I'd love to talk a little bit about hormone replacement therapy in men. When one looks on social media and the internet, there seems to be a younger and younger cohort of guys, people in their teens and 20s showing up to the table thinking that injecting testosterone cypionate or taking Anivar or whatever it is is going to be the right idea.

There mainly seem to be focus on cosmetic effects. I'm not a physician, so I can't say whether or not they were actually hypogonadal, etc. But it seems to me, and correct me if I'm wrong, but it seems to me that similar to the Atiyah's rule as it relates to longevity, that we could come up with a broad contour rule in which if a male of any age is not trying to get decent sleep, exercise appropriately, appropriate nutrition, minding their social connections, etc., etc., the idea of going straight to testosterone seems like a bad idea.

That said, just like with depression and antidepressants, there is a kind of a cliff after which low enough testosterone or low enough serotonin prevents people from sleeping, exercise, social connection, etc., so I do want to acknowledge that. But with that in mind, how do you think about and perhaps occasionally prescribe and direct your patients in terms of hormone replacement therapy in men, person in their 30s, person in their 40s, who's doing almost all the other things correctly?

What sorts of levels do you think are meaningful? Because the range is tremendous in terms of blood tests, 300 nanograms per deciliter, I think on the low end now in the US, all the way up to 900 or 1200, that's an enormous range. What are some of the other hormones you like to look at, estrogen, DHT, and so on?

So a lot to unpack there. So let's start with the ranges, right? So the ranges you gave are for total testosterone, of course, and we don't spend a lot of time looking at that the way we used to spend more time looking at total and free when I used more tricks to modulate it.

So I'm actually far more simple in my manipulation of testosterone today than I was six or seven years ago. Six or seven years ago, I mean, we would use a microdose of Anovar to lower SHBG in a person who had normal testosterone but low free testosterone. What was a low dose of Anovar in that context?

10 milligrams subling, two to three times a week. Anovar basically being DHT, Oxandrolone, that guy has used it. Yeah, exactly. And again, we're not recommending this. This is actually, if you're playing a competitive sport, it can get you banned from that sport. No, no, yeah, yeah. It can also get you banned from having children if you do it incorrectly.

Yeah. So a microdose of this has to be small enough that it doesn't impair your body's ability to make testosterone. But Anovar has such a high affinity for SHBG that it basically distracts your SHBG from binding your testosterone. Freeing up testosterone. That's exactly right. So the goal was, how do I just give you more free testosterone?

So if a patient shows up and they've got a total testosterone of 900 nanograms per deciliter, which would place them at, you know, depending on the scale you look at. The scale we look at, that would place you at about the 70th percentile. But your free testosterone is, you know, 8 nanograms per deciliter.

So that's pretty bad. That means you're less than 1% free. A guy should be about 2% free T. So that dude should be closer to 16 to 18 nanograms per deciliter. So in that situation that I just gave you, his SHBG is really high. His SHBG is probably in the 80 to 90 range.

That's very high. Yeah. Because I think the upper range is somewhere around 55-56. Exactly. Yeah. So we would first backstall for what's driving his SHBG. So there's basically three hormones. So genetics plays a huge role in this. There's no question that just out of the box, people have a different like set point for SHBG.

Mine is incredibly low. My SHBG is like kind of in the 30s, 20s to 30s. But from a hormone perspective, there's basically three hormones that run it. So estradiol being probably the most important, insulin, and thyroxine. So we're going to look at all of those and decide if any of those are playing a role.

So insulin suppresses it. So this is actually the great irony of helping a person get metabolically healthy is in the short run you can actually lower their free testosterone all things equal. Because as insulin comes down, SHBG goes up. And if testosterone hasn't gone up with it, you're lowering free testosterone.

So somebody who goes on a very low carbohydrate diet and attempt to drop some water and drop some weight is going to increase their SHBG. Yeah. If their insulin goes down. Bind up testosterone, less free testosterone. I can tell the carnivore diet people are going to be coming after me with bone marrow in hand.

But then again, after this discussion extends a little further, I'm sure the vegans will be coming after me with celery stalks. So then the same is with estradiol, except in the opposite direction. So higher estradiol is higher SHBG. So again, occasionally you'll see a guy with normal testosterone, but he's a very high aromatase activity person.

So he has a lot of the enzyme that converts testosterone into estradiol. You can lower estradiol a bit with an aromatase inhibitor and that can bring down SHBG. Now again, these things individually are rarely enough to move the needle. The last is thyroxine. So if you have a person whose thyroid is out of whack, you have to fix that before you, if their T4 is out of whack, you're going to interfere with SHBG.

There are also some supplements, which I think you've probably talked about these on the podcast. I feel like I've heard you talk about these on the podcast. Yeah. There are a few that will adjust. You know, there is this idea. Now there's a much better review. It just came out.

