Testosterone & Testosterone Replacement Therapy (TRT) | Dr. Peter Attia & Dr. Andrew Huberman
Chapters
0:05:43 Supplements
12:12 Clomid
15:53 Aromatase Inhibitors
00:00:00.000 | I'd love to talk a little bit about hormone replacement therapy in men.
00:00:09.440 | When one looks on social media and the internet, there seems to be a younger and younger cohort
00:00:13.660 | of guys, people in their teens and 20s showing up to the table thinking that injecting testosterone
00:00:20.640 | cypionate or taking Anivar or whatever it is is going to be the right idea.
00:00:24.580 | There mainly seem to be focus on cosmetic effects.
00:00:27.600 | I'm not a physician, so I can't say whether or not they were actually hypogonadal, etc.
00:00:31.880 | But it seems to me, and correct me if I'm wrong, but it seems to me that similar to
00:00:36.820 | the Atiyah's rule as it relates to longevity, that we could come up with a broad contour
00:00:42.600 | rule in which if a male of any age is not trying to get decent sleep, exercise appropriately,
00:00:51.520 | appropriate nutrition, minding their social connections, etc., etc., the idea of going
00:00:55.720 | straight to testosterone seems like a bad idea.
00:00:59.540 | That said, just like with depression and antidepressants, there is a kind of a cliff after which low
00:01:07.740 | enough testosterone or low enough serotonin prevents people from sleeping, exercise, social
00:01:12.380 | connection, etc., so I do want to acknowledge that.
00:01:14.980 | But with that in mind, how do you think about and perhaps occasionally prescribe and direct
00:01:22.020 | your patients in terms of hormone replacement therapy in men, person in their 30s, person
00:01:26.420 | in their 40s, who's doing almost all the other things correctly?
00:01:30.900 | What sorts of levels do you think are meaningful?
00:01:34.080 | Because the range is tremendous in terms of blood tests, 300 nanograms per deciliter, I
00:01:37.980 | think on the low end now in the US, all the way up to 900 or 1200, that's an enormous
00:01:42.180 | range.
00:01:43.180 | What are some of the other hormones you like to look at, estrogen, DHT, and so on?
00:01:47.500 | So a lot to unpack there.
00:01:50.700 | So let's start with the ranges, right?
00:01:53.380 | So the ranges you gave are for total testosterone, of course, and we don't spend a lot of time
00:02:00.740 | looking at that the way we used to spend more time looking at total and free when I used
00:02:07.900 | more tricks to modulate it.
00:02:09.920 | So I'm actually far more simple in my manipulation of testosterone today than I was six or seven
00:02:15.460 | years ago.
00:02:16.460 | Six or seven years ago, I mean, we would use a microdose of Anovar to lower SHBG in a person
00:02:24.500 | who had normal testosterone but low free testosterone.
00:02:27.740 | What was a low dose of Anovar in that context?
00:02:30.620 | 10 milligrams subling, two to three times a week.
00:02:35.140 | Anovar basically being DHT, Oxandrolone, that guy has used it.
00:02:39.780 | Yeah, exactly.
00:02:40.780 | And again, we're not recommending this.
00:02:41.780 | This is actually, if you're playing a competitive sport, it can get you banned from that sport.
00:02:44.460 | No, no, yeah, yeah.
00:02:45.460 | It can also get you banned from having children if you do it incorrectly.
00:02:49.020 | Yeah.
00:02:50.020 | So a microdose of this has to be small enough that it doesn't impair your body's ability
00:02:54.980 | to make testosterone.
00:02:56.780 | But Anovar has such a high affinity for SHBG that it basically distracts your SHBG from
00:03:03.220 | binding your testosterone.
00:03:05.140 | Freeing up testosterone.
00:03:06.140 | That's exactly right.
00:03:07.140 | So the goal was, how do I just give you more free testosterone?
00:03:09.520 | So if a patient shows up and they've got a total testosterone of 900 nanograms per deciliter,
00:03:14.900 | which would place them at, you know, depending on the scale you look at.
00:03:17.600 | The scale we look at, that would place you at about the 70th percentile.
00:03:21.940 | But your free testosterone is, you know, 8 nanograms per deciliter.
00:03:27.340 | So that's pretty bad.
00:03:28.340 | That means you're less than 1% free.
00:03:30.820 | A guy should be about 2% free T. So that dude should be closer to 16 to 18 nanograms per
00:03:37.820 | deciliter.
