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Mark Wulfe:
From The Aasgaard Company Studios in beautiful Wichita Falls, Texas... From the finest mind in the modern fitness industry... The one true voice in the strength and conditioning profession... The most important podcast on the internet. Ladies and gentlemen... Starting Strength Radio!

Mark Rippetoe:
Welcome back to Starting Strength Radio. It's Friday and this particular Friday is not like any other Friday because, you know, that's just the math, right? Days are different, time being what it is. And we have got a couple of special guests today to talk over some very, very interesting topics with those of you gentlemen in the audience that are concerned with testosterone replacement therapy and several other old male health issues.

Mark Rippetoe:
We're joined today by Keith Nichols and Scott Howell. And these guys operate the Tier 1 Health and Wellness Clinic in Chattanooga, Tennessee. And we're very happy to have you guys with us. I appreciate your time today. We're going to get into the weeds on all this stuff today and those of you guys watching probably want to take some notes, so we're going to give you a minute to get a get a pen and some paper. And take notes.

Mark Rippetoe:
And... All right, that's enough time. All right, you got pen and paper, now you're taking notes and these guys are going to share some interesting details about what they do at Tier 1 Health and Wellness in Chattanooga with us. Scott, Keith, sure appreciate your being here.

Keith Nichols:
Thanks for having us.

Scott Howell:
Good to be here.

Mark Rippetoe:
Why don't we start by letting you guys introduce yourselves and let's talk about your background and your your...h, you know, I hate to say educational qualifications, because that's that's so often misleading, but, you know. We...everybody would like to know exactly what's going on here. So tell us about yourselves.

Scott Howell:
Sure. Well, I'm an exercise physiologist, epidemiologist and androgen researcher. I was a mechanical engineer first, but when I got out of the military, I used anabolic steroids for about a decade of my life. And I used really high doses. And when I came off anabolic steroids, it was over 18 months before I even had any semblance of feeling normal again. And I had to go on hormone replacement therapy after that. And that's what led me into becoming a scientist, a researcher, and then moving in to medicine. So I have a unique view of hormone replacement therapy, but androgen metabolism, that's my specialty.

Mark Rippetoe:
Yeah, I think that a whole lot of people are involved in this industry, as we could probably term the testosterone replacement therapy business, that have actually no personal experience with it themselves. And I think that's a problem.

Mark Rippetoe:
I think it's a problem if you've never taken any of this stuff, you don't really know what it does and you don't have an appreciation for the complexities that are encountered by patients that you may be incorrectly prescribing things to. So this is... Personal experiences is... That's what makes a coach and in this particular situation, it's what makes you a therapist as well. Keith?

Keith Nichols:
Well, I got my medical degree from the Medical College of Georgia, and then I did a residency in physical medicine rehabilitation, which most people realize is the specialty for the disabled. The whole job of physiatrist is to maximize function. So it works well with the maximizing hormones. But I was in sports medicine for well over 20 years, was a consultant with the Tennessee Titans, the UFC. I was a ringside physician for them. I was with the staff of the National Predators of Hockey League for over ten years, had a great time doing all that.

Keith Nichols:
But during the course of my medical career, I started developing symptoms of testosterone deficiency. I was misdiagnosed, mismanaged, understood what I went through and realized that so many men that I was seeing, men and women, were going through the same thing. So I decided at that time, well, hey, I'm going to do everything I can to learn everything I can about hormone replacement therapy. And that was well over a decade ago when I did.

Keith Nichols:
And I started two practices at that time, my spinous sports practice along with my health and wellness practice. And the health and wellness practice got so, so busy and there was such a need that I ultimately, two years ago, retired from spinous sports and now I'm full time hormone replacement therapy.

Mark Rippetoe:
This is this is interesting. You guys both have a much better personal experience base with with this topic than the vast majority of anybody in this in this business. And I you know, I've I've been around this shit for 35 years myself, and it is it's so important that people understand exactly what is going on.

Mark Rippetoe:
For example - I have this conversation with people all the time - a guy shows up to, you know, his primary care physician and he's feeling depressed. He's got symptoms of depression. You know, he may or may not be full clinical, you know, trying to kill himself, depression, but he's not happy. You know, he finds himself crying for no reason from time to time. You guys all know all about that. And as a result, he decides something must be wrong, so he goes to his primary care physician.

Mark Rippetoe:
Now, the primary care physician just being basically a clerk, sends him to a psychiatrist. I don't understand this very important thing: if a guy presents, man presents to a psychiatry appointment with symptoms of mild depression, why not before you do any other thing put this guy on TRT? Why would you not do that? Because what is the downside? But they don't think like that, do they?

Keith Nichols:
No. That guy was me and I was a physician. And I went to my primary care physicians and I was misdiagnosed. I was treated with SSRI and had every side effect you could imagine with regard to sexual dysfunction. That guy was me, that that's why I do what I do. But I didn't know any better either, nor did those physicians. I had to figure it out on my own. And once I did well, hey, you know, things were better. But no, I was that guy. So they are not trained in that. Hormone replacement therapy or testosterone replacement therapy is nowhere in our training in medical school or residency.

Mark Rippetoe:
Isn't that amazing? It's as though they are taught that people are suffering from low levels of selective serotonin reuptake inhibitors.

Keith Nichols:
Well Mark, medicine is about is about treating. If you don't treat, then there's no money to be made, whether you be treated, whether you're treated with medications or surgery. That's that's what makes medicine function. So they're there to provide you medications, to keep you coming back and to do surgery on you.

Keith Nichols:
It's not about prevention. It's about treatment. It's it's like owning a restaurant. If nobody's hungry, you're going to go out of business. So we've got to keep the sick-healthy coming in. I wouldn't call them healthy, but you understand what I'm saying. We should maintain the sick.

Mark Rippetoe:
Well, this is this is such a pressing issue that I thought we would kick the discussion off with that because I have been involved with getting people on testosterone replacement therapy for many years. You know, and people come in to the gym and I'm, you know, of course not a doctor. I just... Look you need to go get your test level checked and you need to get some testosterone.

Mark Rippetoe:
So they go do it. And 72 hours later they come in the gym. And... A real good friend of mine, last year, I did this to him and he came back in three days later and said and I could tell when he walked in the door that he was better. I mean, this guy's talking about, you know, suicide and all this other insane shit. And I I walked in the door and I said, Oh, shit.

Mark Rippetoe:
And he walked through the office door and he said, "You were right." Big smile on his face. It's just it's so astonishingly... It's a significant and abrupt improvement in all of the parameters that define depression for most men.

Scott Howell:
The interesting thing about that is that falls right in line with what we know about androgen receptor signaling. We have non-genomic fast effects and some of those happened rapidly in seconds and minutes. And then you have the effects of testosterone as a transcription factor to make proteins, to repair tissue like muscle tissue. Some of these effects are really fast on the vasculature, neurotransmitters. And so it's not without the realm to for anything like that to happen. It very well could, don't you agree?

Keith Nichols:
Right, but we do encourage men to give things time. It's not only getting enough of the hormone to exert a response, it's giving it time to work. And some issues can take, you know, several months to improve. But they will improve if you just give it time, if it's related to to testosterone insufficiency.

Keith Nichols:
I always tell our patients that the number one reason people stop hormones like testosterone around the world is that they didn't they didn't get the results they expected in the timeframe they wanted. They want it quick and they want what they want. And it doesn't always work that way.

Mark Rippetoe:
Well, but if it's... If the therapies underprescribed, if the dose is is lowballed, you know, this the idea that you titrate up. In a situation like this, I could see how that might be frustrating to people who I have just told 72 hours. And they go to it, they go to their their doctor and the guy gives them 25 mg of test propionate and they go back home expecting something to take place and it doesn't.

Keith Nichols:
Well, you're jumping into the meat, right off the bat.

Mark Rippetoe:
Well, so much of this I just don't understand how these guys...

Keith Nichols:
Well, believe it or not, that's that same thing happens with testosterone clinics around the country themselves. I mean, the average number of clinics that a man has seen when they see me is typically three. They've already been to three clinics.

Keith Nichols:
And once some of the the common denominators that went wrong, you know, it is a simple formula that you're outlining there. It's it's A plus B equals C. What is A? It's getting enough of the hormone to exert a response. Most men never got enough of a dose to exert a response that you're describing. B is giving it time to work and C is symptomatic improvement in the symptoms related to the deficiency. It's as simple as that. Most men never get enough, though. They never get enough.