I'll send it to you. I'd love your thoughts on it. I'm reading it line by line, but I'd love input from experts like you on the use of Tonga Ali for reducing SHBG. In my experience, it does free up some testosterone by which mechanism, it isn't exactly clear and the effects aren't that dramatic.

Yeah. Right. There are probably multiple effects. For all we know, it increases libido and it does generally by way of increasing estrogen slightly, which can also increase libido in some individuals. So we don't know the exact mode of action. So we've talked about a few. The one that a few years back people were claiming could reduce SHBG was stinging nettles.

Stinging nettle. Well, just urine seems to be, urinating seems to be coming up multiple times on this podcast for whatever reason. Stinging nettle extract. I took the most pronounced effect of that was you could basically urinate over a car when taking SHBG. What the underlying mechanism of that was, I do not know.

I took it for a short while. It didn't drop my SHBG very much. But it did drop my DHT sufficiently so that I stopped taking it. I do not like anything that impedes DHT. I don't care if my hairline retreats. I don't care about any of that. DHT to me is something to be hoveted and held on to because you feel so much better when your DHT is in the appropriate range and love your thoughts on that.

Yeah. Again, it really depends on the guy and it depends on what risk you're trying to manage. Right. My prostate size starts to become one of the issues with DHT. Luckily, my prostate specific antigen is low and DHT, the things that I know can reduce it are things like finasteride, Propecia, things like things that people take to try and avoid hair loss can dramatically reduce DHT and lead to all sorts of terrible sexual side effects and mood-based side effects, et cetera.

But yeah, so I'm not aware of anything that can be taken in supplement form that can really profoundly drop SHBG. Yeah. We don't spend much attention on it anymore. Actually, I used to have a much more complicated differential diagnosis eight years ago. I would drive patients nuts with the whiteboard diagrams I would draw for them when in the end I think they were just like, "Dude, what do I need to take?" Today we take a much more simple approach.

The first question is, should you or should you have your free testosterone being higher? That's the metric I care about is free testosterone is the first most important. The second most important is estradiol. Sorry to interrupt you. You said if you look at your total testosterone, you want the free tea to be about 2% of your total.

Well, it should be. Right. I cannot change that anymore. So in other words, if a guy's at 1%, then I know I have to really boost his total testosterone. If he's only going to get one to one and a half percent of it converted to free, I need to boost him.

And that's why I don't care if he's outside the range. Like I'll have a guy who's free tea. I might have to get a guy's total tea up to 1500 to get his free tea to 18. I see. So free tea is the target. Free tea is what we treat.

I like this approach. And do you still use antivirals to try and lower SHBG? I don't. Because it's too potent? No, because it's just too complicated for patients. You know, you know, it's a, it's a, it's a drug that can't be taken orally, so you have to take it under the tongue.

Like a troche or something. Right. But then the, you know, I had one patient once who, even though we told him about 87 times that, he was like swallowing the antivirals and his liver function. And he was like, we're talking 10 milligrams three times a week is a tiny dose.

And three months of him or whatever, two months of him swallowing that every time tripled his liver function test. So it's like, it's just, I was like, you know, it's just not worth the hassle of doing this. For you know, perfection. In reality, we can fix this another way.

So, so the first order question is, do we believe clinically you will benefit from normalizing your free testosterone or taking it to a level, let's call it 80th to 90th percentile. So upper normal limit of physiologic ranges. That's the first order question. And that's going to come down to symptoms and that's going to come down to some biomarkers.

I think there's two years ago, was it two years ago or maybe a year ago, very good study came out that looked at pre-diabetic men, you've probably talked about this study, and looking at insulin resistance and glucose disposal with and without testosterone. And the evidence was overwhelmingly clear. Testosterone improves glycemic control.

Testosterone improves insulin signaling. This shouldn't be surprising, by the way, given the role muscles play as a glucose reservoir and a glucose sink. So now I include that as one of the things that we will consider as a factor for using testosterone. Now, again, it's not the only one.

So you can accomplish that with exercise, you can accomplish that with these other things, but then you get into a little bit of the vicious cycle of will having a normalized testosterone facilitate you doing those things better. So let's just assume we come to the decision that this, this, this person is a good candidate for testosterone replacement therapy.

The next question is, what's the method we're going to do it? Are we going to do it indirectly or directly? Now we used to use a lot of Clomid in our practice. And have you talked about Clomid on the podcast? I haven't talked too much about it. No, we talked a little bit about the fact that some people taking things like an astrazole to reduce aromatase activity run, can potentially run into trouble because they think, oh, well, more testosterone, good, lower estrogen, bad.

