#260 ‒ Men's Sexual Health: why it matters, what can go wrong, and how to fix it | Mohit Khera, M.D., M.B.A., M.P.H.

22:46So what I do is we have a protocol where we can take the tissue, the penile tissue at that time, we send it to the lab, and then we'll look at it. High, high density of androgen receptors within the penile tissue. As the androgens go down, you can start getting atrophy of the penile muscle. That is very interesting. And I do want to come back to the intracellular and nuclear distribution of androgen receptors, testosterone, and DHT. So again, I'm trying to keep track in my mind of all the things I want to come back to. If you said to me, Peter, how can an aging person prevent atrophy of their muscle?

23:18The most obvious thing that comes to my mind is use it. It's a use it or lose it system. Is the same true of the penis? It's very true. So if you look at patients who are not using the penile muscle. For example, let's look at patients who have a radical prostatectomy. Very unfortunate. Young man, say he's 52 years old, and right after that surgery, he's not using the penile tissue, you will start getting atrophy of the muscle just if I put your arm in a cast today. So regular erections, so nocturnal erections are very important also. So that's how we get our oxygen into the penile tissue through the nocturnal erections, through sexual activity.

23:53There are studies suggesting that daily PD-5 inhibitors, Cialis, Viagra, can help with hypertrophy of the cavernosal smooth muscle. So that's why I particularly like to give patients daily Cialis. Even if they don't have ED? So let's think about this for a second. I just mentioned earlier that 40 % of men have ED at 40, 50 % at 50. It's an aging process, right, to some degree. So when you take Viagra, you are not curing your ED. You're just covering it that night while the disease continues to progress. But daily Cialis has been shown to cause hypertrophy of the cavernosal smooth muscle, keep the tissue healthy.

24:30So in many ways, I look at daily Cialis as a preventative measure to keep the tissue healthy. Now, I tell patients, when is the best time to start? When you start noticing if there's a mild degree of ED, something starting to show up for ED, that's when I want you to start taking the daily Cialis, not only to help you with what your issue is, but I look at, to me, as a preventative measure. Talked about daily Cialis. My recollection is that there were basically two dosing strategies, right? There was 20 milligrams. The idea, I think it was, hey, take 20 milligrams on Friday and it'll hold you through till Sunday and you can basically have sex on demand.

25:07Alternatively, it's having five in your system every single day produces the same tissue level. Is that directionally right? Close. So the conversion is 1.6 is the multiplier. So if you take five milligrams every day, it's like having almost like eight milligrams in your system. Eight. The convergence is 1.6. So eight is obviously less than 20, but some men really don't need 20. So that five daily, and remember, there's other benefits. Five daily has been FDA approved for BPH. And we'll talk about BPH and ED. Oh, didn't know that. FDA approved. So you can give someone Flomax or you can give them daily Cialis.

25:39Well, the problem with Flomax is retrograde ejaculation. Got it. So the young men, if they had a choice, he'll say, I'll take the Cialis and a side effect there'll be better erections. So FDA approved for BPH. Why? What's the mechanism? So mechanism unknown. That's what's a little bit interesting. Wow. We do know, it even says in the packet, mechanism unknown, but we do know that IPSS scores, these are urinary symptom scores, do improve in men who take daily PD5 inhibitors. That's true. So you just have to be careful not to, if you do take Cialis and a Flowmax medication, not to take them too close together as a warning because you can get a little hypotensive.

26:12So we have to separate them. But daily PD5 inhibitors are also FDA-approved for pulmonary hypertension. That I knew. And there were wonderful studies looking at daily Cialis versus on-demand Cialis, showing that the patients who took it for four weeks daily, significant improvement in endothelial dysfunction. And we'll talk about that later. Endothelial dysfunction outside of the penis? Outside of the penis. Meaning systemic. Systemic. And they were looking at blood markers, IL-6, C-reactive protein, not so specific. They were looking at flow median vasodilation, brachial artery. And they were showing that even if the patient stopped, this was a study by Aversa, even if the patient stopped the daily Cialis versus the on-demand, those patients who took the daily still had persistent improvement.

