress, Purpose, and the Broader Pillars
Andrew Huberman: Now what are some of the other pillars of creating the proper environment for hormone optimization?
Dr Kyle Gillett: Stress is probably the next one. During both puberty and 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. If someone is overstressed, it can affect all the other lifestyle pillars — they stop dieting well, they stop exercising, and everything else can go askew.
Andrew Huberman: What would be some of the additional things that everybody should do?
Dr Kyle Gillett: Another one is finding what your purpose is in life. I call this "spirit," but it's really just the self-actualization component of Maslow's hierarchy of needs — which covers 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, but to pick a goal, and then once you reach that goal to assess and then pick another goal, and so on.
Andrew Huberman: I think sometimes when people hear about picking a purpose, they're like, "Oh my goodness, I have to define myself" — but you actually can change your goals and purpose over time.
Exercise Regimens That Support Hormonal Health
I'd like to return to 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?
Dr 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 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 is vigorous exercise episodes lasting longer than an hour. They usually track it by a rating of perceived exertion, which isn't perfect and isn't extremely actionable, but it's helpful for clinical science. The takeaway from that is basically: it is not hormonally helpful to train vigorously for longer than an hour, especially regularly.
Testosterone Therapy in Young Men — Is It Ever Justified?
Andrew Huberman: 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, 20s, or even 30s, whose blood levels of testosterone and estrogen are at the appropriate levels within the normal reference range, take exogenous testosterone given all the negative effects on fertility, and some of the challenges that it can present if dosages aren't quite right? If they are playing a sport, chances are they're not allowed to do that anyway — it's on the banned list. It just seems like a crazy idea. Is there ever a case for somebody in their 20s or 30s to take testosterone, especially if their blood levels are within the 300 to 900 nanograms per deciliter reference range?
Dr Kyle Gillett: Everyone has their different reason as far as when the benefit outweighs the detriment. Not very often if you're in your 20s, and almost never if you're very young. There are always rare cases like Kallmann syndrome and whatnot, but almost never if you're very young.
Supplementation for Hormone Optimization Without Suppressing Endogenous Production
Andrew Huberman: So for people in their 20s, 30s, and beyond — 40s, etc. — whose testosterone and estrogen levels are at the appropriate ratios and within the normal reference range, and whose libido, energy, and recovery are at least workable for their lifestyle: what can they do besides get great sleep and train but not too hard or too often? 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?
Dr Kyle Gillett: 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 — holding backup ATP. And it does slightly increase total testosterone. It also increases the conversion of testosterone to dihydrotestosterone. So potentially it's especially useful in men in 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 is one of the primary hormones that can promote male pattern baldness. So the question is: does creatine supplementation increase the rate of hair loss?
Dr Kyle Gillett: In each individual, preventing hair loss is a very poor reason to avoid taking creatine, because it's not going to take you to a supraphysiologic level. It's not going to increase your androgens to an abnormal level of binding.
Andrew Huberman: You mean hair loss is not a reason to avoid taking creatine?
Dr 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 five-alpha reduced to DHT. So it's not going to speed up hair loss more than just naturally being a male does. In some individuals it will have no effect. In some individuals who have almost no five-alpha reductase activity, it will return them to natural or normal.
Betaine, L-Carnitine, and Androgen Receptor Density
Andrew Huberman: What other supplement-based tools can people consider?
Dr Kyle Gillett: Another one we can loop in with creatine is betaine. Some people are non-responders to creatine, so you can increase the creatine dose 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.
Andrew Huberman: Betaine — do you recall what dosage people typically would take if they're a creatine non-responder?
Dr Kyle Gillett: One to three grams. In fact, 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?
Dr Kyle Gillett: Only if their homocysteine is persistently elevated. Homocysteine is kind of like an inflammatory marker that can build up if you're not converting enough of it downstream.
Andrew Huberman: How would I know?
Dr Kyle Gillett: Just a blood test.
Andrew Huberman: So, L-carnitine — what are the ways to take L-carnitine? I know there's an oral form in capsules, and there are injectables. The injectables, I think you need a prescription. Is that right?
Dr Kyle Gillett: Correct. You need a prescription for the injectables, or you should really get a prescription when you inject it. 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 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: So what are the dosages of L-carnitine that one needs to ingest 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?
Dr Kyle Gillett: Usually I recommend for oral L-carnitine between 1,000 milligrams and up to four or 5,000 milligrams.
Andrew Huberman: So one to four, maybe even five grams.
Dr 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. Your gut microbiota determine how much that conversion happens.
Andrew Huberman: Is it true that I can offset any negative effects of alpha-GPC choline or L-carnitine that I take by ingesting garlic? Is that right?
