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Andrew Huberman Health Science

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

Andrew Huberman and physician Dr. Kyle Gillett give a full, quantitative field guide to optimizing male hormones across a lifespan. They start with what to measure in blood work (testosterone, SHBG, free testosterone, DHT) and work outward through diet, fiber, caloric restriction, stress, and exercise, then into the supplement stack that raises hormones without suppressing your own production: creatine, betaine, L-carnitine, boron, Tongkat Ali, and Fadogia agrestis, with specific doses. The back half covers low dose testosterone therapy and its whole body monitoring burden, clomiphene and SERMs, alcohol and aromatase, low dose tadalafil for the prostate, and how to fight hair loss without wrecking libido. The recurring theme is that a higher testosterone number is not automatically better, and the prescription tools demand real monitoring.

Published Jul 2, 2026 36:17 video 27 min read Added Jul 7, 2026 Open on YouTube →

At a glance

Andrew Huberman sits back down with Dr. Kyle Gillett, a physician who works on hormone health, for an Essentials episode that is a full field guide to optimizing male hormones across a lifespan. The frame is simple: treat a human like a brand new car off the assembly line and run the diagnostics first, then work outward from lifestyle to supplements to prescription tools. Gillett walks through what to measure in blood work (testosterone, SHBG, free testosterone, DHT), why diet and fiber and vitamin D set the foundation, and why caloric restriction helps a heavy person but hurts a lean one. He then gets specific and quantitative about the toolkit: creatine, betaine, L-carnitine, boron, Tongkat Ali, Fadogia agrestis, low dose testosterone therapy, clomiphene, tadalafil, and the finasteride family for hair. Throughout, Huberman keeps pressing on the same question: not just what moves a number, but whether it actually makes a man feel and function better without shutting down his own production.

Measure before you touch anything

Gillett opens with the analogy that runs through the whole episode. When a brand new car rolls off the assembly line, you hook it up to the computer and run a full diagnostic workup. He wants the same for humans. Puberty makes you a functioning human, but development never really ends, so the job is to monitor progress across the whole lifespan rather than react late.

What to actually pull in blood work: testosterone paired with SHBG, or a free testosterone directly. SHBG is sex hormone binding globulin, the protein that binds up all androgens and estrogens in the body. The stronger the androgen, the more tightly it binds, and DHT, the strongest bioidentical androgen, plays a prominent role in secondary sexual characteristics during puberty. There is a balance to strike. If SHBG is very high, total DHT can run higher because it is not being metabolized, but the free, active DHT drops. So you want both a high enough free DHT and a high enough total DHT. With no major intervention in play, Gillett uses shared decision making with the patient and repeats blood work roughly every 6 months.

That balance between what is made, what gets converted, and what is left free and active is the spine of everything that follows. Here is the cascade the rest of the episode keeps returning to.

creatine slightly shifts this balance

DHT strongest androgen; hair loss, beard Estrogen useful, but too much causes problems SHBG binds testosterone, DHT and estrogen in blood and limits the free, active fraction. Boron can lower a high SHBG.

Figure 1. The steroidogenesis cascade Gillett tells listeners to understand. Cholesterol is the raw material, testosterone the hub, and the two forks (to DHT via 5 alpha reductase, to estrogen via aromatase) decide how a given testosterone level actually acts. Nearly every tool in the episode nudges one arrow.

Diet across the lifespan

Gillett starts the daily protocol with the two foundational lifestyle pillars, diet and exercise, and adds that in puberty sleep is especially important. His first diet rule is a warning against subtraction: do not cut out things that are helping you. Dairy is his example. During puberty, dairy helps raise IGF-1 and free IGF-1, and enough IGF-1 helps you grow, drives genital development and secondary sexual characteristics, and supports long bone growth, skin growth, and hair growth. Suddenly going dairy free can pull that lever the wrong way.

Vitamin D is next, and it does double duty: it supports testosterone production and it drives bone mineralization and stature. Up to roughly age 25, with no hard cutoff, optimizing growth hormone and IGF-1 helps bone density and bone growth. He makes a point that surprises people: you want enough free estrogen while you are still growing, not too much, but enough to stockpile bone so you are protected from osteoporosis, thin bones, and fractures later in life. Estrogen is not the enemy here, it is part of building the skeleton.

On the animal versus plant question, Gillett is balanced but blunt about the extremes. Most people do well on a mix of quality proteins from both animal and non animal sources, plus fruits, vegetables, and starches. A pure carnivore or pure vegan diet in the late 20s might be a reasonable option. In the early 20s, and certainly in the teens, he calls it a horrible idea, because it is likely to significantly decrease free androgens, meaning less testosterone acting on receptors throughout the body.

Then fiber, which he treats as foundational rather than incidental. Fiber is paramount for setting the set point of your gut microbiome for the rest of your life. He frames prebiotic fiber as fish food for your good gut microbes, and the gut microbiome as an aquarium: whatever you feed it skews the tank toward something more beneficial or more detrimental. Prebiotic fiber and essential fatty acids matter throughout the lifespan, and are particularly important through the teens, 20s, and 30s because they support brain development, which continues to develop across the whole lifespan.

Caloric restriction cuts both ways

Huberman replays a distinction from an earlier conversation and asks Gillett to confirm it. If someone is overweight and carrying excess adipose tissue, losing some of it through caloric restriction and exercise, done at a healthy pace and not too fast, is good for testosterone in the long run. But for a lean person who is not carrying excess body fat, caloric restriction actually lowers testosterone.