00:03:39.580 | So in that situation that I just gave you, his SHBG is really high.
00:03:43.220 | His SHBG is probably in the 80 to 90 range.
00:03:46.900 | That's very high.
00:03:47.900 | Yeah.
00:03:48.900 | Because I think the upper range is somewhere around 55-56.
00:03:49.900 | Exactly.
00:03:50.900 | Yeah.
00:03:51.900 | So we would first backstall for what's driving his SHBG.
00:03:55.940 | So there's basically three hormones.
00:03:57.660 | So genetics plays a huge role in this.
00:03:59.300 | There's no question that just out of the box, people have a different like set point for
00:04:04.740 | SHBG.
00:04:05.740 | Mine is incredibly low.
00:04:06.740 | My SHBG is like kind of in the 30s, 20s to 30s.
00:04:10.920 | But from a hormone perspective, there's basically three hormones that run it.
00:04:14.340 | So estradiol being probably the most important, insulin, and thyroxine.
00:04:20.560 | So we're going to look at all of those and decide if any of those are playing a role.
00:04:24.240 | So insulin suppresses it.
00:04:25.680 | So this is actually the great irony of helping a person get metabolically healthy is in the
00:04:30.480 | short run you can actually lower their free testosterone all things equal.
00:04:35.360 | Because as insulin comes down, SHBG goes up.
00:04:38.400 | And if testosterone hasn't gone up with it, you're lowering free testosterone.
00:04:41.940 | So somebody who goes on a very low carbohydrate diet and attempt to drop some water and drop
00:04:46.720 | some weight is going to increase their SHBG.
00:04:48.920 | Yeah.
00:04:49.920 | If their insulin goes down.
00:04:50.920 | Bind up testosterone, less free testosterone.
00:04:53.440 | I can tell the carnivore diet people are going to be coming after me with bone marrow in
00:04:58.440 | hand.
00:04:59.440 | But then again, after this discussion extends a little further, I'm sure the vegans will
00:05:02.480 | be coming after me with celery stalks.
00:05:04.280 | So then the same is with estradiol, except in the opposite direction.
00:05:08.520 | So higher estradiol is higher SHBG.
00:05:12.720 | So again, occasionally you'll see a guy with normal testosterone, but he's a very high
00:05:18.040 | aromatase activity person.
00:05:20.720 | So he has a lot of the enzyme that converts testosterone into estradiol.
00:05:25.840 | You can lower estradiol a bit with an aromatase inhibitor and that can bring down SHBG.
00:05:29.960 | Now again, these things individually are rarely enough to move the needle.
00:05:34.720 | The last is thyroxine.
00:05:36.040 | So if you have a person whose thyroid is out of whack, you have to fix that before you,
00:05:40.320 | if their T4 is out of whack, you're going to interfere with SHBG.
00:05:44.120 | There are also some supplements, which I think you've probably talked about these on the
00:05:46.680 | podcast.
00:05:47.680 | I feel like I've heard you talk about these on the podcast.
00:05:48.680 | Yeah.
00:05:49.680 | There are a few that will adjust.
00:05:50.680 | You know, there is this idea.
00:05:51.840 | Now there's a much better review.
00:05:53.840 | It just came out.
00:05:54.840 | I'll send it to you.
00:05:55.840 | I'd love your thoughts on it.
00:05:56.840 | I'm reading it line by line, but I'd love input from experts like you on the use of
00:06:02.920 | Tonga Ali for reducing SHBG.
00:06:06.460 | In my experience, it does free up some testosterone by which mechanism, it isn't exactly clear
00:06:12.420 | and the effects aren't that dramatic.
00:06:13.960 | Yeah.
00:06:14.960 | Right.
00:06:15.960 | There are probably multiple effects.
00:06:16.960 | For all we know, it increases libido and it does generally by way of increasing estrogen
00:06:21.240 | slightly, which can also increase libido in some individuals.
00:06:23.640 | So we don't know the exact mode of action.
00:06:26.000 | So we've talked about a few.
00:06:27.000 | The one that a few years back people were claiming could reduce SHBG was stinging nettles.
00:06:33.880 | Stinging nettle.
00:06:34.880 | Well, just urine seems to be, urinating seems to be coming up multiple times on this podcast
00:06:38.600 | for whatever reason.
00:06:40.760 | Stinging nettle extract.
00:06:41.760 | I took the most pronounced effect of that was you could basically urinate over a car
00:06:46.920 | when taking SHBG.
00:06:48.080 | What the underlying mechanism of that was, I do not know.