Dr Kyle Gillett: There's a compound in garlic called allicin — I believe it's spelled 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 in general can decrease conversion. So not everyone needs allicin, but it's something you should certainly consider if you are 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 makes me crave carbohydrates because it drops my blood sugar.
Dr 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: And what we did not talk about is what L-carnitine actually does.
Dr Kyle Gillett: It's a shuttle. 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 — in 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 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, or betaine?
Dr Kyle Gillett: No reason to cycle any of those.
Vitamin D, Boron, and the Steroidogenesis Cascade
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? For me at least, I think about the subjective stuff — do people feel like they're going to have more energy as a consequence of doing these things? Are they going to have more optimized libido? More optimized recovery from exercise? Because 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.
Dr Kyle Gillett: Let's briefly mention vitamin D, which is also a hormone — it's actually a sterol hormone. If you have deficient vitamin D and you replace it, then you will optimize your testosterone. Let's also mention boron. 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 from those areas potentially provides more boron. Boron might also be one of the reasons why the reference range for testosterone is much higher in those countries than in others.
Andrew Huberman: And just to remind people, 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. So, vitamin D3 — I'm guessing you're talking about vitamin D3 specifically — and then boron, 5 to 12 milligrams per day. What are some of the other things to optimize testosterone that are in supplement form?
Dr Kyle Gillett: We can talk about things that affect the steroidogenesis cascade. We could touch on tongkat ali. I know we've talked about that a little bit before.
Andrew Huberman: A number of people probably haven't heard that conversation.
Dr Kyle Gillett: Also known as longjack, it upregulates several different enzymes in the steroidogenesis cascade. And by that — this is another good thing to Google — anyone interested in hormone optimization should understand where sterol hormones come from. They come usually from cholesterol and can be shunted off to vitamin D very easily, or shunted off to testosterone, estrogens, or progestogens quite easily as well. Tongkat ali helps with the conversion of multiple key steps where you synthesize testosterone. Another co-enzyme or co-actor — an upregulator of these steps — is insulin and IGF-1. So a good rule of thumb is: if you're not expecting as much growth hormone, insulin, and IGF-1 — for example, on lower-carb diets or caloric deficits where you're trying to cut body fat or body weight — then tongkat ali is going to be theoretically especially powerful.
Andrew Huberman: What sorts of dosages of tongkat ali do you recommend to your patients?
Dr Kyle Gillett: Anywhere from 300 to 1,200 milligrams a day. With tongkat ali, you need to be careful with the standardization. If you're thinking about a general tongkat ali 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 having the effect on the body. And if you standardize the eurycomanone very high, then theoretically you're having more effect at a lower dose.
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. What are some of the other effects on various hormones that you've observed in the blood work of your patients taking tongkat ali?
Dr Kyle Gillett: Tongkat ali 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 — the higher your SHBG, the more it helps decrease it. They've studied tongkat ali in populations with very normal SHBGs, and it does nothing for SHBG.
Andrew Huberman: Interesting. Does that mean it does nothing for somebody overall? If somebody has SHBG that's in the normal range, will taking tongkat ali benefit them in any other way?
Dr Kyle Gillett: Yes — it'll increase their total and free testosterone.
Fadogia Agrestis — Benefits, Dosing, and Safety
Andrew Huberman: What are some of the other supplements that you recommend to your patients who do not want to go on testosterone replacement therapy or take exogenous DHEA or anything like that?
Dr Kyle Gillett: We could talk about fadogia agrestis next. Fadogia agrestis is interesting because it's a genus of plants — fadogia agrestis is one of them, and there are many others that are very interesting. That species is likely the most well-studied, and it will increase LH. 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 at the LH receptor, kind of like hCG does, and it will increase the release of testosterone.
Andrew Huberman: What dosages do you have patients take? I've heard of some potential toxicity to the testicular cells.
Dr Kyle Gillett: There was one study — and this is a rat study, but you can equate the dose of toxicity in rats to humans. They did not give these rats any antioxidants, but it increases a couple of different pro-inflammatory markers. One is GGT, or gamma-glutamyl transferase, which comes from both the testes and the liver. And one is alkaline phosphatase, also known as ALP, 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 levels. In the rat dose that equates with humans, the dose that had no effect — the safe dose — was an average of 300 milligrams a day.
Andrew Huberman: So 300 milligrams a day in humans is the dosage that did not have toxicity.
Dr 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.
Testosterone Therapy — Dosing, Frequency, and What to Monitor
Andrew Huberman: 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 nanograms per deciliter readings. So they're not replacing anything that is diminished; they're just trying to augment what's already there. My understanding is that taking a low dose more frequently is going to be more beneficial than the 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?