26:50So maybe, there may be something going on in the endothelium as well. So I think about endothelium, I think about pulmonary hypertension, I think about BPH, I think about ED, it's five milligrams daily, very affordable. Okay, maybe we can - What would you say is the biggest downside of Cialis? I used to say cost, and it was unbelievably - How much did Cialis cost? It was almost$15 to$20 a pill. $15 or$20 for a 5-milligram? Well, it was a 20-milligram pill, but it was still absorbent. It was almost$400 for a 30-day supply of 5 milligrams, which was unbelievable. So then we started going to the compounding pharmacies.

27:21We said, okay, the compounding pharmacies said we can make it for a dollar a pill. That's great. But it's hard to trust the quality, right? Some are better than others, and some compounding pharmacies are FDA-approved. So that makes it a little bit better. But then the generics came out, and it was shocking. If I give a patient who goes to HEB, they can get 90 pills of Cialis for$17 with no insurance. 90 pills,$5 million. And are you concerned? I've become very concerned with the quality of generics and realizing that not all companies are the same. You know, like Sandoz is a good company, but some companies are.

27:52Do you have preferred brands of generics that you fancy? I don't have a preferred brand, although I haven't seen the generics significantly less effective than the brand when it comes to PD5 inhibitors. That's one thing that I think I have not seen it less effective. That's great to hear. This is sort of indirectly related to ED, but what about refractory period? So any guy listening to this can think back to being in his 20s where you seem to be able to have an erection, ejaculate, and seven minutes later have another erection. You could have intercourse 27 times in a day. And then something happens when you get older, those days are done.

28:31You might get two a day. Is that considered a lagging or leading indicator of ED? What's different about that 20-year-old versus the 50-year-old? Yeah. So there's no question that the refractory period goes up as we age. One of the implications for refractory time is prolactin. So when you have an ejaculate, your orgasm, your prolactin levels go up. And that's been implicated as the reason for the refractory time. But as men get older, you're right. ED is more prevalent, so it's harder to get the next direction, and the refractory times go out. And I'm sorry, is there anything different about the prolactin secretion?

29:09I've never seen a study showing that, although I would intuitively think the prolactin may be long for a longer period of time, but I have not seen any study showing that. So that might be the indication, basically, that even if you don't have ED, things are changing. Your physiology is changing. Absolutely. And I think the majority of it is it is more difficult to get an erection as we get older, and therefore that contributes to the refractory time. It's so interesting how evolution simply, you would argue that, not that we want to spend too much time speculating on evolution, given that, as Andrew Huberman would say, neither of us were there for the design phase.

29:45But it's interesting in that you can certainly understand, I think, in the case of women, why based on the change in reproductive state, evolution didn't care as much about their sexual health as they got older. Is the same true for us where evolution sort of thought, eh, the older you get, the more genetic mutations in your sperm. I actually don't want you reproducing as much when you're 50 as you are when you're 20. I don't know about that. We have patients who are older that have great semen parameters. I think it's based on your quality of your health. Healthier men - Which, by the way, would make sense.

30:18It makes sense because you're more likely to reproduce. So if we look at men who are in their 80s, who are in great shape, they're having sex, no issues, no even unassisted. Meaning they don't even require, they use a bit of eye growth. Yeah, but some do, some don't. I mean, I have patients at 70, 80 years old, great shape, no issues having erections. The patients that come to me who are older, 60, 70, who are also trying to conceive, they marry someone younger. And you'll be surprised, typically sometimes you will see patients with sperm or spratogenesis even at older ages. It's based on your quality of your health.

30:50I have younger patients who are 30 that are in terrible shape, poor quality erections, terrible semen parameters. So I don't know if age is the main driver. No, I think that makes sense. And I think I talked about this with Sharon on the podcast, but I almost wonder if the greatest motivation for a patient, especially a male patient, with respect to insulin resistance is actually erectile function. Because definitely one of the things I've seen in my practice is that patients who go from having a higher hemoglobin A1c to a lower hemoglobin A1c will often notice an improvement in erections. Again, I'm not talking about a one-point change, but if someone goes from having a hemoglobin A1c from 5.9 to 5, which represents probably about a 25 milligram per deciliter reduction in average blood glucose, That's a person who says, I used to need Cialis for every erection to, I'm totally fine.