Mark Rippetoe:
Yeah, that's that's what I've seen. Certainly what I've seen. This extremely conservative approach to this. And once again, to go back to my original point. If somebody presents at your clinic - and I'm not putting words in your mouth here - but if somebody presents at your clinic and you decide to put 400 mg of test cyp in this guy's butt and send him home. What's the worst possible thing that could happen? Does he die or does he contract cancer? Does he contract covid-19? I mean, that's the worst thing that could possibly happen right now, right, is you get covid-19. But surely four hundred milligram of testosterone cypionate wouldn't give a man covid-19.

Mark Rippetoe:
So what is the downside to a big loading dose of testosterone? I don't know what it would be. Especially for a male. Now, you don't want to do it to your wife. Well, maybe you do, but but, you know, to start off conservative with a therapy like this, I just don't see the point in it.

Scott Howell:
Well, there is a wide variation in response to therapy. And what I mean by that, it's going to get into some of the stuff that's never been talked about on a podcast before... So there's a wide variation in response. Some people need less. Some people need more, quite a bit more. But it's... We have to find what that is. And there's a genetic reason for it.

Keith Nichols:
So today we want to answer the question that kids ask so much: is why do some men need more than others? We're going to answer that today.

Mark Rippetoe:
That's a real good that's a real good point, because a lot of people that have have started down the road toward testosterone replacement therapy have gone to their primary care physician and and they say, OK, we'll do a hormone assay on you. And then they they they draw the blood and the test comes back and they say, yeah, your your testosterone, your free test is 325. And that's within the reference range. So there's nothing... You know, you're fine.

Mark Rippetoe:
Three bullshit statements in a row. Right?

Scott Howell:
Right. Well, there's a lot of. I'll have to ask you this question, though. The party line that you'll read about all the time and that you say is the minimal effective dose to resolve symptoms. Right? Right. That's just perpetrated over every forum. T clinics, minimum effective dose to resolve symptoms. But I'll ask you this, Mark. We can agree there's probably a minimal dose that will improve symptoms, but there's also a dose where you get the maximum benefits of testosterone and symptomatic improvement without causing any harm.

Mark Rippetoe:
That's the optimal dose.

Keith Nichols:
That is the optimal dose. But this these guys on these forums, however, think that 200 oh, anything 200 or above or 200 is the maximum you should ever need anything and above that is abuse. We're going to explain today that some need more than that. And that is just what is perpetrated right by the internet.

Mark Rippetoe:
So very frustrating.

Keith Nichols:
It is. So I mean, so before we talk about why people need more than others, you know, on your previous podcast, there's a lot of guys listening that are out there exercising, following your advice and just feeling terrible.

Keith Nichols:
They'll work out and they can't work out for days in a row because they they hurt so bad or are so fatigued. And so the guys out there don't really know a lot of the symptoms of low testosterone. They're they're very non-specific. Reduce sexual desire and libido is one, the decrease the number of morning erections is a big one. Erectile dysfunction, fatigue, physical exhaustion, irritability, depression as you've mentioned, poor concentration and memory, poor physical performance, weight gain, increase in body fat, decrease in muscle strength, decrease in muscle mass, decreased energy, motivation, initiative and self-confidence, joint pain, muscular aches. I had all those. Sleep disturbances as well as daytime sleepiness. All of that occurs.

Keith Nichols:
But when you optimize levels like you're talking about, in other words, getting that dose that maximizes testosterone versus just symptomatic improvement, then you're going to maximize an increase in lean muscle mass, strength, endurance, healing capacity, exercise tolerance, bone mineral density, energy, motivation, initiative, self-confidence. It improves libido. Sexual performance. Improves your cholesterol, as you know. Improves memory. Cognition. Decreases body fat, both visceral and subcutaneous. Prevents and treats fepression. Prevents Alzheimer's disease. Osteoporosis. Decreases fatigue.

Keith Nichols:
How much of that do you want Do you want a little bit of that or you want a lot of that?

Mark Rippetoe:
In other words, it makes you younger.

Keith Nichols:
It makes you healthier.

Mark Rippetoe:
It makes you healthier like you were when you were younger. Yes. It's all about that's a very good point. How much of all of that stuff do you want? A little bit of it or do you want the most you can get? The optimal.

Keith Nichols:
You do. Now, listen, I get accused, Dr. Nichols, the levels they put me in and they don't know the long term danger they're causing. And what levels are we talking about? Well, hey, a free testosterone thirty, forty, fifty, sixty is a great free testosterone. Those men are going to run between one or two thousand typically on average. OK, you got to remember, whenever I was misdiagnosed, the normal range went up to fifteen hundred. All right. So if you walk to your doctor office today...

Mark Rippetoe:
And they've lowered over some bizarre.

Keith Nichols:
To nine sixteen. So, I mean, the point is, is that whenever you put a man in an optimal range, which we're talking about, what you're talking about, every parameter of health improves everything that we can measure. Everything. Now, what is the harm in that long term? What damage are we doing there?

Mark Rippetoe:
Well, you know, it's an excellent question, isn't it? Why would a clinician be concerned with the long term damage when the short term effects of hypogonadism may include suicide? What the hell are you guys worried about, you know, a guy carrying around a twelve hundred testosterone level if he feels good and he's performing better and every aspect of his physical existence is improved. And you're here worrying about what's going to happen to him forty five years in the future.

Mark Rippetoe:
Well, let me tell you what happens forty five years in the future, you die. We all do that. Well, you know, we're all going to die and we're going to die of something, right?

Keith Nichols:
Well exatly, but the dangers of a man with low testosterone, the danger is not doing it. Not doing it. And so the point I'm trying to make is that whenever you get men at an optimal range, an optimal level, everything improves. Every aspect of their health improves. There is no long term harm. You're increasing their health span.

Mark Rippetoe:
No, I absolutely agree.

Keith Nichols:
This fear of something bad going wrong that hasn't does not occur. They live longer, healthier lives. The end.

Mark Rippetoe:
That's all there is to it. And it's been my experience that the most profound changes, the most the most easily noticed changes, the ones that come on the quickest are not the physical, they're the psychological. The psychological benefits are, like I'd said, 72 hours. It's astonishing how fast the guy walks back in and says "I'm better. I'm better, I like I used to be. I'm normal, I'm not sad" And so you want him a little less sad, so you gave him 25 milligrams???

Scott Howell:
Well, that's that's like castration level dose. But there's a lot of limitations to normal reference intervals and clinicians that are trained in that box thinking - you're in the box, you're good, if you're outside the box, you're not. There's a lot of limitations to that.

Mark Rippetoe:
Well, those people are.... That's what that's what an RN does. Right, and not even a good RN, but that's what that's what LVNs do. They they're taught, they're trained, they're not educated, and they respond to these little intervals they've learned and memorized. And and that's not that's not clear thinking, but it permeates this industry.

Keith Nichols:
Well, let's understand what the normal range is for testosterone. It's just a population average of men that were tested with a BMI less than 30. You and I talked really briefly before and you hit the nail on the head. What the problem with with with everyone in general, the consumers and the physicians, is that normal is not synonymous with healthy, asymptomatic and free of disease. They they think that it is. But it's not. The range of testosterone. It's not a healthy range. It's just the range of the population of men they tested, which are not healthy men.

Mark Rippetoe:
A statistical average. And that's all it is.

Keith Nichols:
Boys and men of sick boys and men of boys and men.

Mark Rippetoe:
The statistical average. It's just so weird that that... It's so weird to me that people are not taught any more about what they're seeing on blood tests. Every one of those reference ranges, if you've got a 14 parameter panel in front of you, every one of these ranges has been arrived at by the company that makes the machine. And they've gone out and surveyed a whole big giant ass population and the, you know, if you present in the office and you're supposedly free of symptoms and they measure this range and they add you to the 20000 member database, you got an N of 20000. Then the middle of that is where you're supposed to be. I don't understand that thinking.

Keith Nichols:
Well, the problem with that normal range of testosterone is those men aren't aren't aren't screened for severe symptoms of testosterone deficiency. I mean, there is no number that denotes a deficiency with regard to testosterone. There's a lot of individual variability with what number a man develops symptoms, but nonetheless, it's just a population average. And what kills me is that the word "superphysiologic" has this negative connotation. Whenever anything above 916 now is super physiological. You are super physiologic, whatever that means.

Keith Nichols:
So men should not want to be within the sick normal range. You want to be...

Mark Rippetoe:
Super-physiologic is what you'd like to be. I mean, if you'll think about it at the really good word. Super-physiologic.

Scott Howell:
Well, you know, there's nowhere in the Western culture that you can sample a population of healthy individuals. You would have to sequester individuals on the island. You'd have to feed them good nutrition, make them physically active, make them get their rest, and then you might be able to see what healthy levels are.

