Ben Greenfield [00:00:00]: My name is Ben Greenfield, and on this episode of the Ben Greenfield Life Podcast.

Dr. Cameron Sepah [00:00:03]: The difference between blood work of someone on TRT versus enclomiphene is TRT. Their LH and FSH levels, as we talked about, are going to be near zero because you're shut down. Your testicles are going to shrink and you're dependent on it. If you go off of it, you're going to feel pretty bad. With enclomiphene, your LH and FSH levels actually typically go up because it's essentially telling the body, hey, you don't have estrogen produced more. It actually makes your testicles bigger. Ironically, the studies that show the higher dosages, it actually increases testicular volume. Total motile sperm count, which is a key fertility marker, actually goes up.

Dr. Cameron Sepah [00:00:36]: So it makes you more fertile as a man, and it generally doubles testosterone. The other advantage is there's no dependency. If you just stop taking it, you'll just go back to your baseline levels. You won't be shut down like you will with TRT.

Ben Greenfield [00:00:47]: Fitness, nutrition, biohacking, longevity, life optimization, spirituality, and a whole lot more. Welcome to the Ben Greenfield Life Show. Are you ready to hack your life? Let's do this.

Ben Greenfield [00:01:12]: I am here Dr. Cameron Sepah, and he's the CEO of a company that's got a pretty cool name, I think, Maximus, which is not the backup website for the movie Gladiator, although I did hear there's a sequel coming out. It is an online medical clinic. Maximus is an online medical clinic, and they do health and hormone optimization. I've exchanged a lot of emails back and forth with doctor Cameron Sepah, who is not only a doctor, but a serial health tech entrepreneur. He has been involved with a number of different startups, but Maximus is his new baby, or relatively new baby online medical clinic that's focused on men's health and hormone optimization. And I wanted to get deep into the field of all things testosterone optimization, fertility management, estrogen, all of those things that I think more guys need to think about before they just stick a needle into their right butt cheek. So all of the show notes are going to be at bengreenfieldlife.com/maximuspodcast. If you want to check out Cam's website, it's bengreenfieldlife.com/maximus to make it easy for you. So Cam, welcome, man.

Dr. Cameron Sepah [00:02:23]: It's a pleasure to be here with you. I've been a fan of your work for years, and it's fun to be able to have this conversation.

Ben Greenfield [00:02:30]: Yeah, I've got all sorts of juicy questions, dude, but I'm just curious. Do you have some kind of pain to purpose wounded healer story where you had severe hypogonadism and couldn't get it up or build muscle or recover or something like that? Or are you just interested in this from a medical standpoint?

Dr. Cameron Sepah [00:02:49]: Yeah, it's a great question. I think origin stories are really important. In the origin story of Maximus. Well, there's two parts to it I'll talk about. One was I ran across this statistic that said that testosterone and sperm count have dropped 50% in the last 50 years. And I thought that was quite remarkable. Not that many people were talking about it.

Ben Greenfield [00:03:11]: It's the plastics. It's plastics, man. Same stuff that's making the frogs female, right?

Dr. Cameron Sepah [00:03:16]: Absolutely. Endocrine disrupting chemicals, as you point out. And our food, water and plastics. The interesting thing is, when you look at the studies, obviously there's an association between obesity and metabolic syndrome, which I've been working on for over a decade. The first company that I helped start, Omada Health, essentially created online weight loss programs to help people avoid diabetes and heart disease. Helped a million people lose 10 million pounds and cut kind of one of the key originating factors, which is just being overweight. The problem is, even when you control for weight, there are still thin people like you and I who are affected by endocrine-disrupting chemicals. Our fathers and grandfathers essentially had twice the testosterone levels that we did.

Ben Greenfield [00:03:59]: Yeah. Yeah. And by the way, I don't think it's just plastics. Yeah. We're not lifting heavy stuff and building fences and rock walls outside. We're not getting sunlight. Relationships have suffered from social media and porn. The food quality has shifted slightly more towards the higher carb, lower fat type of scenarios.

Ben Greenfield [00:04:18]: We're not getting the building blocks. It's kind of a cluster, isn't it?

Dr. Cameron Sepah [00:04:21]: Absolutely, yeah. It's a multivariate problem, but I think the endocrine-disrupting chemical is certainly a large and hard to control factor because it's hard to avoid anywhere. So that's been a huge contributor. The other part of it, though, is that sperm count's gone down 50%. And, in fact, if it continues to do so, theoretically, society would hit sperm count zero by about 2050. I don't think we'll all not be able to reproduce, but I think we're seeing, essentially fertility problems on the rise. In fact, 50% of idiopathic infertility, which has no known cause, is actually male cause nowadays. And so that's kind of the interesting challenge.

Dr. Cameron Sepah [00:05:00]: Obviously, the gold standard treatment for if you have low testosterone is injectable TRT or testosterone replacement therapy. Downside of which, of course, is when you replace your testosterone exogenously or externally, it shuts down your endogenous or internal production, and it makes you infertile. Essentially, TRT is a male contraceptive. And so it fixes one half of the problem in terms of the testosterone problem, but it actually exacerbates or worsens the fertility problem.

Ben Greenfield [00:05:24]: Right. And just real quick, why is that? Can you explain the mechanism behind why when you inject testosterone, it basically makes you less likely to have a baby? Because some people would almost think the opposite. Right. You gotta have a bunch of libido and go out there and populate the planet.

Dr. Cameron Sepah [00:05:40]: Yeah, it's a great question. So there's something called the Hpg axis, the hypothalamus pituitary, gonadal axis, where essentially the hypothalamus produces a hormone called GnRH or gonadotropin-releasing hormone, which simulates the pituitary to release two hormones. One is LH, or luteinizing hormone. The other is FSH, or follicle-stimulating hormone. FSH stimulates the gonads or the testes, where the word testosterone comes from, to produce testosterone. FSH stimulates the gonads or testes to produce sperm. And so what happens is, when you're getting exogenous testosterone, it creates a negative feedback loop up at the hypothalamus and pituitary. And so the brain thinks, ah, I'm getting enough testosterone.

Dr. Cameron Sepah [00:06:21]: You know, the body tries to maintain homeostasis or balance. Right. And so it shuts down the production of GnRH. If you actually do your blood work, your LH and FSH basically go to near zero. So you can tell you're essentially shut down. And so as a result, there's no signal going to the testes. And what happens is essentially the testes because there isn't sort of gas in the gas tank. It's almost like having a dead car battery.

Dr. Cameron Sepah [00:06:46]: So they're not producing. They actually will atrophy. They'll shrink. Most people will notice, essentially a decrease in what's called testicular volume, the size of the testes.

Ben Greenfield [00:06:54]: Right, right. The famous ball shrinkage.

Dr. Cameron Sepah [00:06:57]: Exactly. So it's basically analogous to what type 1 diabetics do who are insulin dependent. Right. Their pancreas can no longer produce insulin, so they injected exogenously. And it's life-saving. But the analogy that I make is most people aren't type 1 diabetic most people are pre diabetic. They're on the type 2 diabetes spectrum, which is what my first company worked on for those people, they should really, to your point, focus on diet, exercise, sleep, maybe take a low dose of a metformin or a glucose reducing agent, and really focus on changing their lifestyle rather than hopping on insulin. Insulin is really the treatment of last resort for uncontrolled type 2 diabetes that I used to see when I was working at the VA.

Ben Greenfield [00:07:32]: And unfortunately, sadly, it's also an easy way out. There's a lot of people going to the cheesecake factory with their insulin syringe.

Dr. Cameron Sepah [00:07:39]: Exactly. And instead of obviously producing their carbohydrate intake, I think injectable TRT is analogous. There's definitely a place for injectable TRT. But increasingly, I think if you talk to clinicians, including the top urologists and med school professors in the country, who are my colleagues and advisors, they really think TRT should be a treatment of injectable TRT should be a treatment of last resort, because you're essentially going to become dependent on it for the rest of your life.

Ben Greenfield [00:08:04]: Okay, got it. Now, backpedal here just a little bit, because I think what you were explaining there regarding the hypogonadal issues and the LH and FSH relates to two ways that testosterone can be low, primary and secondary hypogonadism. Do I have that right?