Gillett confirms it and details the mechanisms in a deficit. You have fewer building blocks for hormones. You sit in a catabolic state more often, so the balance of anabolism and catabolism shifts. Growth hormone and IGF-1 signaling drop. And SHBG rises, which means the free androgens and free estrogens fall. So the same intervention, eating less, can help or hurt depending entirely on where you start.

Stress and purpose

Stress is the next pillar. Through puberty and into the 20s and 30s, people are still working out how they cope with stress and where they put their effort. If someone is over stressed, it topples the other pillars: they stop dieting well, they stop exercising, and everything else goes askew. Stress is not a separate lane, it is the thing that knocks out the other lanes.

The pillar he calls spirit is really the self actualization tier of Maslow's hierarchy of needs: physical needs, mental needs, and then your purpose in life, the thing you genuinely like to do. Huberman adds the reframe that keeps it from being paralyzing. The idea is not to name one final end goal, like naming yourself forever. You pick a goal, reach it, reassess, and pick another. Purpose is allowed to change over time.

Exercise: three to four hard sessions, none over an hour

For vigorous exercise, Gillett puts the sustainable ceiling at about three to four times a week over the long haul. On top of that you can add three or four more sessions of less vigorous movement. The one hard finding he pulls from the research: studies of vigorous exercise, often tracked by rating of perceived exertion, which he admits is imperfect and not very actionable but useful for clinical science, point to a limit. It is not hormonally helpful to regularly train vigorously for longer than an hour. More is not better past that line.

Why young men should not be on TRT

Huberman lays out his own skepticism plainly. Younger men are increasingly asking about and using testosterone replacement therapy, and he thinks that is mostly a mistake. Why would a man in his teens, 20s, or even 30s, whose testosterone and estrogen sit inside the normal reference range, take exogenous testosterone, given the hit to fertility, the trouble that comes when dosing is off, and the fact that it is banned in sport anyway if you are competing. He notes the normal reference range as 300 to 900 nanograms per deciliter, and that his own generation did not think about this until people were in their 40s or 50s, if ever.

Gillett agrees. Everyone has their own threshold for when a benefit outweighs the detriment, but in your 20s it is almost never worth it, and for the very young almost hardly ever. There are rare true indications, like Kallmann syndrome, but those are the exception. For a young man in range, the answer is essentially no.

The supplement stack that does not shut you down

The real center of the episode is what a man with normal testosterone and estrogen can do to optimize energy, libido, and recovery without suppressing his own production. Huberman keeps the goalposts honest: moving testosterone from 600 to 800 is not automatically good, especially if estrogen climbs alongside it. The point is how you feel and function, not just the number.

Creatine leads. It does several things at once: it supports amino acid synthesis, buffers oxidative stress, and acts as a backup fuel tank for your mitochondria by holding reserve ATP. It slightly raises total testosterone and increases the conversion of testosterone to DHT, which makes it potentially valuable even for teens and men in their 20s.

That DHT bump feeds the persistent myth that creatine causes hair loss, traced to a study showing creatine can raise DHT, and DHT drives male pattern baldness. Gillett takes it apart. Preventing hair loss is a poor reason to take or avoid creatine, because creatine does not push you to a supraphysiological level or an abnormal level of androgen binding. It brings you to what you are naturally inclined to have. If your testosterone to DHT conversion is already high, creatine often does nothing to it. What it does is reset the balance between testosterone being aromatized to estrogen versus being 5 alpha reduced to DHT. It will not speed up hair loss more than simply being male already does. In some men it has no effect at all, and in men with almost no 5 alpha reductase activity it just returns them to normal. His verdict, stated plainly: hair loss is not a reason to avoid creatine.

Betaine (and its cousin beta alanine) comes next, looped in with creatine. Some people are creatine non responders, so you can push creatine to 10 grams or use betaine to help with amino acid synthesis and energy shunting. Betaine dose is 1 to 3 grams, and several creatine products already blend betaine in because it helps process methionine and homocysteine. For someone already responding well to creatine, Huberman included, adding betaine only helps if homocysteine, an inflammatory marker that builds up when you are not converting enough of it downstream, is persistently elevated. The way to know is a blood test.

L-carnitine gets the most detailed treatment. It comes in oral capsules and in injectables, and the injectables need a prescription. Injected, under a doctor's supervision, it is usually given intramuscularly as an aqueous solution with no carrier oil, unlike testosterone esters. Inject it too superficially or subcutaneously and it just burns without disseminating through the body, giving only localized effects. Taken orally, bioavailability is very low, maybe only 10 percent, which is why the oral doses are large: Gillett recommends 1,000 milligrams up to 4 or 5,000 milligrams, so 1 to 5 grams a day.

At that dose, especially with a dysregulated gut microbiome, the concern is TMAO, a potential carcinogen that both carnitine and choline can convert into, with your gut microbiota deciding how much. You can blunt that conversion. Garlic contains allicin, which helps lower conversion to TMAO. Berberine also slightly lowers it, probably by altering the gut microbiome, as does simply optimizing that microbiome. Not everyone needs allicin, but it is worth considering at high doses. Huberman says he keeps taking 600 milligrams of garlic every time he takes L-carnitine or alpha GPC choline, but skips berberine because it gives him brutal headaches and carb cravings from dropping his blood sugar. Gillett notes berberine can also cause a dawn phenomenon, dropping blood sugar during sleep without you knowing.