Mark Rippetoe:
Right. But if you just take an average sample of the general public what do you think you're getting? I you know, I really don't understand.

Scott Howell:
Well, I think a lot of people misinterpret hormones to equate to other measures.

Keith Nichols:
Like potassium or calcium, you know, but they're not it's not that way.

Scott Howell:
Not in any stretch. And the variation that he talks about is it's substantial. And so there's about a 40 to 50 percent variation in response from man to man in response to testosterone therapy. And the reason why that occurs in this - I'm talking about when dose is equated. So we equate dose, like a starting dose, there's a 40 to 50 percent variation in response.

Scott Howell:
And the reason that that is there is because there's a single genetic mutation, it's a polymorphism on the androgen receptor gene. It's X-linked. It's on the X chromosome. Both men and women have it. We all have it. But the links to this mutation differ between person to person.

Scott Howell:
So if someone has a short length of this mutation, it's called CAG repeat, then they have a C-A-G repeat. If they have a short length of it, then they'll respond to therapy very quickly at the lowest dose and become asymptomatic.

Scott Howell:
As this length grows, there's a decreased sensitivity of the androgen receptor defined response elements of target genes to do what to do transcription and translation of proteins. And so at a certain point, around 40, it becomes pathologic and it develops into things like Klinefelter's syndrome, Kennedy's disease, really severe genetic disorders.

Scott Howell:
And it's ironic because a lot of the clinics that prescribe testosterone or aromatase inhibitors, they use one study by Pavlovitch in 2001 to justify that use. But it was in Klinefelter's patients =-severe genetic morbidity.

Mark Rippetoe:
You investigate a bunch of people with a profound pathology and then transpose that or to extrapolate that out to the general public, right? Yes that's brilliant methodology.

Keith Nichols:
So what Dr. Howard just said is the reason that some men need more testosterone than others is purely genetic based on the androgen receptor polymorphisms. If you have a long CAG repeat, you're not sensitive to it. If you have a short CAG repeat, you're sensitive to it. Every man differs.

Mark Rippetoe:
In other words, the reference range that you present is utterly meaningless if you're symptomatic.

Scott Howell:
Well, if just the 40 percent variation on the low end, it expands the interval quite a bit. But in 2017, I think Jay had mentioned this on the previous podcast, it dropped, it was almost 300 nanograms per deciliter off the top end. OK, well why did that occur? Was it age-Related? Was it disease related?

Scott Howell:
Well, we do know that endocrine disruptors are implicated in a one point six percent decrease in testosterone levels per year on average. Trevisan, the one that harmonised the reference intervals in 2017 was the same person that sounded the alarm on the endocrine disruptors in 2007. And since that time, even in 2007, Anderson, in Europe, they went back 50 years and they established at one point five percent decrease in testosterone levels per year that could not be attributed to anything else in the analysis, not BMI, not age, not anything that they could adjust in the analysis.

Scott Howell:
And it was concluded in the Travison study that there must be an environmental exposure in place. And since that time, 2007, it's been replicated in Brazil, it's been replicated in Canada, it's been replicated in Europe. It's been replicated at least 10 to 15 times. And the number is similar. And so we do know there was a congressional hearing in 2010 where some of our best scientists testified in front of Congress in a closed hearing, along with scientists from around the world studying the endocrine disruptors. And they were concerned about increased rates of Type two diabetes, hypothyroidism, autism rates. There were some other things, Keith. What was it?

Keith Nichols:
So point that we're trying to make is that men get accused of abusing testosterone when they legitimately have a need based on their genetics as well as their exposure to toxins in the environment.

Mark Rippetoe:
Well, what I what I think you're saying here with this observation that the the reference range has been lowered over the years, is that apparently, we've got environmental influences that are actually lowering testosterone levels. They're measuring the lower testosterone levels as a result of environmental influences.

Keith Nichols:
Correct.

Mark Rippetoe:
And therefore lowering the reference range.

Keith Nichols:
Correct.

Scott Howell:
Without questioning it.

Mark Rippetoe:
With a complete and absolute misunderstanding of what it is that they're seeing.

Keith Nichols:
Correct. Not only does it lower your levels...

Mark Rippetoe:
Do you guys realize how astonishingly stupid this is? You know, you see the the the average at the at the top go go down from 1200 to 900. You watch that go down and then you say, well, you know, then we need to adjust the reference range down without trying to explain why it went down and what might be wrong with it going down. That's just boggles the fucking mind.

Scott Howell:
Well, as we talk about it every day here.

Keith Nichols:
But it just confirms that that range is not a healthy range, they're sick, poisoned men. That's what we need to hit home. Not only are they producing less, they can't use what they're what they're what they're producing because the chemicals also are interrupting with its metabolism. So it's even worse than than it seems.

Keith Nichols:
And here's what's amazing, is that the Endocrine society, if you go to their website, if anybody that's listening to this goes to the Endocrine Society website, they have a whole section on endocrine disrupting chemicals and they will discuss the havoc that it's wreaking on our endocrine system with regard to especially men and women. But men with regard to testosterone and how it blocks testosterone's metabolism.

Keith Nichols:
Here's the problem. Even though they acknowledge that they're there and that this is occurring, it doesn't factor into any treatment guidelines.

Scott Howell:
And to build on top of that, what he's saying. They even acknowledge that there's androgen insensitivity of genetic origin, but they don't offer any clinical guidance on how to deal with that. So if we have this trial data that we've known about since 2001 and it's that big, a variation will establish established literature, then why aren't we actually acting on it in practice?

Scott Howell:
And so what we see in practice was some people needing to be titrated up more than once. Some people need to be titrated down. It fits exactly into what the literature shows. And it's it's unfortunate that some people can't get testosterone treatment when they need it.

Mark Rippetoe:
Oh, it's more than unfortunate. Scott. I disagree. I don't think it's merely unfortunate. I think it's I think it's unprofessional for a clinician to present themselves as prepared to do professional work when they're not. That's unprofessional, it's more than just unfortunate. I understand you guys don't like to talk ugly about people, but I kind of don't mind.

Scott Howell:
Well, here's the thing. It took me... It took us... So it took about 13, 14 years for me to find that mechanism. And I searched and searched. It was one of the things that I searched my whole almost my whole career as a androgen researcher to find why some people, for example, when guys go into a gym and some guys will take a low dose of anabolic steroids and they will not hardly train hard, they won't dial in their nutrition and they just respond through the roof.

Scott Howell:
And then you have another guy that takes massive doses, does everything right, and he never gets anywhere. So why is there a differential response?

Keith Nichols:
I'll tell you what a blow your mind even more is when you look at that CAG repeat link, the longer the length, those guys have higher free testosterone levels. So those are the guys coming into a clinic with normal levels, five, six, seven hundred that are still symptomatic because they're insensitive to it based on the number of their CAG repeats. So that's the amazing thing about it, is the guys with the higher levels are the most sense... Insensitive to it.

Mark Rippetoe:
Right. It you know, if you if you think about it for just a second. But that seems logical, you know. I mean, the guy's just not feeling what he's got.

Mark Rippetoe:
So what is the answer?

Keith Nichols:
His sensitivity is reduced. That's right.

Mark Rippetoe:
So the doctor tells him, you know, well, you know, but your levels are high enough, so you're not supposed to be feeling this way. So go home and continue to feel this way, but but be... But rest assured that your number is where it needs to be.

Keith Nichols:
That's correct.

Scott Howell:
What they're going right... They're going exactly by the clinical guidelines are not reading literature. And so we practice evidence based medicine and try to use the best evidence that's there to guide practice. And this is something that we've been really passionate about, trying to find out why that variation is there.

Scott Howell:
And it's ironic. It's just been established this long. But when guys have Kennedy's disease, they fit it right into what Dr. Nichols was talking about with the high LH, the high free testosterone level. But their CAG repeat is at 40 or beyond. And so it's huge. It's long. And so the insensitivity there and everyone has a degree of sensitivity or insensitivity.

Keith Nichols:
So so have we answered why some mend to more than others with the genetic polymorphisms?

Mark Rippetoe:
Yeah, I think that I think that we've established that any physician that tells that that pulls one hormone test on you and does one assay and then announces to you that your your testosterone is 375 and that's within the reference range. And so I can't give you any testosterone. You need to you need to first thing you need to do is not pay him. Get up and do not pay him because he doesn't know what the fuck he's talking about.