00:06:51.400 | I took it for a short while.
00:06:52.400 | It didn't drop my SHBG very much.
00:06:55.420 | But it did drop my DHT sufficiently so that I stopped taking it.
00:06:59.920 | I do not like anything that impedes DHT.
00:07:02.920 | I don't care if my hairline retreats.
00:07:05.140 | I don't care about any of that.
00:07:06.720 | DHT to me is something to be hoveted and held on to because you feel so much better when
00:07:13.440 | your DHT is in the appropriate range and love your thoughts on that.
00:07:17.120 | Yeah.
00:07:18.120 | Again, it really depends on the guy and it depends on what risk you're trying to manage.
00:07:21.500 | Right.
00:07:22.500 | My prostate size starts to become one of the issues with DHT.
00:07:25.480 | Luckily, my prostate specific antigen is low and DHT, the things that I know can reduce
00:07:31.620 | it are things like finasteride, Propecia, things like things that people take to try
00:07:36.300 | and avoid hair loss can dramatically reduce DHT and lead to all sorts of terrible sexual
00:07:41.400 | side effects and mood-based side effects, et cetera.
00:07:43.900 | But yeah, so I'm not aware of anything that can be taken in supplement form that can really
00:07:48.080 | profoundly drop SHBG.
00:07:49.080 | Yeah.
00:07:50.080 | We don't spend much attention on it anymore.
00:07:52.320 | Actually, I used to have a much more complicated differential diagnosis eight years ago.
00:07:58.080 | I would drive patients nuts with the whiteboard diagrams I would draw for them when in the
00:08:01.680 | end I think they were just like, "Dude, what do I need to take?"
00:08:05.000 | Today we take a much more simple approach.
00:08:06.400 | The first question is, should you or should you have your free testosterone being higher?
00:08:10.320 | That's the metric I care about is free testosterone is the first most important.
00:08:13.780 | The second most important is estradiol.
00:08:15.120 | Sorry to interrupt you.
00:08:16.120 | You said if you look at your total testosterone, you want the free tea to be about 2% of your
00:08:20.160 | total.
00:08:21.160 | Well, it should be.
00:08:22.160 | Right.
00:08:23.160 | I cannot change that anymore.
00:08:24.160 | So in other words, if a guy's at 1%, then I know I have to really boost his total testosterone.
00:08:28.360 | If he's only going to get one to one and a half percent of it converted to free, I need
00:08:31.760 | to boost him.
00:08:32.760 | And that's why I don't care if he's outside the range.
00:08:34.840 | Like I'll have a guy who's free tea.
00:08:37.200 | I might have to get a guy's total tea up to 1500 to get his free tea to 18.
00:08:41.280 | I see.
00:08:42.280 | So free tea is the target.
00:08:43.280 | Free tea is what we treat.
00:08:44.280 | I like this approach.
00:08:45.280 | And do you still use antivirals to try and lower SHBG?
00:08:50.640 | I don't.
00:08:51.640 | Because it's too potent?
00:08:52.640 | No, because it's just too complicated for patients.
00:08:54.760 | You know, you know, it's a, it's a, it's a drug that can't be taken orally, so you have
00:08:58.640 | to take it under the tongue.
00:08:59.640 | Like a troche or something.
00:09:00.640 | Right.
00:09:01.640 | But then the, you know, I had one patient once who, even though we told him about 87 times
00:09:05.720 | that, he was like swallowing the antivirals and his liver function.
00:09:08.200 | And he was like, we're talking 10 milligrams three times a week is a tiny dose.
00:09:12.520 | And three months of him or whatever, two months of him swallowing that every time tripled
00:09:16.800 | his liver function test.
00:09:17.840 | So it's like, it's just, I was like, you know, it's just not worth the hassle of doing this.
00:09:23.120 | For you know, perfection.
00:09:25.160 | In reality, we can fix this another way.
00:09:26.800 | So, so the first order question is, do we believe clinically you will benefit from normalizing
00:09:34.200 | your free testosterone or taking it to a level, let's call it 80th to 90th percentile.
00:09:40.240 | So upper normal limit of physiologic ranges.
00:09:45.600 | That's the first order question.
00:09:47.140 | And that's going to come down to symptoms and that's going to come down to some biomarkers.
00:09:50.720 | I think there's two years ago, was it two years ago or maybe a year ago, very good study
00:09:54.920 | came out that looked at pre-diabetic men, you've probably talked about this study, and
00:10:00.880 | looking at insulin resistance and glucose disposal with and without testosterone.