As for what L-carnitine actually does: it is a shuttle, the carnitine palmitoyltransferase system, moving nutrients from outside the mitochondria to inside. It also has a less obvious effect that it shares with tadalafil: it increases the density of the androgen receptor in the cytoplasm. So even if androgen receptor sensitivity does not change and testosterone does not change, more testosterone binds because there are more receptors to bind to. And none of these three, L-carnitine, creatine, or betaine, need to be cycled.

Tool	Typical dose	What it does	Hormonal effect
Creatine	5 g/day (up to 10 g for non responders)	Amino acid synthesis, oxidative stress buffer, backup ATP for mitochondria	Slight rise in total testosterone; nudges the T to DHT balance no cycling
Betaine	1 to 3 g/day	Amino acid synthesis, processes methionine and homocysteine	Helps mainly if homocysteine is elevated no cycling
L-carnitine	1 to 5 g/day oral (10% absorbed)	Mitochondrial fuel shuttle; raises androgen receptor density	More testosterone binds without changing the level watch TMAO
Vitamin D3	Enough to correct a deficiency	Sterol hormone; supports the cascade and bone	Optimizes testosterone only if you were deficient
Boron	5 to 12 mg/day	Acutely lowers a high SHBG	Frees more testosterone not sustained
Tongkat Ali	300 to 1,200 mg/day	Upregulates steroidogenesis enzymes; eurycomanone is the active compound	Raises total and free testosterone, slight LH and DHEA bump; lowers a high SHBG
Fadogia agrestis	300 mg/day, or 600 mg 3x/week	Raises pituitary LH release, acts at the Leydig cell LH receptor	Drives endogenous testosterone watch GGT, alk phos

Figure 2. The non suppressive toolkit, with the doses and mechanisms Gillett gives. Green marks the low maintenance choices, amber the ones that come with something to monitor. All of these aim to optimize your own hormones rather than replace them.

Vitamin D and boron

Vitamin D reappears as a supplement, and Gillett underlines that it is itself a hormone, a sterol hormone. If you are deficient and you correct it, you optimize testosterone. If you are not deficient, correcting a deficiency you do not have will not do the same thing. Huberman confirms he means vitamin D3 specifically.

Boron is the SHBG lever. For a man with very high SHBG, boron can acutely lower it at 5 to 12 milligrams per day, though the effect is not sustained. Boron is depleted in the soils of many countries and, Gillett believes, high in the soils of Greece and Turkey, so dates or raisins from those regions may carry more of it. He floats boron as one possible reason the testosterone reference range runs higher in those countries. Huberman restates the mechanism for listeners: SHBG attaches to testosterone and limits how much free testosterone is available to act on cells, so lowering SHBG frees more.

Tongkat Ali and Fadogia

Now the plant compounds that act on the cascade itself. Tongkat Ali, also called longjack, upregulates several enzymes in the steroidogenesis cascade. Gillett wants listeners to understand where sterol hormones come from, and calls it a good thing to look up: they start from cholesterol and can be shunted easily toward vitamin D, or toward testosterone, estrogens, or progestogens. Tongkat helps the conversion at multiple key steps. Insulin and IGF-1 act as cofactors or upregulators of those steps, which yields a useful rule of thumb: when you are not expecting much growth hormone, insulin, or IGF-1, for example on a lower carb diet or in a caloric deficit while cutting body fat, Tongkat is theoretically most powerful.

Dose runs 300 to 1,200 milligrams a day, and standardization matters. In a general Tongkat supplement, which is by far the most studied, the active plant compound is eurycomanone, so a product standardized to a high eurycomanone content theoretically delivers more effect at a lower dose. Huberman reports his own blood work shows Tongkat raising his free testosterone and slightly raising his luteinizing hormone. Gillett adds that Tongkat can slightly raise DHEA, and that its effect on SHBG is proportional: the higher your SHBG, the more it lowers it, while in men with already normal SHBG it does nothing to SHBG but still raises total and free testosterone.

Fadogia agrestis works one step upstream. It is one species in a genus of interesting plants, and the most studied one. It raises LH, but Gillett is careful: it is not an LH mimetic, it increases the pituitary's release of LH, and it also binds the Leydig cell LH receptor much like hCG does, driving more release. On safety, there is one rat study, and you can roughly equate the toxic dose between rats and humans. Those rats got no antioxidants, and Fadogia raised a couple of pro inflammatory markers: GGT, gamma glutamyltransferase, which comes from both the testes and the liver, and alkaline phosphatase, alk phos, also from both. You can attenuate the rise several ways, and you can simply test to see whether it happened. The rat equivalent dose that produced no effect was an average of 300 milligrams a day in humans. Toxicity in rats does not always transfer to humans, but to be safe Gillett also uses 600 milligrams every other day, or 600 milligrams three times a week, often Monday, Wednesday, Friday.

Testosterone therapy done carefully

Huberman reframes what most people are actually doing. Many men on testosterone already sit at 600, 700, even 800 nanograms per deciliter, so they are not replacing anything diminished, they are augmenting. He asks Gillett to confirm that a low dose given frequently beats the old school single large injection of 100 or 200 milligrams every two weeks, and to walk through a hypothetical: a patient at 600 nanograms per deciliter, estrogen normal, everything checking out, but complaining of slightly reduced libido, poorer workout recovery, and lower motivation without major depression.