Mark Rippetoe:
So this is terribly important. You don't reward incompetence with money. All right. Really honest to God, you don't, but it's done all the time anyway. That's part of the problem with paying before you go in the office. You know.

Mark Rippetoe:
Some, you know, I've I've been in doctors offices so many times when I when I'm about halfway through the conversation with this guy, I think to myself "I know more about this than he does. And I'm supposed to pay him? You know, but it's already been done. So.

Mark Rippetoe:
Well, you guys had mentioned an interesting aspect of this, there are so many people involved in the TRT business that just reflexively prescribe along with testosterone, they reflexively prescribe estrogen blockers. This is this is terribly interesting. I don't think a lot of people understand this, so let's talk about that for a while.

Scott Howell:
Well, there's a lot of harm that's caused by the prescribing of aromatase inhibitors. And this was actually one of the first phenotypes of injury I mapped out in athletes and bodybuilders using anabolic steroids.

Mark Rippetoe:
Scott, let's explain what goes on with aromatasization, because I don't think that that's generally appreciated. You know, talk about the the the hormone cascade, so to speak.

Scott Howell:
Well, testosterone can be considered a prohormone and it has two main metabolites. And those two main metabolites are actually created through two enzymes. And so one is the aromatase enzyme and the other is 5-alpha-reductase.

Scott Howell:
OK, with aromatase it aromatizes testosterone into estradiol, E2. And most of the main health benefits of testosterone are mediated through that aromatized to estradiol because. I'll get to it in a second...

Mark Rippetoe:
In other words, estradiol is necessary for the beneficial effects of testosterone and there is supposed to be a level of aromatization, a level of conversion from testosterone to estradiol.

Scott Howell:
The aromatase gene autoregulates, yes, there is. And it's different for every person. The aromatase gene autoregulates the amount of aromatase in the body at any one given time, given the internal physiology. And so if you input testosterone, your aromatase gene will autoregulate the amount of aromatase expression unless someone's morbidly obese - and obviously their bodyfat is going to drop when they go on testosterone therapy because it, but that's a different mechanism.

Scott Howell:
But what I'm trying to get to is that any time that process is attenuated, dampened, it causes pathology on a continuum. And the best way to examine it is to look at those that have severe genetic disorders with aromatase deficiency or aromatase surplus. Now, there's only really 20 or 30 documented cases of either one in the literature.

Scott Howell:
And so most people, ninety nine point whatever of the population don't fall into that category. And so, for example, with Klinefelter's syndrome, that disorder causes a need to control estradiol. And that's the reason why they conducted that study. But if you consider athletes and bodybuilders...

Mark Rippetoe:
So, Klinefelter's syndrome, let's talk...what is specifically Klinefelter's syndrome?

Scott Howell:
Klinefelter's is a disorder where there's two X chromosomes and one Y chromosome. And usually the actual number of CAG repeats on the androgen receptor gene on both of those chromosomes are different. And so one is... Has a dominance over the other. And so what happens is Klinefelter's patients, usually they almost certainly need to be on testosterone therapy, but sometimes their estradio has to be controlled as well.

Scott Howell:
But it's that's... They have gynecomastia most often, but their bodyfat distribution is similar to a pear shape or what would be with a woman. And so they have the libido issues and things like that, but their CAG repeat is long as well and so they have a decreased sensitivity to androgens.

Keith Nichols:
And the paper he refers to was done with Klinefelter's patients and others with genetic disorders, where that 10 to one testosterone to estradiol ratio came about, it was not based on normal men or men on testosterone. So you read on these forums or clinics where everybody's aiming for that 10 to one, that was based on a paper done by Pavlovitch 2001.

Mark Rippetoe:
What should the ratio be?

Scott Howell:
It shouldn't be controlled. The aromatase gene autoregulates that. And the issue...if you look at evolutionary biology, it is thought that the aromatase gene concurrently evolved with the androgen receptor gene to protect the organ systems of mammals. So that's the estradiol protecting those organ systems. And that's just a common sense thing looking at a perspective of macro view.

Mark Rippetoe:
What are the effects of estradiol? How does it work?

Scott Howell:
Estradiol for one, let's, for example, when men go on testosterone therapy, sometimes they gain water weight. Right? And that's because testosterone stimulates antidiuretic hormone. So that increases it. When there's enough aromatized estradiol, in attenuates it and drops it back down. And so if that process is not.... Left alone, that water weight will resolve in eight to 12 weeks.

Scott Howell:
And so people automatically think - and it's younger guys mostly on forums and things - they think that if you take testosterone or you increase the dose of testosterone, the estradiol is going to keep on going up exponentially.

Mark Rippetoe:
And they perceive that the estradiol is competing with the testosterone for the anabolic effects. That's what I guess they perceive, right?

Keith Nichols:
Yeah, well, you need to talk about the with estradiol, but, you know, there's this paper here that... And here's the problem, Mark, is that men think that as they increase their androgen dose, that the estradiol is going to climb along with it exponentially. That doesn't happen.

Keith Nichols:
During testosterone administration, both estradiol and DHT exhibit saturable increases with the dose. Meaning that they reach a Vmax, a point of maximum metabolism. All right. So we only have so much aromatase enzyme. Once you get enough androgens in you and that aromatase enzyme is fully saturated, it can't produce any more estradiol.

Keith Nichols:
That's why as you increase androgen dosages, that estrogen to androgen ratio goes down and both young and older men. So as your testosterone, your testosterone grows is a thousand, your estradiol is is thirty five. It goes to 1500 your your your testosterone, your estradiol may climbto 62.

Keith Nichols:
That estrogen testosterone ratio has diminished. It doesn't keep climbing. Once you reach let's say you reach a level of two thousand of testosterone, your estrogen may be done depending on your level of aromatase enzyme. So it reaches a saturation point where it won't rise anymore. It can't because you can only aromatize so much due to the maximum rate of metabolism.

Scott Howell:
And it's the same for 5-alpha-reductase. And a lot of guys are concerned about DHT. Right. And so it's the same. It's every... Every enzyme or every product produced by enzyme is rate-limited by the amount of that enzyme in the body.

Scott Howell:
And so that's why it's one of the things that I found was a lot of people that would complain of androgen insensitivity. They would say their receptors were downregulating when they had been on testosterone for weeks or whatever. That doesn't occur. Androgen receptors upregulate in a dose response. And I was never able to find an upper ceiling to that literature. I know it's there. I just haven't found it. I know it's there because it's saturable.

Mark Rippetoe:
So the the bottleneck are those two enzymes, not the hormones.

Keith Nichols:
And I find it amazing that when you're treating men, when you see them come in that have been to multiple other clinics and they never reach an optimal level, they tend to be the ones that have all the problems. It's amazing that when a man gets an optimal level of testosterone - let's just pick a number - fifteen hundred with a free of 40 to 50. He doesn't have estrogen symptoms.

Keith Nichols:
That's one of the questions I asked men. When they're fully optimal, I ask, how do you feel? Great. Are your levels as good as they ever been? Yes, sir. What kind of estrogen signals are you having? And they laugh. They laugh. They say, I don't have any. I said, but you did before, right? I mean, you did when your other clinics. Yes, I did. But you don't now. But your levels are better. Yeah. So, you know...

Mark Rippetoe:
It's because they're finally getting enough androgen.

Keith Nichols:
Correct. And they learn not to fear estrogen anymore. And they don't have symptoms.

Scott Howell:
Well, estrogen symptoms are is really a myth. Even our trial data supports that. There was a trial by Taylor in 2016 and what they did was they compared men that were on testosterone therapy only and men on testosterone plus an aromatase inhibitor.

Scott Howell:
And those that were on the aromatase inhibitor had higher vasomotor symptoms, also known as estrogen symptoms. They were higher. And so even our our best data supports that. And it's a carryover from bodybuilding. It really is.

Keith Nichols:
It really comes down to this one thing - in every single study done with testosterone showing benefits in men since it was discovered, it was discovered in mid nineteen thirties and every single study showing benefits of men and not one of those studies did they block or control estradiol. What do people not get?

Scott Howell:
It's not in any clinical guideline.

Mark Rippetoe:
Who came up with...and we're talking about Clomid here, right?

Keith Nichols:
No, no, no.

Scott Howell:
We're talking about like anastrozole. We're talking about our Letrozole and anastrozole. Yes.

Mark Rippetoe:
What is clomid?

Scott Howell:
It's a selective estrogen receptor modulator.

Keith Nichols:
It blocks the estrogen receptor of the central region, prevents the negative feedback loop of test. It prevents the negative feedback loop of testosterone. Kind of tricks the body into producing more testosterone in laymen's terms.