Dr. Cameron Sepah [00:08:22]: Yes. Yeah. That's a really important differentiation, and that's analogous to, essentially, the type 1 and type 2 diabetes. In primary hypogonadism, the testes essentially no longer function correctly, just as in type 1 diabetes, the pancreas no longer functions correctly. So basically, no matter how much LH or FSH stimulation you're getting from the pituitary, if your primary hypogonadal, your testicles are not able to essentially respond to that signal, and they're essentially shut off. For those folks, injectable TRT is absolutely the correct solution because. Yeah, your test is no longer work.

Ben Greenfield [00:08:55]: Right. There's no feedback loop to shut down.

Dr. Cameron Sepah [00:08:58]: Exactly right.

Ben Greenfield [00:08:58]: And with primary, what's the reason that something like primary would happen where the signal isn't even being sent? Is that just a bunch of stress? Is that being born with some kind of genetic issue or what causes that?

Dr. Cameron Sepah [00:09:10]: Yeah, sometimes people have testicular injury, testicular cancer, or other sort of very major medical problems. It's actually uncommon. I wouldn't say the majority of folks actually have primary hypogonadism, just like the majority of folks, probably single digit percentages have type 1 diabetes. It's much more the type 2 diabetes and secondary hypogonadism. Secondary hypogonadism, your testicles still work. It's just that they're not as responsive. Just like in type 2 diabetes, your pancreas still works.

Dr. Cameron Sepah [00:09:41]: It's just that you're insulin resistant and your body's not responding to the insulin as well. Just like the testicles aren't responding to the LH and FSH as well. So you're getting the signal, but it's not producing as much testosterone. It's not producing as much sperm, generally due to poor lifestyle and health, which is, unfortunately, as you point out, ubiquitous these days.

Ben Greenfield [00:10:01]: So how would you test for primary versus secondary hypogonadism? Would it be someone who's not on testosterone and you're measuring their LH and FSH levels, and if they were not on testosterone and those levels were low, that could give you a clue that they might have primary?

Dr. Cameron Sepah [00:10:17]: Yeah. So in both cases, both individuals would have low testosterone. Right. Now, traditionally, what people do is they do look at the LH and FSH. So sometimes people who are primary hypogonadal have very high LH levels. And so they'll use that because it's like the pituitary. The testicles aren't responding. So it's almost like trying to send more gas in order to turn it on.

Dr. Cameron Sepah [00:10:45]: We find, however, that's not a perfect prognostic sign of whether you're primary hypogonadal. I think the best way to actually know conclusively is to actually put people on a SERM. So, traditionally, there's something called the Clomid challenge. Clomid is a selective estrogen receptor modulator, or SERM. It basically not everywhere in the body, but in selective places, including at the hypothalamus level, blocks the estrogen receptor. It's an estrogen receptor antagonist. There's also an agonist as well. Cause it's two different drugs, technically speaking.

Dr. Cameron Sepah [00:11:19]: But basically what it does is it tricks the body into thinking, I don't have enough estrogen or estradiol. That's derived actually from testosterone. And so the body will produce more.

Ben Greenfield [00:11:28]: Testosterone in response to it because estrogen is being blocked. The body thinks, okay, I need to make more estrogen. And the only way that you can efficiently do that as a male is to go through the testosterone pathway.

Dr. Cameron Sepah [00:11:40]: Exactly. So you'll produce more testosterone. So Clomid has been an FDA approved drug since 1967. It's used for female fertility and it's been used off-label for men's infertility, actually for many decades as well. It works pretty well. And what will happen is if you are secondary hypogonadal, it will restart your system and get you to produce more testosterone. If you're primary hypogonadal, it won't work. You can do this pretty efficiently.

Dr. Cameron Sepah [00:12:06]: You do that for a week or two, and you can tell if you're responsive, great. Your testicles still function, essentially. And then you should probably figure out ways of increasing your endogenous or natural production. If you don't, you can go right to injectable TRT.

Ben Greenfield [00:12:20]: Okay. And you call that the Clomid challenge.

Dr. Cameron Sepah [00:12:22]: That's typically what's been called in the academic research literature. When we've analyzed LH and FSH, by the way, in terms of what predicts treatment response to a SERM, it's actually usually when people. It's not when their LH is too high, contrary to popular opinion. It's when their LH or FSH are below one, or they're almost zero. Those folks, essentially, they either have had a testicular injury, their testicles aren't working, or they've been suppressed because they've been on injectable testosterone so long that they're essentially no longer able to really produce.

Ben Greenfield [00:12:54]: Oh, so you can basically self-induce primary hypogonadism absent of something like testicular injury from using something like repeated testosterone injection, for example.

Dr. Cameron Sepah [00:13:04]: Yeah, that's kind of the irony of TRT, right? Is it essentially will can induce primary hypogonadism. Now, not always. There are some folks who, they go on it, and when they decide, hey, it's time to have a baby, they can go off of it and they can recover. There's a little bit of individual variability in terms of that. And you can use, in fact, a SERM or HCG to restart the system. It does work, but basically, in clinical observation, it depends on how long you were on TRT and what the dose was, because if you were on it for too long and too strong, essentially, then it may not totally come back. That's why conservative clinicians basically tell people, if you, at any point in the future, would like to still have children, it's probably not wise to mess with your fertility. In fact, Jim Hotaling, who was on my podcast, basically argued that really, like, if you're under 50 or you still want to maintain your fertility, you should consider other options before jumping on injectable testosterone.

Ben Greenfield [00:14:01]: Okay. Yeah. It kind of reminds me of coffee but much more serious. Coffee, paradoxically, can induce sleep issues, because you get yourself to a state where you really only feel fully awake when you've had your cup of coffee. And then once you stop your coffee, you start to get all sleepy, and it takes a little while to reset those receptors. But unfortunately, as you were just explaining, with testosterone, they can be much more serious and take a much longer time. And you might feel a lot crappier coming off it unless you're introducing some of these things like Clomid and HCG to help. How long do you typically see that men are on testosterone before they start to create some of those potential issues for it being really hard to get off it?

Dr. Cameron Sepah [00:14:42]: Yeah, it's really hard to say because it is individual. And like I said, it also depends on the dosage involved. More commonly, if it's true medical TRT or HRT, people are taking 100-120 milligrams of typically a testosterone ester a week. These days you're seeing sport TRT, which is, I think, a euphemism for more bodybuilder levels, where people are taking 200 milligrams. Plus they're certainly getting super physiological levels that are not achievable by any natural human being. And when you're pushing the boundaries of that, it's way more suppressive and it can induce it a lot faster. It could be months, it could be years, but it depends on all those variables that I mentioned.

Ben Greenfield [00:15:23]: Okay. And what if someone were cycling? I'm actually curious. Not only, like, if someone were cycling testosterone, going on and off it, is that a common practice that would allow you to more easily come off it if you wanted to, say, have a baby? And then outside of that, just do you recommend cycling testosterone in general, whether or not you want to maintain fertility?

Dr. Cameron Sepah [00:15:45]: Yeah, it's a great question. We get this question asked a lot about do I need to cycle? And cycling really comes from the bodybuilding world and their experience with anabolic steroids. Testosterone, technically speaking, is the original anabolic steroid. It's just the one that our body endogenously produces. People would typically go on these 8-12 week cycles of very strong, very harsh, very suppressive anabolic steroids, which not only cause the testicular shutdown, shrinkage, and fertility, but mess with people's lipids and increase their risk for cardiovascular disease, which is why a lot of bodybuilders obviously die of heart disease in their forties and fifties. So they would recycle this to try to mitigate the effects. Now, for fertility purposes, as you're discussing. Yes, theoretically speaking, if you cycled, testosterone went off of it in order to let your body recover, and then went on a SERM or an HCG, that could, theoretically prevent testicular atrophy from the testicles shrinking and being offline.

Dr. Cameron Sepah [00:16:45]: Now, I think actually it's an old school approach, this going on and off, just like sort of the bulking and the cutting that people do.