31:44So you bring up a really important point. It's lifestyle modification. Lifestyle modification has a huge impact on the quality of a man's erections. And the four pillars that I stress all the time for most sexual dysfunctions, diet, exercise, sleep, and stress reduction. If you chose to do one of them, it would have an impact on your quality of erections and your quality of life. And there's other manifestations that would improve as well. But you're talking about insulin resistance. And when you improve insulin resistance, when you improve obesity, stop smoking, all of these things improve. Now, I think there's a reason for this.

32:16There's a strong correlation between cardiovascular disease and ED. If I made a column of the risk factors for ED and cardiovascular disease, they're almost identical on both sides. So I say, what is the common link? Why is ED? So many studies say that if you get ED today, within seven years, 15 % of those men will have a card attack or a stroke. 15%. It's the first sign of cardiovascular disease. Numerous studies have shown that. And just to be clear, this is not psychogenic ED. Organic, has to be. So say that again. What percent? 15 % of men. So in 2004, Ian Thompson had the prostate cancer prevention trial.

32:52Roughly 4 ,000 men did not have ED, healthy men. He followed them prospectively. From the day they developed ED, 15 % of them in seven years had a cardiovascular event. That's significant. And he wasn't the first. numerous studies have shown a correlation between ED and cardiovascular disease. Montorsi that same year showed that if you had a cardiovascular event, 50 % of those men had ED 39 months prior to having the cardiovascular event. It is the sentinel sign of cardiovascular disease. So it's a real canary in the coal mine when it comes to microvascular health. Particularly if it's arterial insufficiency.

33:25So the question is, what's the relation? So one theory was arterial diameter theory. And it doesn't make a lot of sense, but this is the theory. If you look at the penile arteries, they're 1 to 2 millimeters. The coronaries are 3 to 4 millimeters. The peripheral arteries are 6 to 7 millimeters. And if you get 50 % occlusion of an artery, you know you get an organ damage. So you're more likely to occlude the penile artery before you occlude the coronary, coronary before the peripheral. So that was the theory. Now, it doesn't work very well because most of ED is an occlusive disease. And really, it's the pudendal artery, not cavernosal artery.

33:55But that was one theory. The most prevailing theory is endothelial dysfunction. That is the common link between ED and cardiovascular disease. Well, the cardiologists were very clever before the urologist to show that if you improve endothelial dysfunction, you can actually reverse cardiovascular disease. So if that's the common link, as urologists, we just copy them. Well, two of the three biggest risk factors for cardiovascular disease are taking aim at the endothelium. So the three big ones, APOB, that's not an endothelial issue, but smoking and blood pressure are, one being a chemical, one being a mechanical disruption of the endothelium.

34:31And I suspect both blood pressure and smoking elimination would mediate ED. For sure. Obese, diabetes is one of them also. This is called reversal. The best study I ever saw was Esposito, 2004 in JAMA. She just simply said, I'm going to give you a diet and exercise program, 110 obese men, 55 went on a diet and exercise program, 55 went on nothing. And she followed them for two years prospectively. If you simply had diet and exercise, you lost weight. It was a Mediterranean diet, by the way. I really believe in the Mediterranean diet. If you lost weight and took the Mediterranean diet, you saw three-point, which was significant, increase on the IIEF score.

35:09This is on that six-point scale? On the six questions after 25, but a three-point and on the IIEF with no Viagra, no intervention except diet and exercise alone. Does that three-point increase translate to a clinical meaningful improvement? Close. Usually it's four, so it's pretty close. And the meaningful improvement is broken down into, think of this as two, five, and seven. If you have mild AD, you want to see at least two, moderate AD five, and severe AD seven. So - Depends where they started. Depends where they started, right? But typically you want to see about a four, but even just a three, just on diet and exercise alone, they saw improvements in endothelial function in terms of IL-6, they lost weight.

35:46I mean, just diet and exercise alone reversed or had an improvement in AD. So lifestyle modification is very important. when we talk about sexual dysfunction. So let's go back to what you were saying in the office, some of the diagnostic tests. So a guy comes in, you quickly, or maybe not quickly, but you rule out psychogenic ED, and now you're realizing this is something physiologic. So you mentioned a diagnostic ultrasound. So you're doing an ultrasound of the penis. You inject something into the penis to induce an erection? Yes. So we typically inject Trimix, which is a medication that's compounded.