Scott Howell:
And SERMs increase thrombotic risk. So, just a tidbit.

Mark Rippetoe:
So when we're talking about aromatase inhibitors, we're we're talking about Arimidex [a brand name of anastrozole], is that is that most commonly?

Keith Nichols:
That's the most used one. That's the most commonly used one.

Mark Rippetoe:
From what I understand, that drug was actually developed to block the effects of estrogen in estrogen sensitive tumors in women. Is that right?

Keith Nichols:
Correct.

Scott Howell:
That is correct.

Scott Howell:
And if you look at the effects of those women after they're put on aromatase inhibitors, at five years their bone mineral density decreases 15 to 20 percent in five years. At 10 years, they're getting advanced cardiovascular disease. So if the cancer doesn't kill them, then the aromatase inhibitor will because they're going to be frail and they're going to die earlier.

Mark Rippetoe:
Well, so what genius decided that the protocol needs to be testosterone and Arimidex? Where did that come from?

Keith Nichols:
Well, there is one study that tends to kind of talk about it. And this is where some of it came from. Most of it come from. You've probably heard of the estrogen sweet spot, right? That sweet spot? So it came from this. There was a study done in JAMA that looked at 501 men with congestive heart failure and they looked at their estrogen levels and they put them in five quintiles.

Keith Nichols:
The third quintile, the middle the middle estrogen level, you know, had a range of let's see what it was. It was the third quintile was...That estrogen level was 21 to 30, so that became that sweet spot. And what they saw in that study is that men with low estrogen levels and high estrogen levels had increased mortality. But here's the funny thing is that the men with low estrogen levels had kidney failure. The men with high estrogen levels had liver failure.

Keith Nichols:
So we've got congestive heart failure on top of two different mechanisms failed. So you've got a population of sick men that, of course, are dying. So they extrapolated that data and said, you know, put that to men, normal men on testosterone.

Keith Nichols:
This study had nothing to do with normal men, nothing to do with testosterone at all. But they took that data and said, you need to be in that sweet spot. But yet it's the congestive heart failure and kidney disease that caused the low estrogen. And it was the kidney failure, I mean, it was the congestive heart failure and the and the liver disease that killed him as well. But yet they blamed estradiol.

Mark Rippetoe:
Well, let me lask you a real important question just kind of as an aside here. How do you explain the tendency to do studies like that where nobody's thinking clearly?

Keith Nichols:
It's just and observation.

Mark Rippetoe:
What in the hell is is... Why would you take five hundred guys who are sick and and do anything with that data and try to extrapolate it to a healthy population? Because that's all you've got in front of you that day? Is that what the deal is?

Mark Rippetoe:
Is this a is this another example of where... We have that machine, so that's the test we're going to run, right?

Scott Howell:
Well, you know, off often results like that or misattributed by the person that interprets them. And so a fundamental principle in science is whatever population you study with the characteristics of the sample, you can only extrapolate to that population.

Mark Rippetoe:
But it's done the other way all the time, isn't it?

Scott Howell:
It's incessant. And that's because people shouldn't be interpreted or shouldn't be trying to interpret research unless they know the methods.

Mark Rippetoe:
But these are the researchers. Even the researchers are making these mistakes!

Scott Howell:
Well, in this one with Pavlovitch, they were only concerned about Klinefelter's patients and highly genetic disease. But still, it was extrapolated for that into an estradiol ratio should be ten.

Keith Nichols:
The bane of our existence truly is men taking observational studies and extrapolating that to men on testosterone. You just can't do that. You just can't do that.

Scott Howell:
Look at the black box warning on testosterone. It was established by two flawed studies and the vegan study in 2013, when the actual data was received because so many researchers signed petitions petitioning the journal to retract, when they actually got the data there was women that were included in the study. It was a retrospective review. And so... It was so faulty, but JAMA still has it up, but they have some notes there, but it's still up there.

Keith Nichols:
For the black box warning for increased risk of heart attack, strokes by the FDA was based on reviewing five observational studies, two of which showed negative results. The vegan and the Finckel studies, three that didn't. And then two systematic reviews. That's it. And they put the black box warning on there, which still remains based on two extremely flawed studies that have subsequently been debunked by the medical community.

Mark Rippetoe:
Ok. Let's get to this other thing that... There are a couple of things that we need to talk about today. Now, one of the one of the most widely recognized problems with testosterone replacement therapy is H&H elevation. So let's let's discuss that, because this is this is on a lot of people's minds, and I think we need to dissect that.

Keith Nichols:
Well, Dr. Howell's going to go into the dig in the details on that, but before he even does I'm just going to tell you this once again, we talked about testosterone and beneficial effects on man. Testosterone was discovered in the mid nineteen thirties, been used since that time. it's been used and abused since that time. We can both agree on that.

Keith Nichols:
There's not a single randomized controlled trial to date that show that it increases a man's risk of heart attacks, strokes, or blood clots. We'll start with that.

Mark Rippetoe:
Despite the fact that H&H is increased.

Keith Nichols:
And most of those men who aren't even being followed by a physician. Once again - used and abused.

Scott Howell:
That's right.

Keith Nichols:
And still, men aren't dropping dead with heart attacks, strokes, or blood clots. Our ERs aren't full of those men.

Scott Howell:
Well you know, a lot of the the things that you hear in the media, they don't account for the use of tamoxifen, aromatase inhibitors with testosterone therapy, which do increased thrombotic risk. And so that's a confounding factor when someone is on...

Mark Rippetoe:
That would seem important.

Scott Howell:
But for hematocrit increases when...any time, Oh, yeah.

Keith Nichols:
As soon as they see androgen, it gets blamed on androgen. They won't look at the co-founders like the aromatase inhibitors.

Scott Howell:
They won't do that. But I mean, it's it's substantial. If you look at the literature on it, there is thrombotic risk. Tamoxifen is pretty high. So bodybuilders, they use it. I mean, and they're taking high dose androgen it's problematic. Anyone that takes it.

Scott Howell:
But any time someone goes on testosterone therapy, they get an increase in red cell mass. And there's... It's consistent across the board. It varies in how much it changes. But it's a truly beneficial effect. And I'll tell you why. I don't believe that hematocrit increases are an independent risk factor. Now, before we get into that...

Mark Rippetoe:
Now, let's define our terms here for the lay people listening to ust. Haematocrit is the mass of red blood cells in the in the in the bloodstream, and it it is expressed as a I guess as a percentage of the volume, right? So haematocrit of 57 is that 57 percent of the of the blood sample is red blood cells.

Scott Howell:
Yes. And hematocrit is an indirect measure. And that's something we'll talk about. It's a surrogate.

Mark Rippetoe:
And a haemoglobin is the amount of that particular iron based protein within the red cells, right? OK.

Scott Howell:
And so any time someone goes on testosterone therapy, there's basically two mechanisms that cause this to happen. The one is what I call an indirect mechanism. And it's the androgen EPO mechanism. And you've heard of EPO before?

Mark Rippetoe:
Yes.

Scott Howell:
Erythropoeitin. It's what cyclists used to dope with. OK, this is released from the kidneys and in animal models, androgens do stimulate that release from the kidneys. And what EPO does is it actually commits erythroid cells that aren't committed or they're like stem cells in the bone marrow to take on an erythroid lineage. So it commits them to that.

Scott Howell:
But in the human trials that's been done, the EPO differences on testosterone therapy have varied. In some trials there's hardly none that's stimulated.

Scott Howell:
So there's a direct mechanism at play here. And the direct mechanism is direct stimulation of androgens on those hematopoietic stem cells. And what it does is it stimulates those red marrow cells to express EPO receptors early. And so then at any level of EPO, they will be committed and start to mature and then expand.

Scott Howell:
So that's the two, now...

Mark Rippetoe:
What is the highest HGH you've seen in a guy on EPO? Just out of curiosity.

Scott Howell:
I've I've seen guys... Now we're talking about something completely different than hormone replacement therapy.

Mark Rippetoe:
Right. No, I mean cyclists on EPO. What do those guys do? 65 and 21, something like that?

Scott Howell:
Well see they have a maximal oxygen offloading at that high. And what you'll see here in a second is the experimental studies, what they show. See on...well, let me explain it right now.

Scott Howell:
On static a lot of people believe - and you'll see this on forums everywhere - that as your haematocrit increases, your blood viscosity increases exponentially. OK. There is no consensus in hematology among hematologists about whether haematocrit is an independent risk factor. And I'll tell you why.

Scott Howell:
That exponential increase comes from static experiments. In vitro. Where they use plate viscometers, glass tube viscometers that don't mimic the vasculature. They don't expand and vasodilate and they don't contract like the vasculature.