Ben Greenfield [00:16:52]: Kind of reminds me of creatine. Right. The advice of creatine used to be, you know, take 20, sometimes 30 grams a day for one to two weeks and then cycle down to five, when in fact, by taking 5 grams for about a month, you're going to get your levels topped off and keep them there anyways without cycling or loading or cramping or diarrhea or all the other stuff that happens when you load.

Dr. Cameron Sepah [00:17:10]: Yeah. And logically speaking, if you're. If you're taking something that you probably need to cycle, it's probably not that good for you in the first place. So I think the smarter and more cutting edge approach is to always try to maintain your own endogenous production or your natural production of testosterone. That's really where the SERMs that I mentioned earlier come in. They used to be basically only used as what's called PCT or post cycle therapy. After you've done a cycle, as you mentioned, of testosterone or a steroid, people would go on Clomid or another SERM in order to restart their production. They would take very high dosages of it, 25-50 milligrams.

Dr. Cameron Sepah [00:17:49]: The problem with Clomid is it's really two stereoisomers, or what's called mirror molecules, just like your left and your right hand. One of them is enclomiphene and.

Ben Greenfield [00:17:58]: The other one's zuclomifene.

Dr. Cameron Sepah [00:17:59]: Right, exactly. That one's basically an estrogen. It acts just like estrogen. It's an estrogen agonist that actually binds the receptor. The problem is when men take high dosages of Clomid, it will increase their testosterone because the enclomiphene is working, but they're basically taking it with an estrogen. And so they'll get moody, they'll cry at movies, they'll get emotionally labile. And that's why a Clomid has generally been only used for shorter durations when people trying to get their wife pregnant or they're doing their post cycle therapy because men, even though their testosterone is higher, they don't feel great on Clomid because of the estrogenic, essentially, side effects that are happening.

Ben Greenfield [00:18:35]: Okay, so just real quick to clarify. So I'm keeping up here. Clomid is a selective estrogen receptor modulator. And when you take it, you are modulating, or in this case, even blocking the estrogen receptors in such a fashion that your body produces more testosterone in the hopes that it might get converted into estrogen for that estrogen that something like Clomid is blocking. Right?

Dr. Cameron Sepah [00:19:02]: Correct. Yes.

Ben Greenfield [00:19:02]: And then the problem is, because Clomid has zuclomifene as one part of Clomid, you're dumping a bunch of extra estrogen into the system simultaneously and creating side effects like mood swings. I don't know, man boobs, getting weepy during chick flicks, stuff like that.

Dr. Cameron Sepah [00:19:21]: Yeah. I mean, it won't induce gynecomastia. Interestingly, the man boob that you mentioned because, sir, ironically, because they generally do block estrogen, are actually used as a treatment for gynecomastia. So raloxifene, for instance, is an example of a serum that's actually prescribed when people have gyno.

Ben Greenfield [00:19:37]: Okay, so the enclomiphene is balancing out the zuclomifene.

Dr. Cameron Sepah [00:19:40]: Yeah, exactly. At least when it comes to gyno. Cause it does bind to, actually, the estrogen receptors in the nipples. But, yeah. Now, here, I would say low to medium doses of Clomid are safe and effective. In fact, there's a study that was published where they put people on it for, they tracked people over three years, and the scientists basically concluded that Clomid, which is the brand name for clomiphene citrate, is essentially a safe and effective treatment for hypogonadism. There's actually zero adverse offense in the trial that caused people to drop out. And so the problem is, usually people overdo the dosing, and then they get too much of the estrogenic effects.

Dr. Cameron Sepah [00:20:20]: Now, there is a superior approach, which is a pharmaceutical company came along, realized that this problem was happening, and they purified Clomid. So they got rid of the zuclomifene isomer that was causing most of the side effects. What only remained is enclomiphene, the estrogen receptor antagonist. And that's actually what was almost the genesis of Maximus in that I realized this is an incredibly effective drug. It was kind of used in the private practices that are more on the cutting edge of stuff, like you're doing for hormone optimization. And it's incredibly effective. On average, enclomiphene can increase testosterone, usually between 1.5 to 2.5 x. So essentially, we can double testosterone levels.

Ben Greenfield [00:21:05]: Without being on testosterone.

Dr. Cameron Sepah [00:21:07]: Without being on testosterone. Just one daily pill. So it has huge advantages over TRT that, first of all, you don't have to inject yourself. It's literally an oral medication that's bioavailable and it stimulates your own natural production. So the difference between blood work of someone on TRT versus enclomiphene is TRT, their LH and FSH levels, as we talked about, are going to be near zero because you're shut down. Your testicles are going to shrink and you're dependent on it. If you go off of it, you're going to feel pretty bad. With enclomiphene, your LH and FSH levels actually typically go up because it's essentially telling the body, hey, you don't have estrogen, produce more. It actually makes your testicles bigger.

Dr. Cameron Sepah [00:21:44]: Ironically, the studies that show the higher dosages, it actually increases testicular volume, it increases fertility. Total motile sperm count, which is a key fertility marker, actually goes up. So it makes you more fertile as a man and it generally doubles testosterone. The other advantage is there's no dependency. If you just stop taking it, you'll just go back to your baseline levels. You won't be shut down like you will with TRT. It's a lot safer of an option because it's not a lifelong option. Obviously, you can choose to take it if it's benefiting you, but you're not dependent on it.

Dr. Cameron Sepah [00:22:16]: And so the huge advantages for guys under 50 or anyone who wants to maintain their fertility or have kids, it's a really great option because it's not that drastic kind of lifelong decision that you need to make. And you can prescribe it to men as young as 18 because it doesn't mess with their fertility and in fact, it enhances their fertility.

Ben Greenfield [00:22:35]: How much bigger are we talking, by the way? We're not getting into, like, teabagging when you use the bathroom to type of territory, are we?

Dr. Cameron Sepah [00:22:41]: There is actually a poster presentation, I believe is presented at like a urology conference, and they found that it was a statistically significant increase in testicular volume.

Ben Greenfield [00:22:52]: So I want to talk a little bit more about clomiphene because I have more questions about it. But you also mentioned HCG. Why wouldn't you use HCG? Because didn't you say you could use that to either increase testosterone, increase fertility, or both?

Dr. Cameron Sepah [00:23:05]: Yeah, HCG is a viable, but it's kind of an incomplete solution if you actually think about what HCG is. HCG is essentially synthetic LH, right. So oftentimes when people are taking TRT, as I mentioned, they shut down their natural endogenous LH and FSH production. So you can replace your LH with synthetic LH, which is essentially HCG. So if you really think about what HCG is, HCG is LH replacement therapy, just as testosterone is testosterone replacement therapy. So what it can do is it can maintain some of that testicular volume function and fertility if you're on TRT.

Dr. Cameron Sepah [00:23:43]: The problem, though, is the FDA now considers HCG a biologic. It can no longer be compounded. It's very expensive now, and it's harder to get. And so it's less commonly used, unfortunately, because of the costs and the scarcity around it. The other part of it, though, is it doesn't replace FSH. You'd have to actually take another compound, which I believe is HMG, which is even harder to get, even more expensive. And now you're basically injecting three different compounds, testosterone, HCG, HMG to replace testosterone, LH, and FSH. And so you can do it.

Dr. Cameron Sepah [00:24:19]: I don't actually meet a lot of people who take all three. Maybe they'll take the third one if they're trying to maintain their fertility in the future. But it's kind of an onerous solution. That's why enclomiphene is kind of elegant, because through one medication, maintaining your body's own natural LH and FSH production and is producing its own testosterone. So it's simpler, essentially, especially for people who don't want to inject.

Ben Greenfield [00:24:43]: Now, you mentioned something important. You were describing HCG. You said it can no longer be compounded for people who don't know what you mean by that. Can you explain how this compounding and compounding pharmacies work?