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 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 might be a good option to explore. What's a typical dosage range and frequency of administration that you might consider?
Dr Kyle Gillett: 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 — and they have a free testosterone of two, then they might need a different dose because they need enough testosterone 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 to hit that 120 milligrams per week as kind of the typical average.
Dr Kyle Gillett: Yes, very common dosing. And I would consider this 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, 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: In your experience, when patients do that, I'm guessing they report the normal constellation of positive effects — improved mood, improved energy, improved sleep, recovery, etc. 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 two or three dosages per week is too high?
Dr Kyle Gillett: This is when you really have to be at least well-versed in every organ system, not just the gonadal 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 — it can occasionally even induce a manic or a bipolar episode because testosterone is also dopaminergic. And then cardiovascularly — not just in the heart, but also concerns for microvascular ischemic disease, ferritin buildup because estrogen also increases, and then fertility concerns and lipid concerns too. So you really have to be hematologist, dermatologist, cardiologist, lipidologist — the whole nine yards.
Andrew Huberman: So another reason — or set of reasons rather — 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 is one thing, but knowing whether or not your LDL is going up, your ApoB is going up — that needs to be done through blood work.
Dr Kyle Gillett: Correct. And if your physician managing or prescribing your testosterone therapy or 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.
Clomiphene — Mechanism, Risks, and Appropriate Use
Andrew Huberman: There are males out there who want to increase their testosterone and other hormones — maybe growth hormone, etc. — who opt not to take exogenous testosterone. No cream, no pellet, no pill, no injectable cypionate, but decide to take Clomiphene a couple of times a week. My understanding is that taking Clomiphene — maybe two 50-milligram tablets a week — will increase luteinizing hormone and 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.
Dr Kyle Gillett: It will increase testosterone in a dose-dependent manner, but it has many other pharmacodynamic effects — the effect of the drug on the body — other than its effect on the hypothalamus and the pituitary. 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: 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.
Dr Kyle Gillett: 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 anyway. So most of the time it is not clinically useful, and SERMs should not be prescribed very often. Certainly not as long-term testosterone replacement or testosterone optimization in most individuals. There are always exceptions to everything, but there are five different estrogen and estrogen-related receptors. There are 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, 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 modulators are very common.
Alcohol and Its Effect on Testosterone
Andrew Huberman: Alcohol — does it increase aromatase, the enzyme that converts testosterone into estrogen? And is there a dose dependence there?
Dr Kyle Gillett: It significantly does. There is a dose dependence. In general, I would not recommend more than three to four standard drinks — and 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: 7 kilocalories per gram, almost as much as fat, which is nine. And then it's also very GABAergic — so it can activate inhibitory neurotransmission. And that can also affect how much LH and FSH is released. So that can also decrease testosterone, almost similarly to how opiates can decrease testosterone.
Low-Dose Tadalafil for Prostate Health and Androgen Receptor Density
Andrew Huberman: I want to go back to the prostate and talk to you about something that's kind of a newer emerging trend. A number of physicians are prescribing low-dose tadalafil — also known as Cialis — to their male patients in dosage ranges of like 2.5 milligrams to 5 milligrams per day, but not for erectile dysfunction. Rather, for improving prostate health and presumably getting a boost in terms of blood flow to the genitalia as well. Is that something that you sometimes prescribe to your patients, and at what age?
Dr Kyle Gillett: Tadalafil is a very underrated medication. The age would kind of depend on the indication. Tadalafil is also a blood pressure medication — it can very slightly decrease blood pressure, especially at higher doses. At higher doses — and a high dose would be 20 milligrams, not 2.5 milligrams — but consistently it can somewhat affect 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 good red-green discrimination, you can take higher doses. But in general I recommend no higher than 10 milligrams a day, usually just 2 or 5 milligrams.
One other benefit 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 — it will generally 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.
Andrew Huberman: Interesting. So you said 2.5 to 5 milligrams per day is kind of typical for these prostate-enhancing effects.
Dr Kyle Gillett: Yes.
Hair Loss — Topical Treatments and Systemic Absorption
Andrew Huberman: 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 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 or disrupt the DHT pathway are going to experience diminished sex drive, diminished motivation, and general diminished 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?
Dr Kyle Gillett: Many people who have just a bit of predisposition can use things that are topical anti-androgens. Ketoconazole is one of them. Caffeine is actually another one.
Andrew Huberman: Wait — you have to explain how this works. How do people get caffeine into the hair follicle?
Dr Kyle Gillett: Topically, the caffeine enters the scalp and 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 anti-androgens. 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 not extremely well. 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 in many people on topical dutasteride therapy.
Andrew Huberman: 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.
Dr Kyle Gillett: My pleasure.