Some of the dosing depends on SHBG and free testosterone. A man with extremely high SHBG and a free testosterone of only 2 might need a different dose to reach a normal eugonadal free level. But the general starting range is about 100 to 120 milligrams divided across a week, given every other day or three times a week, occasionally twice a week, with higher SHBG men often getting away with twice weekly. This assumes the ester is cypionate or enanthate. In concrete terms, two 60 milligram injections of testosterone cypionate per week to hit 120 milligrams, which Gillett calls a physiologic eugonadal dose. For many people even 200 milligrams a week is far above the reference range.

The caveat he attaches matters more than the number. Natural testosterone is released in a pulsatile manner, high in the morning and low in the evening. On testosterone therapy you get a steady state instead, so the level is roughly the same at night as during the day. You are trading the body's daily rhythm for a flat line.

Figure 3. What testosterone therapy actually changes about the shape of your day. Natural release peaks in the morning and falls in pulses toward night (amber); frequent low dose therapy holds a flat steady state (blue). The total may look similar, but the daily rhythm is gone.

The side effects a good prescriber watches

Huberman asks what warning signs, in blood work or subjectively, mean that even a modest 120 milligram weekly dose is too high. Gillett's answer is the strongest argument in the episode for not doing this casually: you have to be well versed in every organ system, not just the gonadal one. Acne is common, along with other skin changes and even bruising. Hair loss is common. There can be mental status changes, and because testosterone is dopaminergic it can occasionally tip someone into a manic or bipolar episode. Cardiovascular concerns extend beyond the heart to microvascular ischemic disease and ferritin buildup as estrogen rises. There are fertility concerns and lipid concerns. In his phrase, you need to be hematologist, dermatologist, cardiologist, and lipidologist all at once.

Huberman draws the practical line: knowing whether you have acne is easy, but knowing whether your LDL or apoB is climbing takes blood work. Gillett agrees, and adds that if your prescriber is not versed in all these systems, they should be part of an interdisciplinary team that can monitor them.

Figure 4. One prescription, seven systems to monitor. Gillett's point is that testosterone therapy touches skin, blood, brain, heart, lipids, fertility, and hair at once, which is why it needs a prescriber (or team) who can read all of them, not just a testosterone number.

Clomiphene and the case against SERMs

Some men avoid all exogenous testosterone, no cream, pellet, pill, or cypionate, and instead take clomiphene a couple of times a week, often two 50 milligram tablets. It raises testosterone in a dose dependent way. In the hypothalamus and pituitary it performs negative feedback inhibition by blocking estrogen, crowding estrogen out of the estrogen receptor there, which lifts LH and testosterone.

Huberman cannot find the rationale, and Gillett largely agrees. The main case for a SERM (selective estrogen receptor modulator) is as a very temporary measure that will not suppress pituitary or hypothalamic function, for a man whose testosterone is so drastically low it is unlikely to recover anyway. Most of the time it is not clinically useful, and it should not be prescribed often, certainly not as long term testosterone optimization. There are five estrogen and estrogen related receptors, two of them the main estrogen receptors, and every SERM has a unique profile because it inhibits some receptors in some tissues but not others. Clomid, for instance, can hit receptors in the eye and cause visual changes and blurry vision, especially at higher doses, and it acts in every other tissue too, which is why side effects are common.

Alcohol and aromatase

Alcohol significantly raises aromatase, the enzyme that converts testosterone into estrogen, and the effect is dose dependent. Gillett would not recommend more than three to four standard drinks, noting one huge glass of wine is probably five standard drinks, every two weeks. Two more problems ride along: alcohol carries a lot of calories at 7 kilocalories per gram, nearly the 9 of fat, and it is strongly GABAergic, activating inhibitory neurotransmission in a way that reduces LH and FSH release, which lowers testosterone, in a manner he likens to how opiates suppress it.

The prostate, tadalafil, and night time urination

Huberman raises a newer trend: physicians prescribing low dose tadalafil, the drug also sold as Cialis, at 2.5 to 5 milligrams per day, not for erectile dysfunction but for prostate health and blood flow to the prostate and genitalia. Gillett calls tadalafil very underrated and says the appropriate age depends on the indication. It is also a blood pressure medication that can slightly lower blood pressure, more so at a high dose of 20 milligrams, far above the 2.5 in question. Consistently, it can affect the cones in the eye responsible for red and green vision, though that reverses when you stop, so if you do not need excellent red green discrimination you can go higher. He recommends no more than 10 milligrams a day, usually just 2 or 5.

Two bonus effects: like L-carnitine, tadalafil increases androgen receptor density. And for men with nocturia, waking to urinate at night, it can cut the episodes in half, from two to one, which meaningfully improves sleep, and better sleep in turn supports growth hormone and testosterone optimization.

Hair loss without wrecking your libido

Most hair loss drugs work through the DHT system, and DHT receptors on the scalp are the same ones that drive beard growth on the face. That is why men on finasteride (Propecia) and other DHT blockers can lose sex drive, motivation, and general vigor. Gillett's alternatives for men with just a bit of predisposition are topical anti androgens. Ketoconazole is one. Caffeine is another, and when Huberman asks how caffeine reaches the follicle, Gillett explains it enters the scalp topically and weakly crowds out the androgen, just strong enough to be clinically significant, which is why it is usually formulated alongside other weak anti androgens like ketoconazole.

A caution on the stronger topicals. Spironolactone can be prescribed topically but is absorbed systemically because of its molecule size, so a man should not use topical spironolactone unless a doctor specifically prescribes it. Topical finasteride is a smaller molecule and also systemically absorbed, though not extremely well, and typically lowers systemic DHT by about 30 percent. Topical dutasteride is likely absorbed only a tiny bit and is unique in that its half life is much faster at a lower dose, so, Gillett says from anecdotal experience across many patients, topical dutasteride does not affect systemic DHT at all. That makes it the option that most cleanly protects the hair without paying the systemic price.