Dr. Cameron Sepah [00:24:53]: Yeah, it's a great question. Most people are familiar with sort of traditional retail pharmacies. These are the CVS and Walgreens of the world. They essentially will provide you with manufactured, either generic or on-brand medications. But these are things that are essentially standard medications and standard dosages. Right? Like you might get a, I don't know, 20 milligrams of Viagra, but if you wanted a custom dosage of it, your doctor would actually have to write a prescription to a compounding pharmacy and say, hey, maybe for your size and weight, or you don't have that much ED, you only need ten milligrams. And so if you can't kind of break the pill in half, or you need a custom dosage, like 7 milligrams, you get a compounding pharmacy. To produce that in either a customized dosage, it could be a customized combination of two different medications, or it could be a different delivery system.

Dr. Cameron Sepah [00:25:43]: Some people, for instance, have trouble swallowing pills, so they might give it to you in a liquid or a dropper form that's more easily consumable. So essentially, compounding pharmacies produce customized or personalized medications that are a lot more adjustable in terms of meeting people's needs.

Ben Greenfield [00:26:00]: Okay, so if you have a compounding pharmacy making enclomiphene, is it like a tablet or a capsule or. I'm assuming it's not injection.

Dr. Cameron Sepah [00:26:08]: It's not an injection. It is very orally bioavailable. It's almost 100%. So it doesn't need to be injected. It absorbs pretty well. It can be taken as a capsule, or it can actually be taken sublingually as a tablet. Just stick it under your tongue, it'll dissolve and gets absorbed that way.

Ben Greenfield [00:26:24]: Huh. Are there side effects to enclomophine?

Dr. Cameron Sepah [00:26:27]: All medications, as you know, have side effects. The good news is the side effects for enclomiphene are rare. They're about one to 3%. They're mild, most common being headaches, dizziness, nausea. And they're reversible in that if you do run into them, typically you just need to adjust the dosage and they can go away. More is not always better, contrary to American opinion. Sometimes if you increase the dose way too much, it can reduce libido and other things. But that's actually true of testosterone as well.

Dr. Cameron Sepah [00:27:00]: It's really about maintaining that equilibrium or that homeostasis that I mentioned. The nice thing is, for instance, the compounding pharmacies that we work with can prescribe eight different dosages of enclomiphene all the way from 3.125 milligrams all the way up to 25 milligrams, and find the right dosage that allows you to maximize testosterone while minimizing side effects. And usually the way you do that is you find what's called the MED, the minimal effective dose. So what gets you the most bang for your buck without running into side effects? And the nice thing about the, you know, what we're doing now with telemedicine is you can start people on a conservative dose, especially if they're not hypogonadal. You might put them on half the dose that's been effective in the clinical trials, which is twelve and a half milligrams. You can put people on, let's say, 6.25 milligrams, see how they respond. If they get a nice testosterone boost, they have twice as high levels. They're feeling pretty good in terms of their energy and their function, great.

Dr. Cameron Sepah [00:27:53]: They can stay on it. If they find, ah, maybe I'm at 1.4 x, I want a little higher levels. They can type and they're doing well. They can titrate the dosage up to twelve and a half milligrams, see if they tolerate it well, adjust it up or down. And so it's really true, personalized medicine, which is the way, as you know, medicine really should be practiced.

Ben Greenfield [00:28:14]: With enclomophine, don't some people also combine it with testosterone? And if so, what would be the reason for doing that?

Dr. Cameron Sepah [00:28:20]: Yeah, it's a great question. So, with injectable testosterone, it's so suppressive, it will shut down your LH and FSH by 90-95%. Nothing really mitigates that suppression. People have tried, in fact, for years to combine injectable testosterone with Clomid, which has, like I said, been around for a long time. It doesn't negate the suppressive effects. It may be that HCG can negate some of the testicular volume issues and the fertility issues, Clomid a little bit less. So it's not as effective.

Ben Greenfield [00:28:53]: No, no. I'm going to jump in here real quick. I have to ask, when you're saying it's not as effective, is that based on what you've observed in patients, or is there actual research that compares Clomid and testosterone with enclomiphene and testosterone?

Dr. Cameron Sepah [00:29:10]: This is from clinical observation of doctors who've seen patients on injectable testosterone and Clomid. It doesn't negate the suppression, essentially. And like I said, HCG doesn't totally negate it either. It just maintains some testicular function, but maybe not even to 100%. Kind of keeps the lights on. But it's not the same as your sort of natty levels, so to speak.

Ben Greenfield [00:29:30]: Okay, got it. But what you've clinically observed is that enclomiphene seems superior because you're able to maintain fertility without testicular shrinkage, even if you're also on testosterone.

Dr. Cameron Sepah [00:29:42]: Not injectable testosterone. Like I said, injectable testosterone is still too suppressive. Now, here's the interesting thing. This is going to answer your question. There are other forms of testosterone now on the market. There is topical testosterone, which is typically a gel or cream that you can apply to your scrotum, your arms, your chest, that suppresses LH or FSH by 50-60%. There are intranasal forms like Natesto, where you can swab the inside of your nose that are only suppressive by about 20-30%. And there's actually new oral forms of testosterone.

Dr. Cameron Sepah [00:30:15]: So as you mentioned, testosterone is typically injected because it's not bioavailable. However, there have been advances in pharmaceutical science that make testosterone orally bioavailable. And the trick to that is it's typically consumed with some fat. Your fat is absorbed by your lymphatic system, and so it kind of piggybacks off of the lymphatic absorption in your intestines instead of your stomach and actually can be absorbed as a pill or a capsule. So oral testosterone is still suppressive. It's kind of like topical, about 50, 60% suppression of LH or FSH levels, but it's not as suppressive as the injectable at 90-95% suppression. What we've discovered, and we published clinical trial data, which you can read at maximustribe.com, is that when you combine enclomiphene with oral testosterone, it can actually mitigate the suppression. In fact, 100% of the people in our clinical trial maintained LH or FSH levels within the normal range, even though they're on exogenous oral testosterone, which should otherwise be suppressive.

Ben Greenfield [00:31:18]: Now, one thing that comes to mind a lot of times when we're talking about oral delivery versus transdermal delivery mechanisms would be some of the first pass liver stuff. Like, is there any concern about hepatotoxicity or anything like that with either oral enclomiphene or oral testosterone?

Dr. Cameron Sepah [00:31:33]: Yeah, great question. So let's start with oral enclimophene. Oral enclomiphene is not a steroid, and so it doesn't actually have liver toxicity. It is processed through first pass liver metabolism, but it doesn't typically elevate liver markers, and so it doesn't have any adverse effects on the liver. Testosterone, unfortunately, gets a bad rap because back in the seventies, there was a form of it called methyltestosterone, which is kind of a modified form of testosterone that had hepatotoxicity. And obviously, oral steroids can be liver toxic. But this new form, this oral testosterone, like I said, it's actually designed not to get absorbed in the stomach. It gets absorbed and piggybacks off the lymphatic system.

Dr. Cameron Sepah [00:32:18]: So it actually, for the most part, actually bypasses first pass liver metabolism, and it doesn't have negative effects on liver enzymes. And we're sure of this, in fact, because not only do the studies show that, in fact, there are three FDA approved forms of oral testosterone. They wouldn't have gotten FDA approved, obviously, if they were harmful to your liver. In fact, there's some interesting emerging research that they may be used as a treatment for fatty liver disease. But we actually measure liver markers as part of our blood work, and so you don't have to take my word for it. We assess it before and after, and make sure that it doesn't cause any elevations in liver enzymes.

Ben Greenfield [00:32:56]: Yeah, that's good. That's critical. Anytime you're working with a company is make sure you get your testosterone, your DHT, your hematocrit, your liver. There's a lot of stuff to keep track of before you just get started on something like this. Super important. Now, the oral tea, you said you take it with a fat. How much fat are we talking? Is this like half a jar of peanut butter, an egg, a little bit of olive oil in your smoothie, or what's the quantity?

Dr. Cameron Sepah [00:33:20]: Yeah, it's a great question. So, first, the thing I wanted to clarify is that the testosterone that's actually used in oral testosterone is basically what we call native testosterone. Native testosterone is literally the same bioidentical testosterone that your body produces. It is unmodified, or what's called unasterified testosterone. Testosterone that you inject is typically an ester. You've heard of probably the term testosterone enanthanate, propionate, cypionate. These are essentially modified versions of testosterone that allow for them to have a longer half-life. So you only have to inject it once a week, rather than inject it every day, which is obviously an annoyance.