Mark Rippetoe:
Well, that's interesting. I didn't know that.

Scott Howell:
In those experiments, yes, you do have it. Well, it is in in those experiments, you do have an exponential increase, but they're missing the whole point. It doesn't replicate the vasculature.

Mark Rippetoe:
No, it's not a dynamic system. It's in vitro.

Keith Nichols:
Yes, it's a glass tube.

Scott Howell:
That's it. In in vivo, in animal and human studies of hemoconcentration. What is established is a 25 to 33 percent above baseline you can increase your hematocrit before there's an inflection point.

Scott Howell:
Now, before that inflection point - and I'm going to read this right completely off a study - "the increase in blood volume accompanied by this increase in red cell mass enlarges the vascular bed, decreases peripheral resistance and increases cardiac output." It makes hemodynamics more efficient.

Mark Rippetoe:
Well, that's interesting.

Scott Howell:
So how many how many people do you think that go on testosterone therapy are going to move to that 33 percent? They're not. I've never seen it.

Keith Nichols:
I've not either, but let's say they did have a haematocrit of 45. Thirty three percent increase going to be up to 60. I've never seen anybody go from 45 to 60.

Mark Rippetoe:
Mine has...I have caught mine at 57.

Keith Nichols:
Mine's been 57 as well.

Mark Rippetoe:
Several times, and, oh, I don't know I've I've donated blood, quote unquote at 57 and what, eighteen point two, something like that, before. And I do feel better after I get that off. What what what do you think's going on?

Keith Nichols:
The distinction we're trying to make now is that, you know, that's what increases your endurance and what increases your healing capacity. That's how we can heal diabetic ulcers with testosterone is that increased his oxygenation.

Keith Nichols:
But I think the point that we want to get across is a lot of guys will say they feel better with a phlebotomy. That's that's perfectly fine. I mean, you do lose some of those benefits. But I will tell you, there's a difference between wanting to and needing to. What we're seeing from a medical standpoint is you don't have to because there's no danger at 57 where you're at.

Mark Rippetoe:
So that's that's the basic question that I'm asking. So you guys are not going to advise me to worry about 57 and eighteen point nine.

Keith Nichols:
What I would tell you is that you can donate if you want. You're just going to lose some of the benefits of that secondary erythrocytes.

Mark Rippetoe:
But there's no danger of running that high.

Keith Nichols:
Again, have you noticed any heart attack, strokes or blood clots in any randomised control trial since the 1930s? No. And there's plenty of men out there running fifty seven or more.

Mark Rippetoe:
There you have it.

Keith Nichols:
The other side on that token is we're talking about in someone that has their lifestyle factors are in check. They're not taking all these other things like bodybuilders do. All this polypharmacy in the mix. Because that's really where the case reports pile up is when there's polypharmacy with all this stuff. But I mean, here's a study...

Mark Rippetoe:
I mean, I don't know if you've been watching our podcast today understand that...understand this very important fact: Bodybuilders are crazy. They're all fucking lost their minds. They're not normal people and they will do anything. Right, guys?

Keith Nichols:
They will.

Mark Rippetoe:
I know Scott knows that. I know Scott knows.

Scott Howell:
Yeah, definitely.

Scott Howell:
Well, you ask about 400 milligrams knocking anybody over, well, I've been way higher than that.

Mark Rippetoe:
Oh, I know. I know guys that take a gram a week. Gram of test a week. Like that's perfectly... well, it's a round number. It's a nice round number.

Scott Howell:
Yeah. Well, to your point about hematocrit, I wanted to touch on this because it's an interesting study. This was a study where it was in mice that had a genetic mutation. They increased their hematocrit levels. And these mice had hematocrit of 85 percent. 85 percent, and they followed them until all of them died, none of them developed thrombotic events. None of them.

Mark Rippetoe:
Even at 85 percent.

Scott Howell:
Now, I'm not saying that that is something that someone should think is safe in a human because there's so many other factors, individual risk factor, genetic.

Mark Rippetoe:
Well, it's it's always chancy to extrapolate rodent data to humans, but it does indicate that they're not throwing thrombotic clusters out even at 85 percent of blood volume being solid. That's yeah, that's kind of important.

Scott Howell:
Have you ever thought about how vivisection or phlebotomy came into the clinical picture?

Mark Rippetoe:
Well, you know, I have wondered about phlebotomy for quite some time because 250 years ago that was the primary intervention. Well, you know, you've got too much blood. You know, we've got to get some of that blood off. And... Why. I mean, it's hard to understand what doctors were thinking. It's hard enough to understand what doctors are thinking now. But it's it's terribly difficult to to to try to explain what they were thinking in the late seventeen hundreds when all of this when all this came about, it was a it was a primary intervention, you know, I you know, surgeons, quote, unquote and barbers were kind of the same guys back then. And they all did phlebotomy and I don't know why, I have no idea where they came up with the idea that you've just got too damn much blood.

Scott Howell:
Well, I can I can tell you recent phlebotomy., I had to trace it back and it took a couple of months for me to trace it back in literature, but it came from a study that was it at my birth year, in 1978. And it was a retrospective review of polycythemia vera patients. These patients have bone marrow cancer. And so what they suggested after they did this retrospective review was that in this population of individuals, it might be beneficial to venisect them to phlebotomize them. Since that point, it's stuck in the literature.

Scott Howell:
And so now when someone goes in on testosterone therapy, their hematocrit is high. The first thing the keys in the clinician's mind is phlebotomy. If their haematocrit's higher than 51. Right. Because they think they have polycythemia vera.

Keith Nichols:
Are are going to develop the same thrombotic risk that a person with polycythemia vera does and they don't.

Mark Rippetoe:
One pathology in the other is not. But they look at a number.

Keith Nichols:
Yes. Yes.

Scott Howell:
There's a huge difference in the polycythemia vera, and what it does in secondary erythrocytosis. Polycythemia vera, you got increased red cell count, increased white cell count, increased platelets. Those thrombocytes, those platelets are the issue.

Mark Rippetoe:
So all of the solids are up, not just the not just the red.

Keith Nichols:
The platelets clot, not red blood cells, right?

Scott Howell:
Well, see, there's a difference between secondary erythrocytosis with testosterone therapy, what that does and what happens in polycythemia vera, which is the bone marrow cancer. And so with secondary erythrocytosis, there is only an increase in red cell count. There is no increase in platelets. With polycythemia vera, the bone cancer, there's an increase in red cells, white cells and also platelets. And those thrombocytes, or platelets are the are the issue.

Scott Howell:
But if you compare phlebotomy...

Mark Rippetoe:
Platelets clot red blood cells don't.

Scott Howell:
You have to have an activation cascade to occur from vascular injury.

Mark Rippetoe:
Well. I think that probably puts that topic to bed, so let's get to the big one. Shall we? Boys and girls, let's get to the big one. Your poor little primary care physician has told you that he's not going to put you on testosterone because testosterone causes prostate cancer.

Mark Rippetoe:
Now, he's told you that, you know he's told you that I know he's told you that. He thinks he's right. Well, he doesn't think. He just talks.

Mark Rippetoe:
And this is a big giant problem that you've got medical professionals practicing outside their field of expertise. That's never slowed a doctor down, right? Squats are bad for the knees. Right. And testosterone is going to give you prostate cancer.

Mark Rippetoe:
This has this this has held so many guys back from correcting an obvious problem they've got because they're afraid they're going to get prostate cancer.

Mark Rippetoe:
Now, the most superficial refutation of this is who gets prostate cancer? Old men.

Keith Nichols:
Older man, because prostate cancer is a disease of aging. That's right.

Mark Rippetoe:
And who has low testosterone?

Keith Nichols:
Older men.

Mark Rippetoe:
Older men. A does not equal B. And, you know, I don't know how, you know, I mean, you know... Seventy five year old guy, a 75 year old guy, a healthy 75 year old guy, is going to have some prostate cancer cells, that's just a function of being 75.

Mark Rippetoe:
Now, whether it'll kill him or not is an entirely different matter. But the question would be for your primary care physician, does the fact that the man at 75 have some prostate cancer cells... Is that the result of his previously having had normal levels of testosterone? What does the literature show on this terribly important topic?

Keith Nichols:
Well, it shows us that men with low testosterone levels are at highest risk of developing prostate cancer.

Mark Rippetoe:
It certainly does, doesn't it?