And then they end up with issues like joint pain, memory issues, and severe drops in libido. And I think a lot of the reason. And even fat accumulation. So if estrogen is too low, you'll, you can develop adiposity in a way that you wouldn't otherwise. There's a great New England journal paper.

It's probably 10 years old now that looked at five, I believe it was five different doses of testosterone cypionate. So these men were chemically castrated and divided into 10 groups. It's pretty remarkable. Somebody signed up for this study. Yeah. So you were with and without an astrazole and five doses of testosterone.

So now you basically had five testosterone levels, plus or minus high or low estradiol. And the results were really clear that the higher your testosterone and the more your estradiol was in kind of that 30 to 50 range, the better you were. So if estrogen was too low, even in the presence of high testosterone, the outcomes were less significant.

So it was 30 to 50 nanograms per deciliter, not 30 to 50% of your, of one's testosterone. Okay. Great. Okay. So we haven't talked, but clomid is, you know, we have not talked a lot about clomid. I'd love to get your thoughts on clomid. So clomiphene is a fertility drug.

It's a synthetic hormone. It's actually two drugs, M-clomiphene and I forget the other one. And it tells the pituitary to secrete FSH and LH. So you, and so the advantage of clomid is it's oral and it's meant to be taken orally. So you know, a typical starting dose would be like 50 milligrams, three times a week.

And if you do that, you'll notice in most men, especially young men, FSH, LH goes up. In any man, the FSH and LH go up. But if a man still has testicular reserve, he'll make lots of testosterone in response to that. Because that's the first order question we're trying to answer is, do you, is your failure to make testosterone central or peripheral?

Yeah. And I think just one point out, again, correct me if I'm wrong, but my understanding is that a lot of the drugs that we're talking about, the synthetic compounds, testosterone, estrogen, things related to growth hormone, et cetera, were discovered and designed in order to treat and, excuse me, in order to isolate and treat exactly these kinds of syndromes, whether or not it was the hypothalamus, the pituitary, or the target tissue, the ovaries or the testes.

Correct. Correct. Yeah. I mean, I think the easiest way to go about doing this is just give the hormone that's missing without attention to where the deficiency is. Why this becomes relevant is if you have a 35 year old guy whose testosterone is low, but you can demonstrate that it's low because he's not getting enough of a signal from the pituitary, why would you bother giving him more testosterone when he has the capacity?

He has the Leydig cells and the Sertulli cells to make testosterone. He just needs the signal. Sometimes though, not always, just a course of Clomid can wake him up and he's back to making normal testosterone. So he'll do this three times a week, 50 milligrams, three times a week for a short course and then- Yeah, we would do that for eight to 12 weeks and then we reevaluate.

And estrogen and testosterone will increase in parallel. Yes. And again, it depends, you know, aromatase activity is dependent on how much body fat you have and genetics. And if estradiol gets too high, we think if it gets over about 55, 60, we will give micro doses of an astrozole, but it has to be real micro doses.

I mean, you cannot pound people with an astrozole. To give you perspective, the sort of on label use, like if you just go to a pharmacy and order an astrozole, you're going to get one milligram tablets. Like we can't give anybody a milligram. They'll feel like garbage. We have to have it compounded at 0.1 milligrams and we might give a patient 0.1, two to three times a week.

That would be a big dose of an astrozole. Yeah. I think that the typical TRT clinic out there is giving 200 milligrams per mil, one mil, 200 milligrams of testosterone once every two weeks and then hitting people with multiple milligrams of an astrozole and they're all over the place.

I've never really understood. I mean, I guess I shouldn't be surprised, but it's kind of blows my mind that these TRT clinics are up all over the place given how bad, I mean, I see the results because I have patients that come from them and I don't understand like why they're so incompetent.

I actually think it's worse than that. I think that they simply don't understand and don't care because it's a pill mill and it's a money mill. I think that nowadays it seems almost everybody who's doing TRT is taking lower doses more frequently every other day or twice a week, dividing the dose and being very, very careful with these estrogen or aromatase blockers.

We, most of our patients do not take aromatase inhibitors. It's not needed. It's really only the high aromatizers that need it. And so, yeah, when we'll talk about testosterone, we'll talk about dosing there because I agree, the more frequently you can take it, the better. And frankly, you don't need to go more frequently than twice a week.

Because it's so slow. The half-life. Yeah, yeah. The half-life of the drug is, I think it's about three and a half days is the plasma half-life or something like that. It could be off a little bit, but twice a week dosing is really nice. So if you go to a testosterone clinic that's giving you 200 every two weeks, 50 twice a week is the same total dose, which by the way is a physiologic dose.

That's not going to give somebody any of the side effects you would see. You're not going to get acne with that. You're not going to get gynecomastia. You're not going to get anything. The only real side effect you get from that is you will get testicular atrophy.