Dr. Cameron Sepah [00:33:57]: However, they behave differently than the natural endogenous testosterone that's truly bioavailable. I think a lot of people say that testosterone's bioavailable, but it's not. Not unless it's native testosterone. Oral testosterone and actually topical testosterone are really the only two forms that are true native, bio identical testosterone that's essentially chemically identical to the testosterone that your body naturally produces from its gonads. And so that's the form that's actually used in oral testosterone, and we find actually works pretty well. Sorry. Now, remind me what your question was about it.

Ben Greenfield [00:34:32]: How much peanut butter, doctor?

Dr. Cameron Sepah [00:34:33]: Oh, okay. So there's studies that show, for instance, if you compare oral testosterone undecanate, which is an ester, it does require fat absorption. Studies that use native testosterone, which is the form that we use, do not require as much fat in order to be bioavailable. So even if you take it without any fat, it will still increase your testosterone levels, so it does not require fat. However, if you take it with fat, it will enhance the absorption. Studies show that typically you need about 30 grams of fat in order to maximize the bioavailability, which is not a lot.

Ben Greenfield [00:35:11]: It's like, just like 250-300 calories from there.

Dr. Cameron Sepah [00:35:15]: I literally eat an avocado and half a cup of kefir or yogurt, and that's 30 grams right there.

Ben Greenfield [00:35:21]: Okay. Yummy. So with the oral and the transdermal, you're basically doing something far different than injecting once a week. You're taking a small amount. I'm assuming, by the way, is the oral twice a day or once a day?

Dr. Cameron Sepah [00:35:34]: You can actually. That's the nice thing about it. You can flexibly use it however you like. A lot of people will take it once a day, in the morning with their breakfast or lunch, whatever their kind of fatty meal is. That's the other thing too. It's like you don't necessarily need to go out of your way to eat fat. Best thing to do is just eat it with the meal that you were having.

Ben Greenfield [00:35:49]: Yeah. So you don't have to put ghee into your breakfast cereal. You can just wait till the first fat-containing meal, which might be lunch.

Dr. Cameron Sepah [00:35:56]: Exactly right. If you're eating your eggs, which you should be having anyway, because eggs have cholesterol. Cholesterol is essentially the steroid backbone in which all your hormones are produced. You have to consume some fat in order for it for you to produce your own hormones. You consume it with that. It will work if you take it once a day. So the half-life of the reason that oral testosterone is not very suppressive is it has a shorter half-life. It will typically peak at about 3 to 4 hours, and it'll be out of your system generally within 8 hours.

Dr. Cameron Sepah [00:36:25]: Now, it can induce quite a high peak. We found in our studies that oral testosterone, in conjunction with enclomiphene, will increase your total testosterone levels by about 2-5 x and your free testosterone levels by 3-7 x. So it can peak quite high and then go back down. And then that is enough to essentially stimulate the androgen receptors and induce anabolism, the muscle building and all the beneficial qualities of testosterone. Now, some people, because they want to feel it a little bit more in the afternoon or evening, you can split up your dosages. You can take it breakfast or lunch, breakfast or dinner, or one tablet per meal if you really want to spread it out. The nice thing is you have the flexibility, in conjunction with your physician, to kind of do what works with your schedule. If you're more of a morning workout person or an evening workout person and you want to try to piggyback it off to maximize your testosterone levels while you're working out.

Ben Greenfield [00:37:18]: Got it. I know I said it earlier, and it could be inaccurate, so I should run it by you. I mentioned that taking testosterone might increase your libido and make you want to go out and have a bunch of babies. But is it true that testosterone doesn't have a real big impact on libido versus strength recovery, vitality, sleep performance, things like that?

Dr. Cameron Sepah [00:37:40]: It does. It's just that testosterone is not the only hormone, as you know, that impacts libido. Testosterone and estrogen or estradiol is also really important for libido. You don't want estradiol to be too high or too low. It kind of needs to be in a Goldilocks zone. And it also varies by individual. Some people actually feel quite good on having high estradiol levels, which is why increasingly, in sort of the injectable testosterone world, doctors are not prescribing aromatase inhibitors, or AIs, like anastrozole, as much they used to always cause. One of the problems with injectable testosterone is it tends to aromatize or convert into estrogen or estradiol at a very high level.

Dr. Cameron Sepah [00:38:22]: And so even though it's jacking up your testosterone, when you inject, your estrogen levels can get quite high, too. That can mess with your libido. And so they give you an aromatase inhibitor to try to control it. But you got to be really careful about that because you do need some estrogen. It's important for your bone mineral density, it's important for your mood, it's important for your neurocognitive function.

Ben Greenfield [00:38:40]: Yeah, I was going to say, a lot of guys get on AIs and they get brain fog because estrogen so, or estradiol specifically, is so critical to brain performance.

Dr. Cameron Sepah [00:38:47]: Yeah, exactly. And so increasingly, the better thing to do is just lower your TRT dosage. So your estrogen is not out of control. The nice thing about both topical and oral testosterone is it actually preferentially metabolizes into DHT, which you mentioned earlier. DHT is an androgenic hormone. It's responsible for pubertal development, the development of facial hair. It's kind of the aggressive hormone and is implicated in libido as well because it preferentially converts to DHT over estradiol, you typically actually don't need an aromatase inhibitor when you take oral and topical testosterone versus injectable testosterone. The other really interesting thing is DHT.

Dr. Cameron Sepah [00:39:34]: The body's natural androgenic hormone, is essentially a natural aromatase inhibitor. It's the way the body naturally regulates its own estradiol. So if your DHT levels go high, it essentially keeps your estrogen or estradiol levels under control. In fact, in our clinical trial, even though, like I said, we're increasing testosterone by 2-5 x, free testosterone by 3-7 x, estradiol levels actually stayed the same, if not slightly lower. And that was because of the increase in DHT. And in that case, DHT can actually increase libido. In fact, when we did before and after measures of a measure called the Q atom, and we specifically asked, you know, how was your libido before treatment? How was your libido after treatment? About 70% of people reported actually improvements in libido and erections being on this oral testosterone plus enclomiphene protocol.

Ben Greenfield [00:40:27]: Now, doesn't DHT, though, isn't it associated with male pattern baldness or increased PSA or prostate issues? If it gets too high, yes.

Dr. Cameron Sepah [00:40:36]: Now, if you read too much of the Twitter sphere, there's a lot of back and forth about whether that's true.

Ben Greenfield [00:41:19]: I'm a Reddit guy.

Dr. Cameron Sepah [00:41:19]: But yes, it can, if you are already prone to androgenic alopecia or BPH. Right. Benign prostate enlargement, essentially. So in those folks, it can exacerbate it. So what we tell people is, basically, if you're already losing your hair, you have to be mindful. Now, the good thing about enclomiphene, if you're just talking about enclomiphene monotherapy, if you're taking it by itself, it actually maintains the same T to DHT ratio. And so even though your testosterone is going up and your DHT is going up with it, it's relatively balanced.

Dr. Cameron Sepah [00:41:19]: And so we find it's actually pretty hair friendly, if you will. It doesn't seem to cause a lot of shedding or hair loss in folks. With oral testosterone, it definitely converts more to DHT. And so the balance between T and DHT becomes a little skewed to in those folks, if you're not prone to balding, you're probably not going to start balding. If you're already losing hair, then, yes, it can exacerbate hair loss. It can exacerbate acne, because DHT can stimulate the sebum production in your skin, the oily production of your skin.

Ben Greenfield [00:41:52]: Never seen that at a bodybuilding show ever.

Dr. Cameron Sepah [00:41:54]: Yeah, for sure. And it can enlarge the prostate. Now, the good news is oral testosterone, compared to injectable testosterone, does not increase PSA as much, does not increase hematocrit as much, and does not increase blood pressure as much. It's probably because it's a short half-life and it doesn't kind of redline your body. But in those folks who are predisposed to and sensitive to kind of DHT increases, you can take a low dose of 5-alpha reductase inhibitor, which most people know as finasteride or propecia, or there's dutasteride or Avodart. Those are the brand names of it. What that does is it basically blocks the conversion of testosterone to DHT.