00:10:05.640 | And the evidence was overwhelmingly clear.
00:10:08.600 | Testosterone improves glycemic control.
00:10:11.880 | Testosterone improves insulin signaling.
00:10:12.880 | This shouldn't be surprising, by the way, given the role muscles play as a glucose reservoir
00:10:17.380 | and a glucose sink.
00:10:18.660 | So now I include that as one of the things that we will consider as a factor for using
00:10:23.080 | testosterone.
00:10:24.080 | Now, again, it's not the only one.
00:10:25.760 | So you can accomplish that with exercise, you can accomplish that with these other things,
00:10:28.780 | but then you get into a little bit of the vicious cycle of will having a normalized
00:10:32.460 | testosterone facilitate you doing those things better.
00:10:35.760 | So let's just assume we come to the decision that this, this, this person is a good candidate
00:10:41.680 | for testosterone replacement therapy.
00:10:44.160 | The next question is, what's the method we're going to do it?
00:10:47.880 | Are we going to do it indirectly or directly?
00:10:50.420 | Now we used to use a lot of Clomid in our practice.
00:10:55.480 | And have you talked about Clomid on the podcast?
00:10:56.680 | I haven't talked too much about it.
00:10:58.200 | No, we talked a little bit about the fact that some people taking things like an astrazole
00:11:03.160 | to reduce aromatase activity run, can potentially run into trouble because they think, oh, well,
00:11:10.120 | more testosterone, good, lower estrogen, bad.
00:11:12.720 | And then they end up with issues like joint pain, memory issues, and severe drops in libido.
00:11:17.800 | And I think a lot of the reason.
00:11:18.800 | And even fat accumulation.
00:11:20.400 | So if estrogen is too low, you'll, you can develop adiposity in a way that you wouldn't
00:11:24.840 | otherwise.
00:11:25.840 | There's a great New England journal paper.
00:11:26.840 | It's probably 10 years old now that looked at five, I believe it was five different doses
00:11:31.720 | of testosterone cypionate.
00:11:32.720 | So these men were chemically castrated and divided into 10 groups.
00:11:35.880 | It's pretty remarkable.
00:11:36.880 | Somebody signed up for this study.
00:11:38.720 | Yeah.
00:11:39.720 | So you were with and without an astrazole and five doses of testosterone.
00:11:44.000 | So now you basically had five testosterone levels, plus or minus high or low estradiol.
00:11:50.520 | And the results were really clear that the higher your testosterone and the more your
00:11:54.780 | estradiol was in kind of that 30 to 50 range, the better you were.
00:11:59.200 | So if estrogen was too low, even in the presence of high testosterone, the outcomes were less
00:12:05.120 | significant.
00:12:06.120 | So it was 30 to 50 nanograms per deciliter, not 30 to 50% of your, of one's testosterone.
00:12:10.560 | Okay.
00:12:11.560 | Great.
00:12:12.560 | Okay.
00:12:13.560 | So we haven't talked, but clomid is, you know, we have not talked a lot about clomid.
00:12:15.920 | I'd love to get your thoughts on clomid.
00:12:17.520 | So clomiphene is a fertility drug.
00:12:20.240 | It's a synthetic hormone.
00:12:21.680 | It's actually two drugs, M-clomiphene and I forget the other one.
00:12:26.240 | And it tells the pituitary to secrete FSH and LH.
00:12:33.680 | So you, and so the advantage of clomid is it's oral and it's meant to be taken orally.
00:12:41.120 | So you know, a typical starting dose would be like 50 milligrams, three times a week.
00:12:46.580 | And if you do that, you'll notice in most men, especially young men, FSH, LH goes up.
00:12:52.680 | In any man, the FSH and LH go up.
00:12:54.520 | But if a man still has testicular reserve, he'll make lots of testosterone in response
00:12:58.460 | to that.
00:13:01.080 | Because that's the first order question we're trying to answer is, do you, is your failure
00:13:05.800 | to make testosterone central or peripheral?
00:13:08.600 | Yeah.
00:13:09.600 | And I think just one point out, again, correct me if I'm wrong, but my understanding is that
00:13:12.920 | a lot of the drugs that we're talking about, the synthetic compounds, testosterone, estrogen,
00:13:18.760 | things related to growth hormone, et cetera, were discovered and designed in order to treat
00:13:24.360 | and, excuse me, in order to isolate and treat exactly these kinds of syndromes, whether
00:13:28.520 | or not it was the hypothalamus, the pituitary, or the target tissue, the ovaries or the testes.