36:16You can actually also inject Alprosadil, which is commercially available, like EDEX. And you're injecting this into the corpus? Into the corpus. And it will cause a vasodilation. And just because every guy listening to this is freaking out saying, you're sticking a needle in my penis. But you'd be surprised. Not in the urethra. Not in the urethra. At the base of the penis, we inject it at the 2 or 10 o 'clock position. And within 5 to 10 minutes, it induces a very good erection. But what we're able to do with that is we're able to look at something called the peak systolic velocity. If the peak systolic velocity is less than 30, particularly if it's less than 25 millimeters per second, he has arterial insufficiency.

36:50Now, that's important. That means not enough blood flow is coming into the penile tissue. If the end diastolic velocity is greater than five millimeters per second, then he has a venous leak. So that's important. So I can now see if there's a hemodynamic problem going on in the penile tissue. And just so folks understand this, right? Diastole, or let's start with systole. Systole is what's happening when the heart is contracting. So you think about that as the flow out. Diastole is when the heart is relaxing in itself. it's filling. And so you're measuring kind of backflow through the venous system.

37:24Right. And that venous leak is important because remember, that's the number one cause. That's half the problem. Majority of the patients who have ED will start out with a venous leak. So, but then there's other - Just to be clear, the venous leak is usually happening before you see arterial insufficiency. In most cases. And what's important is you can also look at the corpora cavernosa. I can look at plaque. I can look at plaques. That plaque's important because that's what causes an abnormal curvature. You actually see plaque in the muscle? Not in the muscle. So in the wall, the tunica albigenia.

37:51So think about the two tunica albigenia coming together. As they come together in that V is where you see the plaque predominantly. Most of the plaque happens in the V. So most curvature in the penis is dorsal. So it actually goes upward. So 80%. And so these patients will have a curvature of the penis when it's erect. It's important when it gets greater than 60 degrees because that's prohibitive for intercourse. And it is 60 degrees. So patients can have 90 degrees. They can have almost 180 degrees. It can be very significant. Wow. That is a very significant disease. Patients who have Peyronie's disease really suffer from depression.

38:25They feel like there's a disfigurement. There's a treatment now. In 2015, the first FDA approved treatment in the world came out for Peyronie's, which is called Xyaflex or collagenase, where I can inject collagenase into the plaque and break it down so that I can improve the curvature. So that's very important because historically until 2015, we had no medical treatment. Everything was off-label. And what would that include? So people used to give vitamin E and they used to give colchicine. So in 2015, I was involved in the American Neurologic Association Peroni's guidelines, first guidelines.

38:56And we said, do not give vitamin E. It's not indicated. Colchicine doesn't work. But the only medication that's indicated are anti-inflammatories. The way Peroni's works is - This is administered locally or systemically? Systemically. So that's what we give. Think about this. The way Peyronie's disease works, there's an active phase and there's a quiescent phase. So the day you have an injury for about 12 months, it's constantly changing. We have the rule called the 15-40-45 rule. 15 % of patients will get better within the first year. That's awesome. Sorry, does this mean that Peyronie's disease is always born of trauma?

39:31It's the prevailing theory. And sex is trauma, by the way. And so when a patient engages in sexual activity, if he has 100 % rigid penis, less likely to injure. If he's 70, 80, or 90 % rigid, he's going to penetrate and he's going to injure. So ED many times precedes PD, Peroni's disease. Interesting. But we do think it's due to trauma during intercourse. That buckling trauma will then cause a plaque. So I tell patients, think about this. You have a balloon. I put a piece of duct tape on the balloon. I blow up the balloon. What's going to happen? Everything's going to expand except the duct tape, and you're going to curve in the direction of the duct tape.

40:07And the greater the duct tape, the greater the curve. So how can I treat this? I can use medications to remove the duct tape or the plaque. And you can't incise, you can't put a slit in the duct tape? You can. So that's the surgical therapy. But in terms of medical therapy, you can actually put the injection called collagenase. It breaks it up and it can help straighten the penis. The second thing you can do is actually surgical. You can put stitches on the opposite side and placate it to make it straight, or I can cut out the plaque and put a patch, a graft, a tutoplast or human pericardium. So we put a patch.