Dr. Cameron Sepah [00:42:40]: And so you can kind of have your cake and eat it, too. In that if you're taking an oral or topical testosterone and you're concerned about the increase in DHT, adding a 5ar inhibitor will not only block the conversion of DHT, but it actually increases testosterone even more because it's not converting so much to DHT.

Ben Greenfield [00:42:57]: Now, would I be incorrect to theorize that if you're doing a big injection of testosterone once a week, that flood that big surge in testosterone versus, like a once or twice a day small spike, which I think might more closely mimic the natural diurnal variation that would occur in a man anyways when it comes to testosterone. But that big spike, would that potentially cause even more concern about overaromatization, PSA issues, hematocrit issues, etc., because it just seems like a lot all at once that doesn't occur in a natural scenario.

Dr. Cameron Sepah [00:43:31]: Absolutely. It's not mimicking the natural biorhythm. So you definitely get much more spikes in estradiol, DHT, and, yeah, so people can sort of develop issues with increases in their hemoglobin and hematocrit, right, which is called polycythemia. Sometimes you'll hear about people on injectable TRT actually having to donate blood because their blood is getting so thick and increases, obviously, your risk of heart attack and stroke. The risk of polycythemia on oral forms of testosterone is extraordinarily small. It's like 0.003% in a study that I was looking at. Now, we still monitor hemoglobin, hematocrit, just in case, because there's some people who are just almost high to begin with. If you're living at very high altitudes, your body naturally produces more red blood cells and produces more hemoglobin.

Dr. Cameron Sepah [00:44:22]: So we just make sure no one's getting too, too high. But, yes, I think the reason it doesn't cause as many side effects is, to your point, your body has a natural rhythm of testosterone in which basically very early in the morning, you achieve peak levels of testosterone. It goes down as you wake up into the afternoon and it elevates again into the evening. There's that natural 24-hour rhythm of testosterone in which it's released in sort of this pulsatile manner. Testosterone is really not meant to be redlined all the time. The reason that we're doing that is just because, to your point, it's more convenient to inject once a week, so you get this huge surge. Your testosterone is actually super physiological. It can be well above 1000, sometimes 2000 plus, and then it will coast and go down over the course of the week.

Dr. Cameron Sepah [00:45:10]: So that by the time you're on day seven and you're ready for your next injection, you're at your so-called trough levels. Your peak in your trough levels, you feel really great. When you get that initial testosterone surge, it's almost euphoric, which I think sometimes gets people a little addicted to it, psychologically speaking. And then they don't feel as good by day seven, which is why increasingly you're seeing a move towards actually people injecting more frequently. They'll inject daily to every other day, so they're getting less of the highs and the lows. Downside is you got to inject every day to every other day and you feel like a human pin cushion.

Ben Greenfield [00:45:43]: So you guys are testing at Maximus, obviously, and I know you do some testing to monitor values. You talked about supraphysiological values of testosterone. But let's say somebody comes to you, like, what are you looking for when it comes to deciding whether or not their testosterone is low or their free testosterone?

Dr. Cameron Sepah [00:46:03]: Yeah. So our advisors always say we treat people, not numbers. The treatment or the designation of hypogonadism based on testosterone values is highly problematic because the reference range, as I mentioned earlier, has actually shifted. Usually super physiological testosterone back in the day was considered a total testosterone over 1,200. But because it keeps dropping over the last couple decades, some of the recent lab reference ranges, which is usually between the second and a half to 97.5 percentile, have dropped to almost 900. I think I saw one that was like, 827 is considered high, which back in the day was almost like normal for an athletic male. And so what is considered low is honestly kind of arbitrary. And there's, in fact, there's published research papers that prove that, because what is low for a 20-something year old male is probably very different than low for an 80-something year old male.

Dr. Cameron Sepah [00:46:58]: These are not even age referenced samples.

Ben Greenfield [00:47:01]: You mean they're not age referenced? Like, if I go to a doctor and I'm 80 versus when I'm 20, they're looking at the same chart?

Dr. Cameron Sepah [00:47:06]: Exactly. The reference range for a lab is based on 18 to 80-something year old men. Also, people who are really sick, as you know, 88% of people have some form of metabolic syndrome. 70% are overweight or obese. And they're comparing their normal testosterone levels to yours, which is a healthy, young, athletic male should be totally different. So it's a bit of a joke to use standard reference ranges in the sick care system, as I call it. In order to be diagnosed with low testosterone or hypogonadism, as we discussed, typically you have to have a total testosterone under 300, which is right around the second and a half percentile. That's obviously a shitty way of doing a diagnosis, because what if you're third percentile, you're at 301? Technically, you don't have hypogonadism anymore, then.

Dr. Cameron Sepah [00:47:55]: The other problem is we didn't talk about the difference between total and free testosterone. Total testosterone is the total amount of testosterone in your system, but it's not necessarily bioavailable in order to bind to the androgen receptor, because it gets bound to these two different molecules, one being albumin, the other being SHBG, or sex hormone binding globulin. Free testosterone is the unbound testosterone that's actually free, like a lock and key to bind to the androgen receptor. Free testosterone is more associated with clinical symptoms like libido, energy, all the things that we're talking about. So most clinicians who are experts in testosterone actually pay attention to free testosterone. You can calculate it pretty easily. If you've measured total testosterone, you have albumin or SHBG. You can calculate, essentially, what's your free testosterone.

Dr. Cameron Sepah [00:48:40]: So that's essentially what we do.

Ben Greenfield [00:48:42]: Oh, really? How do you calculate that? For some reason I thought you just measured the actual free T, but it's a ratio type of thing with SHBG?

Dr. Cameron Sepah [00:48:49]: You can. The problem is, a lot of the measures of free testosterone are not accurate unless it's done by an LC-MS test, which is more expensive, takes longer to run, etcetera. There's something called the vermilion equation. So if you basically have. Even if you just have total testosterone and SHBG, you can plug it into a little online calculator. It'll calculate your free testosterone, and it's actually pretty accurate. There's a lot of clinical validation for that.

Ben Greenfield [00:49:17]: Kind of makes logical sense, because sex hormone-binding globulin would bind total testosterone, and if it's high, you're gonna have less free testosterone. So I'm assuming this calculation is based on big data or something like that?

Dr. Cameron Sepah [00:49:28]: Yeah, it's large cohorts, and, yeah, to your point, high SHBG means lower free testosterone, low SHBG, higher free testosterone. So what we do, and this is really the innovation, is it's obviously kind of a pain in your arm to go to a quest or Labcorp and get a huge needle stuck in your vein. Now, it's great because you can measure 100 biomarkers, but it's inconvenient to do. And so what we've done is we've partnered with a medical device company that's actually gotten these FDA approved. This is what the device looks like.

Ben Greenfield [00:49:59]: Holding it up. For those of you watching the video, check it out on YouTube or bengreenfieldlife.com/maximuspodcast.

Dr. Cameron Sepah [00:50:07]: Yeah, it basically looks a lot like a CGM, and it works in a similar way. You just stick it on your shoulder. There's a big red button, as you can see here. You press it, and it actually uses microneedles. So they're very small. And it's virtually painless. Like I would say on a 1 to 10 pain scale, it's like a, maybe a 2.

Dr. Cameron Sepah [00:50:24]: So I have friends, in fact, who are blood phobic. They'll pass out of the site of blood. They can do this test. While they would have a lot of trouble with a traditional blood test, you can literally do this in the comfort and convenience of your home in five minutes. And it'll draw out. I'm showing this on the camera, basically, for those who are listening on audio, it's about half of your pinky's worth of whole blood. This is whole blood that comes from capillary blood, and it's mailed off to a lab via Next Day Air, via FedEx, and then it arrives in the lab in the wind. Within two days, they can analyze your total testosterone, your SHBG, calculate your free testosterone, and then measure other key markers, including your estradiol, your LH, your FSH, your PSA that you mentioned, your hemoglobin, hematocrit, and your liver enzymes like ALT and GGT.