Key takeaways

Measure first, then act. Get testosterone plus SHBG or free testosterone, watch both free and total DHT, and repeat blood work about every 6 months. Do not intervene blind.
Lifestyle is the foundation, and subtraction can hurt. Do not cut helpful foods like dairy in development. Get vitamin D, enough estrogen to build bone before 25, prebiotic fiber to set the microbiome, and essential fatty acids across life. Avoid pure carnivore or vegan diets in the teens and early 20s.
Caloric restriction is start dependent. Good for testosterone if you are carrying excess fat, harmful if you are already lean.
Train hard three to four times a week, and keep vigorous sessions under an hour. Longer regular vigorous training is not hormonally helpful.
Young men in normal range should not be on TRT. The fertility and dosing costs almost never justify it under the 40s outside rare conditions like Kallmann syndrome.
The non suppressive stack: creatine 5 g (hair loss is not a reason to avoid it), betaine 1 to 3 g if homocysteine is high, L-carnitine 1 to 5 g oral with garlic to blunt TMAO, vitamin D3 if deficient, boron 5 to 12 mg to lower high SHBG, Tongkat Ali 300 to 1,200 mg standardized to eurycomanone, Fadogia around 300 mg daily or 600 mg three times a week. None of the first three need cycling.
If you do testosterone therapy, go low and frequent: roughly 100 to 120 mg a week of cypionate or enanthate, split two or three times weekly, and accept that you trade natural morning to night pulsatility for a flat steady state.
Testosterone therapy is a whole body prescription. Monitor skin, hair, mood, blood (hematocrit, ferritin), heart and vessels, lipids (LDL, apoB), and fertility. Use a prescriber or team who reads all of them.
SERMs like clomiphene are a narrow, temporary tool, not a long term plan. Side effects, including visual changes, are common.
Alcohol raises aromatase dose dependently and suppresses LH and FSH. Keep it low.
Low dose tadalafil (2.5 to 5 mg/day) supports the prostate, raises androgen receptor density, and halves nighttime urination, which improves sleep and downstream hormones.
For hair, protect the libido. Topical dutasteride appears not to lower systemic DHT, unlike oral finasteride; caffeine and ketoconazole are weak topical helpers; avoid topical spironolactone as a male unless prescribed.

Where it stands

Two honest notes to set alongside the protocol. First, the evidence base is uneven. Testosterone therapy, tadalafil, finasteride, dutasteride, and clomiphene are well characterized prescription drugs, and creatine and vitamin D are among the best studied supplements there are. Tongkat Ali has a reasonable and growing human literature. Fadogia agrestis does not: the safety and efficacy picture rests heavily on animal work, including the single rat toxicity study Gillett cites, and Huberman has elsewhere flagged that he paused his own Fadogia use over liver marker questions. The 300 milligram human figure is extrapolated from rats, not established in a human trial. Treat Fadogia as the most speculative item here.

Second, effect sizes for the legal supplements are generally modest, and the recurring theme, that a higher testosterone number is not automatically better if estrogen rises with it, cuts against chasing any single lever. Gillett is a practicing physician and frames nearly everything around blood testing and shared decision making with a doctor, and the strongest through line of the episode is that the prescription tools in particular demand real monitoring across many organ systems. This is a map of what is possible, not a self prescription.

Chapters

0:00 Kyle Gillett 0:20 Male Hormone Optimization, Testosterone, Tool: Blood Tests 2:17 Diet & Hormone Health, Diary, Vitamin D, Fiber 5:36 Caloric Restriction & Testosterone 6:44 Lifestyle Pillars: Stress, Life Purpose 7:56 Exercise & Hormone Health 8:59 Testosterone Replacement Therapy (TRT) & Young Adults 10:32 Supplements for Testosterone, Creatine & Hair Loss; Betaine, Doses 14:16 L-Carnitine, Forms, Dose, TMAO, Garlic & Berberine 17:29 Vitamin D, Boron 19:10 Tongkat Ali (Longjack); Fadogia Agrestis 23:56 Testosterone Therapy, Dose; Side Effects 28:32 Clomiphene, SERM & Testosterone 31:06 Alcohol, Aromatase & Testosterone 31:58 Prostate Health & Tadalafil, Nighttime Urination 33:59 Hair Loss, Caffeine, Finasteride, Dutasteride 36:02 Acknowledgements

Notable quotes

"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." (0:38, Gillett)
"Your gut microbiome's kind of like an aquarium or a fish tank. Any fiber or food that you're putting in your gut, it's going to skew your gut microbiome towards something that is more beneficial or more detrimental." (3:40, Gillett)
"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." (11:55, Gillett)
"It just kind of resets your balance between testosterone being aromatized to estrogen or being 5 alpha reduced to DHT. So it's not going to speed up hair loss more than just naturally being male does." (12:15, Gillett)
"Testosterone is normally released in a pulsatile manner. So it's high in the morning, low in the evening. Whereas if you're on testosterone therapy, then you're going to have a steady state." (26:35, Gillett)
"You really have to be a hematologist, dermatologist, cardiologist, a lipidologist, the whole nine yards." (27:20, Gillett)
"Tadalafil is a very underrated medication." (32:10, Gillett)