Keith Nichols:
All right. It does and it's also shows us the literature now shows that it's safe to treat men who have been treated for prostate cancer. I have many of those patients. And it's also safe to treat men that are under active surveillance for low grade cancers. Those men, when compared to men not on testosterone, there's no worsening of the disease, no increase in the PSA over men not treated with testosterone. It doesn't cause prostate cancer to grow like like throwing gasoline on a fire like it used to be thought.

Mark Rippetoe:
That's what they told everyone. That's what they told everyone. And there are guys my age and older walking around right now with this nonsense stuck in their heads.

Keith Nichols:
Well, if you look at the saturation model put forth by Dr. Morgentaler, if you have a level of around 250 or more of testosterone, taking testosterone will not cause prostate cancer to grow. It's already fully saturated by the androgen receptor. I mean, the androgen receptor is really saturated by the androgen.

Keith Nichols:
It's men with castrate levels of testosterone, very low levels of testosterone, where prostate cancer grow up to a level of 250. You know, castrate levels of testosterone, the tumor is very sensitive to the androgen. It will grow up to a level of 250. And then after that, it's fully saturated and has no further effect on the growth.

Keith Nichols:
But it doesn't cause prostate cancer. I think what men need to understand, it doesn't cause it. If anything, it helps prevent prostate cancer.

Mark Rippetoe:
That's also kind of important, isn't it? That is probably been the biggest factor in people who actually need testosterone replacement having not gotten it over the years.

Mark Rippetoe:
So let's talk about how we're measuring prostate cancer. Let's talk about PSA and what that protein actually is, what it actually does, and what influences the level of prostate specific antigen.

Keith Nichols:
Ready?

Mark Rippetoe:
Go ahead.

Keith Nichols:
All right. What is PSA? Prostate specific antigen is a glycoprotein enzyme secreted by the epithelial cells of the prostate whose job is to liquefy semen so that sperm can swim freely.

Mark Rippetoe:
It improves sperm motility, doesn't it?

Keith Nichols:
Motility. It also dissolves the cervical mucus plug so that the sperm can enter the uterus. That's what it does. I is secreted it in the ejaculate. A very, very small amount is excreted in the blood, which is what we measure when we measure the PSA test. All right.

Keith Nichols:
It was discovered in 1970 about Dr. Richard Ablin. It was FDA approved in 1986 just to monitor the progression of disease in men with prostate cancer. It was never intended to be a screening tool at that time because it's not a good screening tool. It was only 1994 the FDA approved its use, along with the digital rectal exam, to test asymptomatic men for prostate cancer. And that's where all the problems arose.

Mark Rippetoe:
Keith, this is... Keith this is so interesting to me because of the fact that this glycoprotein is secreted by the epithelial cells in the in the encapsulated prostate. It is secreted into the ejaculate. And its primary function is on the sperm motility and at the end point for the sperm at the at the at the cervical plug. Right?

Mark Rippetoe:
Yet we measure this as a blood value. And the only way it gets into the blood is through some extremely low level diffusion mechanism.

Keith Nichols:
Correct.

Mark Rippetoe:
That it has to enter since it's secreted in the prostate, it has to it has to enter in into the blood at that margin. The vascular margin between the epithelium of the of the prostate and bloodstream. Right?

Mark Rippetoe:
Now, now, this is and that's so it's kind of accidental that it's in the blood anyway.

Mark Rippetoe:
Now, let me ask you a question here. What is the vascular situation in a in a in a in a prostate with BPH - benign prostatic hypertrophy? What is the what's the vascular situation in a situation like this? Is the is the is the hypertrophy vascular in nature. Is it is the hypertrophic connective tissue in nature? And what difference would that make on the ability of the blood to elevate PSA in that particular pathology? You understand my question?

Keith Nichols:
I do, I think the main thing yes, and I think I'll answer this way... Is the PSA cannot diagnose prostate cancer. All right. It's not cancer specific. It's not called prostate cancer specific antigen. It is it is measured in the normal, the benign BPH, and the cancerous prostate. And it can be elevated by a multitude of reasons.

Mark Rippetoe:
Like ejaculation, right?

Keith Nichols:
Here we go. Urinary tract infection, prostatitis, ejaculated within 24 to 48 hours of the test. Anything that puts pressure on the perineum - horseback riding, four wheeler riding, motorcycle riding, riding a bike, a truck driver.

Mark Rippetoe:
You know, one of my one of my high priorities in in life has always been to have ejaculated within the past 48 hours. I don't know about you guys, but I've I've been real bad about that. And, you know, I haven't paid any attention to my PSA in quite some time as a result primarily of that. But...

Mark Rippetoe:
What in the hell? Do you realize I have had conversations with at least two and maybe three different urologists. And when I asked them this question. I said, what is PSA? And they patiently explained, well, that is a marker for prostate cancer.

Mark Rippetoe:
And I said, you don't understand. I don't think you understand my question. I'm asking you what chemically, physiologically, prostate specific antigen is, because I find it very difficult to believe that the cancer cells have done us the courtesy of identifying themselves with the protein. I find that difficult to believe.

Mark Rippetoe:
So what is PSA? And they patiently explain, well, it is a marker for prostate cancer. You know, it just so... It just is boo-doo-doo-doo-boo repeat, you know, the same shit over and over again.

Mark Rippetoe:
A very good friend of mine, a mentor of mine, was the victim of this kind of fucking shit many years ago. And they basically killed him. And he had, you know, slightly elevated PSA. And these criminal bastards wanted to do a biopsy. You know, 12 needle biopsy of a perfectly encapsulated prostate gland.

Mark Rippetoe:
And you cannot tell me that poking 12 holes in a prostate gland does not free the contents of the prostate gland. You can't tell me that. Because mechanically, you just perforated the goddamn thing. Now, you know you know, maybe you guys have got some information on this that I don't have, but does that not seem like an excellent way to metastasize a cancerous prostate?

Keith Nichols:
Well, I'll tell you, we can be glad to get in that with you for the men out there. Yes, there there have been studies to show that that can indeed occur.

Mark Rippetoe:
Well, isn't that interesting.

Keith Nichols:
So, you know, we've already established a PSA can't diagnose prostate cancer. It's elevated in the normal prostate, the benign prostate, in the cancerous prostate. There's also no specific level that detects prostate cancer. A man can have prostate cancer with a level of point five, and he can not have prostate cancer at 11.

Keith Nichols:
So we have this arbitrary cutoff of 4. It's an arbitrary number. Some would advocate for a lower cut off, others want higher. The lower number would allow more men to undergo biopsy like your friend and that's what it's all about. We're going to get to that. It's money makes the world go round.

Keith Nichols:
It's been written that if it wasn't for prostate biopsies and radical prostatectomies, half of all urology practices would go out of business in the United States.

Keith Nichols:
All right. Now, the PSA also can't detect or distinguish between indolent and aggressive cancers. And something else you've already alluded to it is prostate cancer is age-related. The older you are, the more likely you are to have it. You'll die with it. Most likely not from it. The lifetime risk of dying for prostate cancer is three percent. All right.

Keith Nichols:
But here's the thing about prostate specific antigen as a screening tool, it hasn't been shown to decrease mortality. If you were to test a thousand men...

Mark Rippetoe:
This is basic. You guys listen carefully, now. Listen very carefully to what Keith is telling you.

Keith Nichols:
It hasn't been shown to decrease mortality. If you measure a thousand men with PSA, age 55 to 69, four of them are going to die. If you don't measure PSA in a thousand men, five are going to die. So measuring PSA will allow one man to live out of 1000. That's not a big decrease in mortality.

Mark Rippetoe:
No, I suppose that's probably statistically significant, but is it clinically significant? You guys understand the difference in that right?

Keith Nichols:
Well, here's what it really comes down to, is it's not that. Well it is that because it really hasn't shown to significantly reduce mortality. All right. But here's the real problem is what your friend went to. It's that the PSA test results in false positives and false negatives.

Keith Nichols:
The false negative is, when you know, you're told you have a negative test. There's no cancer there. When it really is. False positive is that your PSA goes up, but you don't have cancer. But what happens? What happened like what happened to your friend? They undergo a biopsy.

Keith Nichols:
OK, the biopsy generates money for the doctor and the hospital. That's right. But it also can create a lot of physical and psychological harm, anxiety, stress. It is painful to have one. It can lead to an infection, painful urination, urinary retention, blood in your stool, blood in your sperm, I mean, blood in your urine.

Keith Nichols:
And that that what that biopsy will also do, it can potentially see that cancer, as your friend unfortunately had. OK, there was a study done in 2019 by Hosain Clinical Chemistry that they looked at tumor associated release of prostate cancer cells after a trans rectal ultrasound, got a biopsy. There were circulating tumor cells significantly increased, and that correlated with a worse progression free survival rate for those men. And so it can happen. All right.