Ben Greenfield [00:51:17]: Oh, so you're getting it all from that one. It's like the staples easy button, that red button. That begs the question, though, because a lot of these companies that do the at-home lab testing, they got the little cards, and you prick your finger, and sometimes it bleeds, and sometimes it doesn't. You got to milk it like a cow and wait and get x number of drops, and sometimes, you know, relance at your finger to get it to start bleeding again. But is there a reason everybody doesn't just use the little slap-it-on your arm thing you just showed us?

Dr. Cameron Sepah [00:51:45]: Because there's a lot of unethical and pseudoscientific companies, basically, that are out there. It's much cheaper to do the dried blood spot test. We actually looked into it.

Ben Greenfield [00:51:53]: Oh, it's cheaper. Okay.

Dr. Cameron Sepah [00:51:54]: It's cheaper. Yeah. There's some companies out there that for $45, you can do this little milk-your-finger-dry blood spot test, which, by the way, 20% of men can't even do it because their fingers are so callus.

Ben Greenfield [00:52:06]: Yeah, no, I got super callus. I gotta get in the sauna to do it. I gotta heat my body up in the sauna, and then I can't even. This is gonna sound super unhygienic, but I can't even use the lancet. It's not deep enough. I literally have to use an insulin syringe and plunge it into my hand to get the blood to come out. Now I realize I've got very thick, my whole family, all the men in my family have these big sausage fingers. But, yeah, it is a little annoying.

Dr. Cameron Sepah [00:52:28]: Yeah. And so, yeah, it has a one in five failure rate, so it's just a terrible user experience. You have to do this multiple times, so it's hard to even get the blood out in the first place. And the problem is, when it gets on the card, it's prone to heat issues because it's going off. It's mailed, regular mail, and so if it's hot where you are, or the postal carriers, you know, the temperature's off, it can mess with the reading. And so dried blood spot testosterone tests are not very accurate.

Ben Greenfield [00:52:59]: That's what you call the cards? Dried blood spot?

Dr. Cameron Sepah [00:53:02]: Yeah. If there's any company that's out there, if you're. If you're researching companies, salivary testosterone and dry blood spot testosterone, even though there's big companies that are selling them online, are just not accurate. And we know this because we tried it, because obviously it's convenient to just spit into a tube. And these tests are, the dry blood spot tests are cheaper, but they're just not accurate. And if you're obviously trying to have an accurate assessment of your health and whether these treatments are working, you need an accurate blood test. And so this is best in class technology.

Dr. Cameron Sepah [00:53:34]: Like I said, it's whole real blood. It's just like. And it's clinically validated. It's just as effective, reliable, and valid is essentially going to a quest or a Labcorp. And so if people are not using this, I would not trust that company, basically.

Ben Greenfield [00:53:49]: Yeah. I mean, there is that DUTCH test that does all the different metabolites and does melatonin and a whole bunch of other stuff via dried urine, but that was pretty expensive.

Dr. Cameron Sepah [00:53:57]: Yeah, I think that's. I've heard of that. It's not a lot of, like, more naturopathic doctors are using that. I wouldn't say it's super accepted in sort of traditional clinical.

Ben Greenfield [00:54:10]: It's not. I think you can get a ton of data out of it. I think you can get more data out of it than saliva or blood. But again, it is spendy. So that's the downside. But I think it is a good test.

Dr. Cameron Sepah [00:54:21]: So, yeah, what we do with the tasso, just to wrap this up.

Ben Greenfield [00:54:25]: That's called the tasso, the blood one you held up. T-a-s-s-o.

Dr. Cameron Sepah [00:54:30]: Yeah, that we use. So we measured, obviously a baseline, and then the doctor will look at your numbers, but also your symptoms. And so you can technically be what's called eugenadyl, meaning your normal testosterone. But like I said, that could be third percentile. It could be 50th percentile. And so that's less important as your symptoms. If you're saying. I used to have great energy, I was happy, had great libido, but now I'm falling asleep in the afternoon or after dinner, I don't have the pep that I used to have, and I'm having symptoms of low testosterone. And your numbers are maybe not optimal.

Dr. Cameron Sepah [00:55:05]: You still can be a good candidate for, especially the type of treatment that we provide with enclomiphene, oral testosterone, or the combination thereof, because it's maintaining your natural production and your fertility. So it's not that. Oh, my God, this is a drastic treatment of last resort, where I got to be honest, for the rest of my life and shut off my own production. With this, you can really do more optimization or performance enhancement because it's a lot safer, essentially, than the old school, just injectable approach.

Ben Greenfield [00:55:34]: Right. And I can still meet with a doctor and get lab tests and everything. The only downside is, of course, insurance wouldn't cover it because I'm not hypogonadal. Right.

Dr. Cameron Sepah [00:55:42]: Yeah. I mean, I think insurance is a scam in this country because, like I said, they're in the business of denying care, not providing care, and they will only provide it to people who are really drastic below the second and a half percentile. We're a cash pay, basically private practice.

Ben Greenfield [00:55:57]: Another good reason to have an FSA and HSA.

Dr. Cameron Sepah [00:56:00]: Yeah. Which we do accept. So we, you know, obviously, you can get at least the tax savings from doing so. And, you know, the plans that we have, if you're committing for a year or more, it's typically $100 to $200 a month. Enclomiphene's 100 a month. Oral testosterone with enclomiphene's 200 a month. So it's actually pretty reasonable.

Ben Greenfield [00:56:17]: No, that's, that's not bad. I know some people would pay $100 a day for how they feel on testosterone when their testosterone is low. You know, you mentioned eggs, and, you know, we're joking about peanut butter, and you talked about the avocado and the kefir that you have. And it kind of makes me think, you know, you hear a lot of people talk about the pregnenolone steel, how you have really high cortisol levels. Your pregnenolone levels plummet, and all your hormones drop, because pregnenolin is like the mother building block from cholesterol of all the other hormones. And just backpedaling here for a second, back to what delivery mechanism you choose to increase testosterone. Why couldn't you just give somebody pregnenolone?

Dr. Cameron Sepah [00:57:00]: Yeah, it's a great question. Pregnenolone and DHCA are precursor hormones. They're technically neurosteroids. So as you pointed out, when you consume cholesterol, it gets metabolized into pregnenolone, which is considered the mother, grandmother, grandfather, whatever analogy you want to use hormone. And that converts into other hormones, including DHEA, testosterone, estradiol, and the whole steroidal cascade. The problem is the body kind of chooses how it converts pregnenolone into the rest of the hormone. So it typically actually doesn't increase testosterone on its own in men. And same thing with DHEA.

Dr. Cameron Sepah [00:57:41]: DHEA actually preferentially converts to estradiol, which is why it's not actually a preferred option, unless for some reason, you're trying to increase your estrogen. The major benefits of pregnenolone is it turns into another neurosteroid, allopregnenolone, which is kind of a GABA agonist. GABA is obviously the calming antianxiety receptor system. It's literally what alcohol works on, which is why people kind of chill out, obviously, when they drink.

Ben Greenfield [00:58:10]: Have your glass at your glass of evening, pregnenolone?

Dr. Cameron Sepah [00:58:13]: Exactly. So pregnenolone typically is taken to enhance mood. So it has mood and energy enhancing effects. Interesting. It also may improve sort of visual acuity, kind of makes the colors and life brighter. But so when people are on TRT, by the way, that's the other thing that people don't appreciate. And, you know, I'm a psychologist and psychiatry professor, so I really care about neurohormones and cognitive function. When you shut down your LH or FSH production, you're also shutting down your neurohormone production.

Dr. Cameron Sepah [00:58:42]: So your pregnenolone and DHeA plummet. And so not only, as I said, you have to take testosterone, maybe HCG, maybe HMG, but they're also putting people on pregnenolone and DHEA to backfill to your point, the neurosteroidal cascade, when you're on enclomiphene or enclomiphene and oral testosterone, because you're maintaining your natural LH and FSH production, you're also maintaining your natural pregnenolone and DHEA production, so you're not getting those neurocognitive impairments or deficits. Now, we still sometimes provide pregnenolone just to give people a little extra mood and energy boost to kind of optimize levels, but it provides kind of further benefit, essentially.