40:39Or if they have some erectile dysfunction with it, then I put in a penile prosthesis. Because what's the point of making the penis straight if you can't get an erection? In that case, I would put a penile prosthesis. And does a patient know if trauma is the predisposing factor? Is it apparent to him that he has induced trauma? Sometimes, majority no. Oh, wow. So sometimes - So you can't even say, if you act quickly, you have a better chance of salvaging this. The only way is when someone has something called a penile fracture. A penile fracture is when they're engaging in sexual activity and there's a sudden pop, a sudden injury that occurs, significant swelling that occurs in the penile shaft, and you should seek immediate medical therapy.

41:18And usually it's surgical. So you'll go to the ER, they'll call me on the phone, say, doctor, could we think we have a penile fracture? We'll go in and we'll take him to surgery and we'll sew up the fracture. And the fracture is what? Break in the tunica albigenia, in the casing I was talking about earlier. And the swelling is now because fluid is leaking out. It's all blood. It's a hematoma? It's a hematoma. So you want to act quickly. But majority of men, because we always ask them on the intake, do you remember any trauma? 90 % say no. I have no idea why this is happening. I'm completely freaked out why this is happening.

41:46How did this happen to me? And then you have to say, did you know that 7 % to 9 % of men have this? You're not alone. This is very prevalent. And it's very, very concerning for these men. Age? age does affect it's more prevalent as men get older but i do think so in 2009 i wrote a paper looking at testosterone as a possible implicator so we found that 74 percent of men had low testosterone and that's interesting because you know when you have low testosterone you have decreased rigidity of the penis so i think you're more likely to injure but testosterone has been implicated for wound healing merely in the dermatologic literature as well so it's almost like a double hit you're more likely to be less rigid and injure you're less likely to heal because many people have trauma, but they don't have a plaque.

42:29And so there has to be something going on with the healing process. So these patients will have an injury, but then the way they heal is it's a plaque that forms. 15 % of men have this, or sorry, 7 % to 9 % of men have this. Is it painful or is it just disfiguring? Yeah. So at the beginning, there's an active phase for 12 months. And in that 12 months, it's the 15, 40, 45 rule. 15 % of patients get better. We just get better. 40 % of patients stay the same. 45 % of patients get worse. In the active phase, it's typically associated with pain. Every time I get an erection, I'm having pain. The patient, you say, look, I'm not going to operate on you because if I operate on you and you happen to be the 45 % that get worse, I'm going to have to operate on you again.

43:11It hasn't stabilized. It hasn't remodeled fully. It's not finished. So when I get to the quiescent phase - Which is a year. About a year, sometimes a little less, sometimes a little more, but about a year, I say, have you noticed any changes that have occurred? No, doc, it's pretty stable. Is there any more pain with an erection? No, there's no more pain. Okay, now do you want to consider a surgical option, which would be an option. The other treatment that's off-label for this that's gotten a lot of favor is traction devices. So that's been very commonly used. And these devices are devices that are - I use one on my neck, but I'm guessing it's different.

43:42The same concept. Same idea, yeah. Any part of the body is pliable. People wear braces because it changes. So constant traction can make the penis longer, wider, but straighter. How do you actually apply a traction device to the penis? There is a portion of the device that goes around the glands and basically clamps the glands. Then you have ability to extend the traction. The glands is the head for folks listening. And the base goes at the base of the penis as well. And you can extend it as far as is comfortable. The one that I really like. But this is on a flaccid penis. Flaccid penis. The one that has gotten the most interest is one out of the Mayo Clinic called the Restorex.

44:19because the Restorex, you actually bend it in the opposite direction where you're curving in the flat state. It actually bends. So if you're curving up, you can bend it down. If you're curving left, you bend it right. And you hold it there for 30 minutes, at least twice a day, for three months, has been shown to have about 30 % to 40 % improvement in curvature. So penis larger, wider, and straighter, but you got to do the work. They're about$500, a little pricey, but they are effective. And I know somebody listening is going to think, Well, wait a minute. If you don't have Peyronie's, can you still use this device to increase length or girth?