Keith Nichols:
But what does the biopsy also lead to? It leads to an overdiagnosis and overtreatment. What is overdiagnosis? It's the detection of a prostate cancer that it would have remained undetected during the lifetime of that man and caused him no problem.But they still get a diagnosis of cancer.

Mark Rippetoe:
Because they found a couple of cells.

Keith Nichols:
Right. And so they get the C word, they hear the C word. They hear the word cancer. It develops a lot of anxiety and depression. Some studies have shown that it's caused cardiovascular events in men as well as suicide. They get the diagnosis of cancer. Some can't, some can't handle that.

Keith Nichols:
But then they end up with overtreatment. Even if a man has found to have an indolent, non-aggressive cancer, they want it out. 90 percent of men elect to have a treatment after they get diagnosed with cancer. So they end up undergoing a radical prostatectomy, which is almost guaranteed to leave them incontinent and impotent or both.

Mark Rippetoe:
And you know what? You know what, Keith, Scott. I don't know about you guys, but if the surgery is going to leave me incontinent and impotent for the last 25 years of my life, I'm not that happy. I'm not sufficiently happy with being alive that I'm going to do it like that, you know.

Keith Nichols:
And that's that's the whole point is so many men regret the screening and the treatment. Because when when they say what the problem is that most of those men that were treated and ended up incontinent and impotent - they call them limp and leaking - those men would have never needed treatment in their lifetime. But they did it because the cancer diagnosis scared them into treatment.

Mark Rippetoe:
Right. This is you know, this isn't one of the most important things that we are talking about here today. I want you guys to to think very carefully about what we're saying here. PSA screening... in other words, having the test done, statistically does not make you live longer. And I wouldn't have it done, and I think that is as time goes on, more and more doctors are are discounting the. The necessity of constant PSA screening. What did they...they were doing it twice a year previously.

Keith Nichols:
The twenty eighteen the American urologist doesn't change their kind of stance on it. They don't recommend it men less than 40. They don't recommend it at 40 to 54 unless you're at increased risk - certain races or family history of adenocarcinomas. From 55 to 69 it's a shared decision making and they don't recommend it over 70.

Mark Rippetoe:
Right. Well, that's that's that's an improvement because 10 years ago, that's not what they were doing is it?

Keith Nichols:
And you are correct, the ones that do get tested in the 40 to 50 for they kind of advise that you might want to consider it every two years instead of every year. That's correct. To once again reduce the chances of a false positive, leading to a biopsy, leading to the overdiagnosis and overtreatment.

Mark Rippetoe:
There is no better way to reduce the chance of a false positive than to not have the test. Right? I think it is practical.

Mark Rippetoe:
So. Well, aside from aside from this, is there any way to construe that the administration of replacement testosterone could stimulate the growth of prostate cancer? Is there any possible way that there is a mechanism by which that could happen?

Keith Nichols:
We've already done the studies, it doesn't.

Scott Howell:
Well, here's the interesting thing..

Keith Nichols:
Because of the saturation model, it just doesn't.

Mark Rippetoe:
It just doesn't.

Mark Rippetoe:
So when the doctor tells you that he's not going to give you any testosterone because it'll give you prostate cancer, don't pay him. Don't pay him. He doesn't know what he's talking about. Don't write him a check. Don't reward incompetence with money.

Keith Nichols:
Well, that was that was figured out. You got to remember, there are millions of men on testosterone replacement therapy, and we know about one in seven men are going to develop prostate cancer. And all these millions of men that are on testosterone that didn't know they had prostate cancer, but they're not seeing this increase in aggressive forms of prostate cancer. Are these grapefruit sized prostate tumors? They didn't see that. And that's how they put it all together.

Scott Howell:
And even the treatments for prostate cancer... If you consider bipolar androgen therapy, they actually give high dose testosterone to treat prostate cancer. There's several pilot trials that already went out. And so... And those individuals with castration resistant prostate cancer, there's a malfunction at the androgen receptor. It doesn't up regulate like it does in normal tissue. It's reverse and low level tissue and or low level androgen environments it actually upregulates instead of higher androgen environments.

Keith Nichols:
That's another sad story there, Mark, is these men that undergo androgen deprivation therapy. These men want to die. I mean it literally, you just you just destroy a man's manhood altogether.

Mark Rippetoe:
That's why I made that previous statement. It's precisely why I made that previous statement. And I think that the vast majority of people, if you if you can give them enough testosterone to where they're not scared of everything anymore would tell you that now, you know, I kind of like using my tee teefor something other than tee tee, you know.

Mark Rippetoe:
I like sex, you know, I like not leaking all over myself. You know, I like to come. You know, I like a sex drive. I enjoy that aspect of my physical existence and.... If you tell him, well, you know, the good part is, is you're not going to have prostate cancer anymore because we're going to take your prostate out, the bad part is you're going to leak all over - you'll have to have Depends on for the rest of your life. You'll never have another hard on. And you don't get to come.

Keith Nichols:
That's a true story. Listen to that, because that is true.

Mark Rippetoe:
Those are your choices. It is, in fact, that stark.

Mark Rippetoe:
So, you know, I think that lots and lots of guys would decide differently.

Mark Rippetoe:
Let me say let me say that again, I don't want this to escape notice. If you give a guy enough testosterone to where his normal, aggressive brain is working, he's able to make those kinds of decisions much more accurately than if you leave him down in two digit testosterone numbers and then scare him to death with the C word. Right?

Keith Nichols:
Well, well, it's about quality of life right? Not quantity, but quality.

Mark Rippetoe:
Yeah, really. You know, and this brings up another interesting topic. We had started the discussion today off with the depression aspects of of testosterone therapy. And just through some personal experience and watching, you know, other men over my over my life.

Mark Rippetoe:
What and I've asked psychiatrist this, and they just don't seem to want to plug in with me here: what is the opposite of depression? Is it euphoria or is it aggression? How do you feel when you're depressed, guys? You know, it's been a while since you've been that way since you're on testosterone...

Keith Nichols:
Well, you don't want to feel that you want to do anything. Just want to sleep and do nothing, not interested in anything.

Mark Rippetoe:
Sit there with your hands in your lap and look down, don't you?

Scott Howell:
Learned hopelessness.

Keith Nichols:
Don't want to do anything.

Mark Rippetoe:
Yes, it's hopelessness. Right.

Mark Rippetoe:
Now...and we'd already observed that one of the most profound and immediate effects of testosterone replacement therapy is psychological. And I submit to you that aggression is the opposite of depression. And that at by aggression, I don't mean getting in a fight. Everybody understands that. I don't mean getting in a fight. Right?

Mark Rippetoe:
I mean that forward motion.

Scott Howell:
Like being male, being a man.

Keith Nichols:
How about what we said earlier? Motivation, initiative, energy, self-confidence. All those will fit into your definition.

Mark Rippetoe:
And the absence of that is depression.

Mark Rippetoe:
And the presence of testosterone increases all of those things. And I don't you know, I appreciate you guys being here with us today because this is such an important thing to talk about with.

Mark Rippetoe:
Guys that are over the age of 45, we all are going to be looking at it unless we get killed in a car wreck, we're all going to be looking at being older men. And there are good ways to be an older man and there are bad ways to be an older man.

Mark Rippetoe:
And I think that you need to consider, if you're an older man, I think you need to consider testosterone replacement therapy. You can get a hold of these guys - Keith Nichols and Scott Howell at their clinic in Chattanooga, Tennessee.

Mark Rippetoe:
And you you want to... How would you rather be contacted - email or telephone or what do you?

Keith Nichols:
They can call or email. The telephone is 423-417-1700. And it's Tier One Health and Wellness. Or you can email us at tier1hw.com

Mark Rippetoe:
Guys, I sure do appreciate this. I think what you're going to what you're going to find is that a lot of other people appreciate it, too. And this is information that that we need. And you and I will talk again about this. I'd like to follow up with you on some stuff.

Mark Rippetoe:
And these things get to where they're too long and they exceed everybody's ability to... Attention span. But we'll talk again about this, because this is this is such an important aspect of of men's physical existence. And it it goes hand in hand with with strength training. And it's a very important topic. And I do appreciate your time. Thank you guys for being with us on Starting Strength Radio.

Scott Howell:
You're very welcome.

Keith Nichols:
Pleasure to be here.

Scott Howell:
Thank you.

Mark Rippetoe:
And we'll see you guys next time on Starting Strength Radio.

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