Ben Greenfield [00:59:24]: Oh, interesting. So, so you can do it. So you could theoretically do, like, pregnenolone with enclomiphene or pregnenolone with enclomiphene and testosterone. Like oral testosterone?

Dr. Cameron Sepah [00:59:34]: Yeah. And it's just like I said, it's more of a supplemental boost. It won't increase testosterone levels, but like I said, for some people, it enhances mood and energy levels.

Ben Greenfield [00:59:42]: Okay, got it. You know, a lot of these, you know, clinics because you see them a lot, right? I even heard them called pill mills.

Dr. Cameron Sepah [00:59:49]: Right.

Ben Greenfield [00:59:49]: In all these places where you fill out questionnaire and do a lab report, and then you get on your testosterone subscription, and you're kind of like, you know, just swiping your credit card every month for the rest of your life. So I think some of them get a bad rap in terms of what you guys are doing. You know, if you could sum up how you would differentiate yourself from the standard pill mill, how would you do that?

Dr. Cameron Sepah [01:00:11]: Yeah, it's a great question. And, you know, I think it's analogous to, you know, seeing any sort of clinician or doctor. Unfortunately, there's a huge amount of variance in terms of the quality of clinicians in this country. And I can say that because I'm involved in training psychiatrists at the number three medical school in the country. They typically produce very high quality clinicians. And there's some people who go to med schools in the Caribbean, or, no offense to those folks, but where the quality can vary, there's some great place doctors who come out of those places, and maybe there's some who were barely smart enough or sentient enough to get into US medical school.

Ben Greenfield [01:00:47]: What do you call a doctor? Somebody mid through medical school. Right?

Dr. Cameron Sepah [01:00:50]: Yeah. And I think clinics are the same way. There are some really high quality clinics and we obviously aspire to be. Now, I'm biased, but I'll tell you objectively why I think this is the case. First of all, we use board certified physicians, and there's a lot of clinics who are just using nurses and MPs. And there's nothing wrong with those folks. They can be really great. But, you know, someone who has a doctorate, typically, on average, is going to have a higher level of education, higher level of intelligence, quality.

Dr. Cameron Sepah [01:01:15]: And so I think MPs are great. We do use them sometimes, but they're ancillary in the care. They might be involved in writing the renewal of your prescription, but you're always going to have a physician as part of your care team that's supervising your care. And I think that's just a really important thing. It costs more. We have to obviously pay doctors more, but I think it's just when it comes to your hormones, really, really critical. So that's the first differentiation. Second differentiation, you see a lot of clinics who weirdly make people choose their own dosages of enclomiphene, which I think is just criminal because how do you know what the amount is that you're supposed to take?

Ben Greenfield [01:01:47]: Check. Check this box.

Dr. Cameron Sepah [01:01:49]: Yeah, check. And you like, pick your own poison. And I'm like, you know, we actually have the largest nationwide prescriber of enclomophine. We've been prescribing it for four plus years, have, you know, in the five digits, you know, patients and a lot of clinical experience with it. So we know, based on your age, height, weight, BMI, your testosterone levels, and your symptomatology, where you should likely start on how to adjust it if you're running into side effects, what the dose adjustments should be. Switching maybe to every other day versus daily dosing. So that there is an art to medicine and the physicians just need to be really experienced with these medications in order to maximize the outcomes. I always tell people, why bargain shop with your health? I'm sure you could theoretically find it cheaper somewhere else, but you're going to have to almost play your own doctor, which I think is kind of a shady thing. So if you see any place that's making you basically choose your own dosages, it's probably kind of a bad sign in terms of they're not really providing high quality clinical care.

Dr. Cameron Sepah [01:02:53]: You may save a few bucks, but you're going to run into, more likely run into side effects.

Ben Greenfield [01:02:58]: In other words, don't get your testosterone off Alibaba.

Dr. Cameron Sepah [01:03:01]: Yeah, exactly. So I think that's the other thing. But the other thing I was going to say, too, is we're the only telemedicine company that actually publishes their data. The two protocols that I mentioned, enclomiphene alone and oral testosterone plus enclomiphene. There are published clinical trials on our website that show our data. And so if you ask me, Cameron, how does this protocol increase my sports performance? I'd be like, great. We've measured that on this protocol. And in terms of people who reported normal levels of functioning before treatment, 62.5% of people said they had normal to excellent levels of athletic or sports performance.

Dr. Cameron Sepah [01:03:42]: That went up to 93.8% on oral testosterone plus enclomiphene. Right. That's a statistically significant finding. You can look at the data yourself and the methodology of our paper. And so it gives you increased confidence as a consumer or a patient that, hey, these guys are not only on the cutting edge of developing these new forms of treatment like oral testosterone, but they're actually measuring the outcomes. And I can have a pretty good sense of what it's going to do for me. I always tell people, look, it's not a panacea, it's not going to necessarily change your life if you're not doing the diet, exercise, sleep, all the other things that you need to do behaviorally, but you should have a good indication of what it's going to do and that we've actually tested this and have clinical data to back up, you know, our experience.

Ben Greenfield [01:04:22]: Yeah, yeah. As far as the FDA goes, you think that it's going to be something that continues to be cool with the FDA using something like enclomiphene instead of Clomid or oral testosterone or do they even look at stuff like that?

Dr. Cameron Sepah [01:04:37]: Yeah. So the FDA does not approve compounded medications. So what they do is they do regulate compounding, in that the pharmacies are inspected essentially by the FDA. They have to make sure they're obviously sterile if they're compounding things like the GLP-1s, the weight loss drugs, or injectable testosterone, because anything that's liquid in a vial needs to be manufactured, obviously, in a way that's very safe. So there's less regulatory oversight on the actual medications themselves. But increasingly, I mean, I can't predict the future, but I will say laws around telemedicine have essentially been relaxing in that. Obviously, post COVID, we've come to a world in which we're zooming, and the evidence generally shows that clinical care can be delivered just as well in person as it can online and outside of, obviously, procedural care where you're doing an injection or a surgery on someone. I think the future of medicine is telemedicine.

Dr. Cameron Sepah [01:05:36]: And so I think a lot of the states are essentially catching up and allowing the prescribing and fulfillment of medications. And hopefully, increasingly it will become more and more prevalent and won't be blocked by too much regulatory oversight. Now, I will say there are certain classes of medication which are more schedule two controlled substances. These are the adderalls of the world, the opioid painkillers that have clear addictive qualities. I've been very public and against those sort of telemedicine pill mills who were prescribing that willy nilly on TikTok. The FBI and the FDA kind of came down on those clinics that I think gave the whole field kind of a bad rap. But we started out very conservatively, right? We were only doing non-controlled, non-injectable stuff. And then now that we have essentially safer controlled substances like oral testosterone that maintains your fertility, we feel safe about prescribing that to a population that meets the eligibility criteria.

Ben Greenfield [01:06:34]: Well, that's fantastic, because on my top ten least favorite things to do is drive to the doctor or drive to the lab.

Dr. Cameron Sepah [01:06:40]: Exactly.

Ben Greenfield [01:06:40]: So saved me a step. So the website, if you guys want to check out more about Dr. Cam and what he does, go to bengreenfieldlife.com/maximus for the podcast show notes, and I'll include other podcasts I've done about all things, hormones, testosterone, libido, etcetera, go to bengreenfieldlife.com/maximuspodcast. If you don't know how to spell Maximus, go watch the movie with Russell Crowe. And Dr. Cam, thanks so much for doing this, man.

Dr. Cameron Sepah [01:07:09]: Thank you so much. It's a pleasure to be with you and hopefully we can do it again and talk about some of the new innovations that we're working on, including the topical testosterone. And we also provide, obviously, GLP-1s. And the first prescription pre workout, which is a combination of tadalafil and bardenafil, which I'd love to talk about more in the future.

Ben Greenfield [01:07:26]: Everybody loves to take Viagra before they work out. All right, man, thanks for coming on, folks. Thanks for listening in. Have an incredible week.

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