00:13:33.680 | Correct.
00:13:34.680 | Correct.
00:13:35.680 | Yeah.
00:13:36.680 | I mean, I think the easiest way to go about doing this is just give the hormone that's
00:13:38.880 | missing without attention to where the deficiency is.
00:13:42.680 | Why this becomes relevant is if you have a 35 year old guy whose testosterone is low,
00:13:49.520 | but you can demonstrate that it's low because he's not getting enough of a signal from the
00:13:53.600 | pituitary, why would you bother giving him more testosterone when he has the capacity?
00:13:57.960 | He has the Leydig cells and the Sertulli cells to make testosterone.
00:14:00.680 | He just needs the signal.
00:14:03.680 | Sometimes though, not always, just a course of Clomid can wake him up and he's back to
00:14:08.720 | making normal testosterone.
00:14:10.160 | So he'll do this three times a week, 50 milligrams, three times a week for a short course and
00:14:14.960 | then-
00:14:15.960 | Yeah, we would do that for eight to 12 weeks and then we reevaluate.
00:14:18.080 | And estrogen and testosterone will increase in parallel.
00:14:21.080 | Yes.
00:14:22.080 | And again, it depends, you know, aromatase activity is dependent on how much body fat
00:14:26.380 | you have and genetics.
00:14:29.240 | And if estradiol gets too high, we think if it gets over about 55, 60, we will give micro
00:14:34.720 | doses of an astrozole, but it has to be real micro doses.
00:14:37.800 | I mean, you cannot pound people with an astrozole.
00:14:40.540 | To give you perspective, the sort of on label use, like if you just go to a pharmacy and
00:14:47.160 | order an astrozole, you're going to get one milligram tablets.
00:14:50.160 | Like we can't give anybody a milligram.
00:14:51.840 | They'll feel like garbage.
00:14:53.360 | We have to have it compounded at 0.1 milligrams and we might give a patient 0.1, two to three
00:14:58.300 | times a week.
00:14:59.300 | That would be a big dose of an astrozole.
00:15:01.060 | Yeah.
00:15:02.060 | I think that the typical TRT clinic out there is giving 200 milligrams per mil, one mil,
00:15:09.180 | 200 milligrams of testosterone once every two weeks and then hitting people with multiple
00:15:13.820 | milligrams of an astrozole and they're all over the place.
00:15:17.180 | I've never really understood.
00:15:18.260 | I mean, I guess I shouldn't be surprised, but it's kind of blows my mind that these
00:15:21.860 | TRT clinics are up all over the place given how bad, I mean, I see the results because
00:15:25.780 | I have patients that come from them and I don't understand like why they're so incompetent.
00:15:31.140 | I actually think it's worse than that.
00:15:32.660 | I think that they simply don't understand and don't care because it's a pill mill and
00:15:38.700 | it's a money mill.
00:15:39.740 | I think that nowadays it seems almost everybody who's doing TRT is taking lower doses more
00:15:44.140 | frequently every other day or twice a week, dividing the dose and being very, very careful
00:15:48.420 | with these estrogen or aromatase blockers.
00:15:51.740 | We, most of our patients do not take aromatase inhibitors.
00:15:55.180 | It's not needed.
00:15:56.180 | It's really only the high aromatizers that need it.
00:16:00.300 | And so, yeah, when we'll talk about testosterone, we'll talk about dosing there because I agree,
00:16:03.820 | the more frequently you can take it, the better.
00:16:05.620 | And frankly, you don't need to go more frequently than twice a week.
00:16:09.420 | Because it's so slow.
00:16:10.420 | The half-life.
00:16:11.420 | Yeah, yeah.
00:16:12.420 | The half-life of the drug is, I think it's about three and a half days is the plasma
00:16:13.900 | half-life or something like that.
00:16:14.900 | It could be off a little bit, but twice a week dosing is really nice.
00:16:19.900 | So if you go to a testosterone clinic that's giving you 200 every two weeks, 50 twice a
00:16:27.140 | week is the same total dose, which by the way is a physiologic dose.
00:16:31.220 | That's not going to give somebody any of the side effects you would see.
00:16:34.900 | You're not going to get acne with that.
00:16:36.460 | You're not going to get gynecomastia.
00:16:38.540 | You're not going to get anything.
00:16:39.540 | The only real side effect you get from that is you will get testicular atrophy.