Resources mentioned

Dr. Kyle Gillett and Gillett Health. The guest and his clinic focused on hormone and preventive health.
Huberman Lab. Andrew Huberman's podcast and protocols hub.
SHBG (sex hormone binding globulin). The binding protein that sets your free hormone fraction.
Dihydrotestosterone (DHT) and 5 alpha reductase. The strongest androgen and the enzyme that makes it.
Aromatase. The enzyme converting testosterone to estrogen.
IGF-1 and growth hormone. Growth signals tied to diet and bone.
Vitamin D3. The sterol hormone that supports testosterone when deficiency is corrected.
Creatine and beta alanine. Foundational performance supplements.
Betaine (trimethylglycine), homocysteine, and methionine. The methylation cluster behind the betaine advice.
L-carnitine and the carnitine palmitoyltransferase shuttle. The mitochondrial fuel transporter that also raises androgen receptor density.
TMAO, allicin in garlic, and berberine. The carnitine safety story.
Boron. The acute SHBG lever.
Tongkat Ali (Eurycoma longifolia) and its active compound eurycomanone.
Fadogia agrestis, acting on luteinizing hormone and the Leydig cell, with markers GGT and alkaline phosphatase.
DHEA and hCG. Related hormones referenced in the cascade.
Testosterone cypionate and enanthate. The injectable esters used in therapy.
Clomiphene (Clomid) and the SERM class.
Tadalafil (Cialis). Low dose use for the prostate and nocturia.
Finasteride (Propecia), dutasteride, ketoconazole, caffeine, and spironolactone. The hair loss toolkit.
Kallmann syndrome. A rare true indication for early testosterone treatment.
Maslow's hierarchy of needs. The framing for the purpose pillar.
LDL, apoB, and ferritin. The blood markers to track on therapy.

Full transcript

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. Huberman: Dr. Gillett, great to have you back. Gillett: Great to be back. Thank you. 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? Gillett: There's many things that you should do. An analogy that I often make is when there's a brand new car that comes off the assembly line, you do a full scope of diagnostic workup, hook it up to the computer, and I think we should do the same thing with humans as well. During puberty, obviously you're a functioning human, but I would say there's still development, and I think that the human always develops. I don't think development ever ends, but you want to monitor that progress across a person's lifespan. 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. Gillett: With testosterone, you want to get either testosterone and a SHBG or a free testosterone. Huberman: Could you define SHBG for our listeners, please? Gillett: It is sex hormone binding globulin. It is the protein that binds up all androgens and estrogens 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 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. Assuming that there's no major intervention, using shared decision-making with their physician, usually a good follow-up is about 6 months. 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. 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. Huberman: For our audience, maybe you just mention what having enough IGF-1 can do for us that's beneficial. Gillett: It helps you grow. It helps with genital development, secondary sexual characteristics, and long bone growth. Skin growth, hair growth, a host of things. Huberman: So getting an array of nutrients that include dairy, what other sorts of nutrients are important during development? Gillett: You want to have adequate vitamin D. Vitamin D helps with testosterone production. It helps again with bone mineralization and stature. After an age of about 25, and there's not a strict cut-off, but up to about age of 25, optimizing your growth hormone and IGF-1 helps with bone density and bone growth. So from the dietary standpoint, you want to have enough free estrogen, not too much when you're growing, but you want to help basically stockpile bone to prevent a risk of osteoporosis or thin bones fractures when you're older. 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? Gillett: In their late 20s, it might be a reasonable option. In early 20s and certainly teens, it is a horrible idea because it is likely to significantly decrease your free androgens. So you will have less testosterone acting on receptors through the body. Huberman: Are there any other micronutrients or macronutrients that people in their 20s and 30s should emphasize? Gillett: 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's kind of like an aquarium or a fish tank. Any fiber or food that you're putting in your gut, it's going to skew your gut microbiome towards something that is more beneficial or more detrimental. Huberman: And would you say that the prebiotic fiber and getting essential fatty acids, that would be important to do throughout the lifespan or just for people in their 20s and 30s? Gillett: Throughout the lifespan, particularly important in the teenage, 20s, 30s because it helps with brain development. You're certainly more of an expert than me when it comes to brain development, but it does continue to develop really throughout the lifespan, but certainly through the 20s and 30s as well. 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, they have an excess fat adipose tissue, then getting rid of some of that adipose tissue through caloric restriction and exercise, provided it's done not too fast in a healthy way, is going to be beneficial for testosterone in the long run. But that for individuals who are not carrying an excess of body fat, caloric restriction is actually going to lower testosterone. First of all, do I have that correct? And second, are there any addendums to that that you'd like to give us now? Gillett: That's correct. If you look at an individual in a caloric deficit, several changes will happen. One is that they'll have less building blocks for hormones. Another is that they will be in a catabolic state more often, so that balance of anabolism and catabolism will be different. They'll likely have less signaling from growth hormone and IGF-1, and they'll also have the high SHBG that we defined earlier as the binding protein, so their free androgens and free estrogens will go down. Huberman: Now, what are some of the other pillars of creating the proper environment for hormone optimization? Gillett: Stress is probably the next one. During both puberty but also the 20s and 30s, individuals are figuring out how they want to cope with stress and also figuring out what they want to choose to put their effort into. So if someone is over stressed, then it can put all the other lifestyle pillars, and then they stop dieting well, they stop exercising, and everything else can go askew. Huberman: What would be some of the additional things that everybody should do? Gillett: 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. Huberman: The idea is not to pick the end goal, it's 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 it." Sort of like naming oneself, that you actually can change your goals and purpose over time. 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 anyone can follow that will also support their hormone status? 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. 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 it is not hormonally helpful to train, especially regularly train, vigorously for longer than an hour. 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 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 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? Certainly, if they are not being paid for a particular endeavor, like they're not making money. If they are playing a sport, chances are they're not allowed to do that anyway. It's on the banned substances list. So to me it just seems like a crazy idea. But then again, I'm of a generation that really hasn't thought about doing that stuff until people were in their 40s and 50s, or even never. So is there ever a case for somebody in their 20s or 30s to take testosterone if their blood levels are within the 300 to 900 nanograms per deciliter reference range? Gillett: 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 rare cases like Kallmann syndrome and whatnot, but almost never if you're very young. Huberman: Okay, 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, libido, energy, recovery, etc. and are feeling at least workable for their lifestyle, for those people, what can they do besides get great sleep, train but not too hard or too often, etc.? 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? 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, so kind of holding backup ATP, and it does slightly increase total testosterone, and also increases the conversion of testosterone to dihydrotestosterone. So potentially it's especially useful in men in their even their teenage years and their 20s. Huberman: You mentioned the conversion of testosterone to dihydrotestosterone and there is mythology out there that creatine can increase hair loss. I'm guessing because there's at least one study showing that creatine can increase DHT, dihydrotestosterone, and DHT is one of the primary hormones that can promote male pattern baldness. So the question therefore is does creatine supplementation increase the rate of hair loss? Gillett: 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 physiological level. It's not going to increase your androgens to an unnormal level of binding. Huberman: Sorry, you mean hair loss is not a reason to avoid taking creatine? Gillett: Correct. Hair loss is not a reason to avoid taking creatine. Think of it as just bringing you to what you are naturally inclined to have. If your conversion of testosterone to DHT is already high, then often creatine does not affect this. It just kind of resets your balance between testosterone being aromatized to estrogen or being 5 alpha reduced to DHT. So it's not going to speed up hair loss more than just naturally being 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. Huberman: So what other supplement based tools can people consider? Gillett: Another one we can loop in with creatine is beta-alanine. Some people are non-responders to creatine so you can increase that to 10 g 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. Huberman: Betaine, do you recall what dosage people typically would take if they're a creatine non-responder? Gillett: 1 to 3 g. In fact, several versions of creatine have betaine mixed in because it helps with the processing of methionine and homocysteine. 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? Gillett: Only if their homocysteine is persistently elevated. And homocysteine is kind of like an inflammatory marker that can build up if you're not converting enough of it downstream. Huberman: How would I know? Gillett: Just a blood test. Huberman: 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? Gillett: Correct. You need 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 a carrier oil in it like testosterone esters do. However, if you inject it too superficially, it's not going to make anything. Often, it just burns if you inject it subcutaneously and it does not disseminate throughout the body. 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%. Huberman: So what are the dosages of L-carnitine that one needs to ingest then if they want to get a benefit because I thought only 10% is being absorbed, it's probably a lot of L-carnitine. How much should people take per day? Gillett: Usually, I recommend for oral L-carnitine between 1,000 mg and up to 4 or 5,000 mg. Huberman: So 1 to 4, maybe even 5 g. Gillett: Correct. Up to 5 g 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. Huberman: Is it true that I can offset any negative effects of alpha-GPC, choline that is, and L-carnitine that I take by ingesting garlic? Is that right? Gillett: There's a compound in garlic called allicin. It's also part of the scientific name, the genus of types of garlic. And this can help decrease the conversion to TMAO. Berberine actually slightly decreases the conversion to TMAO as well. Probably through alteration of the gut microbiome. And then just optimizing your gut microbiome can decrease conversion. So not everyone needs allicin, but it's something that you should certainly consider if you were on a high dose. Huberman: I'm going to continue to take the 600 mg of garlic every time I take my L-carnitine, but I'm going to skip the berberine cuz berberine gives me brutal headaches and it makes me crave carbohydrates because it drops my blood sugar. 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. Huberman: Okay, and what we did not talk about is what L-carnitine does. Gillett: It's a shuttle. So I think it's named carnitine palmitoyl coenzyme A. Basically, it just takes nutrients from outside your mitochondria and puts them in. It also has a unique effect, well, not too unique because tadalafil actually has this effect as well, is that it increases the density of the androgen receptor 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. Huberman: Does one need to cycle L-carnitine, creatine, betaine? Gillett: No reason to cycle any of those. 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 are going to have more energy as a consequence of doing these things? Are they going to have a more optimized libido? Are they going to have 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. Gillett: Let's briefly mention vitamin D, which is also a hormone. It's actually a sterol hormone. And if you have deficient vitamin D, and you replace it, then you will optimize your testosterone. Let's also mention boron. So if you have a very high SHBG, boron can acutely help lower it, usually in a dose of 5 to 12 mg 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. Huberman: And just to remind people that SHBG, sex hormone binding globulin, is attaching to the testosterone molecule and limiting the amount of so-called free testosterone that's available to have its impact on cells. 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 mg per day. And then what are some of the other things to optimize testosterone that are in supplement form? Gillett: We can talk about things that affect the steroidogenesis cascade. So we could touch on tongkat ali. I know we've talked about that a little bit before. Huberman: I'm guessing a number of people probably haven't heard that conversation. Gillett: Also known as longjack, and that upregulates several different enzymes in the steroidogenesis cascade. 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 tongkat helps with the conversion of multiple key steps where you synthesize. Another, think of it as like a coenzyme or a cofactor or 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. Huberman: What sorts of dosages of tongkat do you recommend to your patients? Gillett: Anywhere from 300 to 1,200 mg 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 eurycomanone content, which is a plant compound that is likely the main active pharmacological 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. Huberman: My blood work tells me that it causes an increase in free testosterone for me, and also a slight increase in luteinizing hormone for me. What are some of the other effects on various hormones that you've observed in the blood work of your patients taking Tongkat Ali? Gillett: Tongkat can also slightly increase DHEA. And if you have a very high SHBG, again, that's the protein that binds up your androgens and estrogens, an extremely important protein. The higher your SHBG, the more it helps decrease it. So they've studied Tongkat in populations with very normal SHBGs, and it does nothing for SHBG. Huberman: 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? Gillett: Yes. It'll increase their total and free testosterone. Huberman: 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? Gillett: We could talk about Fadogia next. Fadogia's interesting because it's a genus of plants. Fadogia agrestis is one of them. There's many others that are very interesting. That species is likely the most well-studied, and it will increase LH. Huberman: Luteinizing hormone. Gillett: 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. It's a hormone that binds to the Leydig cell, to the LH receptor, kind of like hCG does, and it will increase the release. Huberman: What dosages do you have patients take? I've heard of some potential toxicity to the testicular cells. Gillett: There was 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 pro-inflammatory markers. One is GGT or gamma glutamyltransferase, 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, the safe dose was an average of 300 mg a day. Huberman: So that would be 300 mg a day in humans is the dosage that did not have toxicity. Correct? 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 mg every other day or 600 mg three times a week, often Monday, Wednesday, Friday. 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 ng per deciliter levels. 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 kind of old-school way of giving 100 or even 200 mg in a single injection once every 2 weeks. Is that right? So let me give you a hypothetical. Somebody comes into your office, you do their blood work, and they have blood levels of let's say 600 ng per deciliter testosterone. Their estrogen is also in normal range. Everything else checks out, but they're complaining of a 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? Gillett: Some of this depends on the SHBG and free testosterone as well. So if that same individual had a very high SHBG, if it is extremely high and they have a free testosterone of two, then they might need a different dose because they need enough testosterone in order to have a normal eugonadal free. But a general normal dosing range, especially for someone starting, is around 100 to 120 mg 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. Huberman: So two 60-mg injections of testosterone cypionate per week. Gillett: Yeah, very common dosing. Huberman: To hit that 120 mg per week as kind of the typical average. Gillett: Correct. And I would consider this like a physiologic eugonadal dose. For many people, even 200 mg a week is far above the reference range. All of this is said with the caveat that testosterone is normally released in a pulsatile manner. So it's high in the morning, low in the evening. Whereas if you're on testosterone therapy, then you're going to have a steady state. So your testosterone level is going to be pretty much the same even in the evening. Huberman: In your experience, when patients do that, 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 mg divided into these two or three dosages per week is too high. Gillett: So 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 could 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 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 a hematologist, dermatologist, cardiologist, a lipidologist, the whole nine yards. Huberman: So another set of reasons to, if one is considering using testosterone therapy, to really do this in close communication with a really good physician cuz 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's a whole other biz and that needs to be done through blood work is what I'm hearing. Gillett: Correct. And if your physician that is managing or prescribing your testosterone therapy or your HRT is not well-versed in these systems, you would want him or her to be part of an interdisciplinary team where they have other experts that can monitor those systems. Huberman: There are males out there who want to increase their testosterone and other hormones, maybe growth hormone, etc., who opt to not take exogenous testosterone. So no cream, no pellet, no pill, no injectable cypionate, but decide to take clomiphene a couple times a week. My understanding, I've never done this, is that taking clomiphene maybe two 50 mg tablets a week is what I hear people are doing, will increase what? Luteinizing hormone? The various estrogen receptor subunits? Could you explain how clomiphene would benefit anyone and is this a good strategy? I'm hearing that it's being done quite a lot now. Gillett: It will increase testosterone in a dose-dependent manner, but it has many other pharmacodynamic effects, which is the effect of the drug on the body, other than its effect on the hypothalamus and the pituitary. So in the hypothalamus and the pituitary it does what's called negative feedback inhibition, or it blocks the action of estrogen. So it crowds out estrogen from the estrogen receptor on the hypothalamus and the pituitary. 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. 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 SERM 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 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, 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. Huberman: Alcohol, does it increase aromatase, the enzyme that converts testosterone into estrogen, or not? And is there a dose dependence there? Gillett: 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 2 weeks. The other thing to keep in mind with alcohol is it has a lot of calories, 7 kcal 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 similar to how opiates can decrease it. Huberman: 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 a previous podcast, that 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 mg to 5 mg 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 to deal with erectile dysfunction, but to deal with prostate health and blood flow to the prostate. Is that something that you sometimes prescribe to your patients and of what age? Gillett: 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. A high dose would be 20 mg, not 2.5 mg. 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 really good red green discrimination, you can take higher doses. But in general, I recommend no higher than 10 mg a day, usually just 2 or 5 mg. 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. Huberman: Interesting. So you said 2.5 to 5 mg per day is kind of typical for these prostate enhancing effects. Gillett: Yes. 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 DHT or disrupt the DHT pathway are going to experience diminished sex drive, diminished 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? Gillett: Many people that have just a bit of predisposition, they can use things that are topical anti-androgens. Ketoconazole is one of them. Caffeine is actually another one. Huberman: Wait, you have to explain how this works. How do people get caffeine into the hair follicle? 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 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. 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. Gillett: My pleasure.