44:50So these devices actually came from the porn sites. So before we started using them medically in 2010, porn sites were using them to increase length and girth. And they do. And actually many patients will come to me - By what percent? Usually about any from one to one and half inch you can get. So - What? Yeah, one inch. I mean, it's not like - That sounds like a lot to me. Two centimeters at the maximum. And is that a permanent change or is that only a change that lasts as long as you continue to use the device? We know that patients have to, there has to be some continued therapy. So some patients, when they finish using it, will have some periodic use, say every month or every, excuse me, every once a week or twice a week just for periodic use.

45:25But some studies will show up to two centimeters you can gain in length. So it's not negligible. So we get patients to come all the time and say, can you do penis enlargement surgery? I don't do that surgery, but I think that the stretcher is a safe way without doing surgery to gain some length. And the guy will use this for how long? It's every day, twice a day, for at least 30 minutes, up to three months. The old stretching devices were two to six, even up to six hours a day, but they were not bent in the opposite direction. They were just straight. And so it was two to six hours a day, every day for at least three months.

46:04But the Restorex, because it's the ability, I think, to bend in the opposite direction, you could shorten the time that you have to wear it 30 minutes twice a day. Wow. Is there a critical window in which that works going back to Peyronie's disease where you have to do it during that 12-month period and thereafter it becomes very difficult for it to be successful? Yeah. So the people have looked at active versus quiescent phase. I think you get benefit in both phases. In my opinion, I think it's better to catch it in the active phase while it's trying to prevent further progression of disease.

46:32So let's think about this. A guy comes in the active phase and he has 30 degree curvature. How do I define success? If I get that 30 down to zero, that is awesome. I'm very happy. But what if I'm able to prevent that 30 from going to 70? That's also success in the active phase. So because if he's greater than 60, it's prohibited for intercourse. So typically I like to, at least the stretching device, now the AUA guidelines, I want to be clear, will say we should probably wait until the patient is in the quiescent phase. The treatment is to give them anti-inflammatories, have them come back when they're in a chrysanct phase, and then start therapy.

47:06And then the AUA guidelines, we did not put in any stretching devices as well. It wasn't mentioned. So the entire use of the stretching device is off-label? It's off-label. Got it. And it's expensive. It's 500 bucks, but potentially worth it depending on the extent of the damage. So going back again to the diagnostics. So you induce the erection chemically. you look for arterial inflow and venous outflow. You diagnose, let's just say the problem is purely on the arterial side. So venous problem, no issue. You mentioned you can still use the phosphodiesterase inhibitor to compensate. You can. So how does the ultrasound result change your management?

47:47It lets me know where the problem is. So if it's a venous leak, you can offer a band. You wouldn't really want to offer a band if you didn't have venous leak because it's arterial insufficiency. and it tells you how bad it is also. So if I see that the venous leak is end diastolic of 10, 15, it just tells you the severity of ED, which is very important. Tell me what normal is again. So you want less than five on the end diastolic. You want at least greater than 25 or 30, preferably on the peak systolic. And so what would the typical numbers be? Not that you're doing this on guys that have no issues, but if you did this on like a 20-year-old who had no issues whatsoever, what would you literally see as the number?

48:21Peak systolic of 40, end diastolic of less than one. Yeah, so nothing. And what's important is that remember that each corpora cavernosa will have a different number sometimes. So you're doing both sides. You have to do both sides. How often do you see significant asymmetry? Usually it's not that significant, but sometimes you can. So I just want to be very clear. You know, look, you're having some low peak systolic on the right, but not on the left. You know, so it just gives you another diagnostic. Remember, what's interesting about the penis is it's fenestrated. So that whatever you have on one side compensates on the other.

48:47So if you inject a medication on the right, it also gets to the left. So it's fenestrated. So it does make it very easy. But you mentioned something important. This peak systolic velocity, if it's low in a young man, I am worried because I think it's a marker for cardiovascular risk. There was this machine I was using in my fellowship. I was a fellow and we got this machine called the Endopat 2000 and it would check endothelial function. What was it called? Endopat 2000. I love that it has the 2000 at the end of it. Reduces any credibility of the machine. If it was just the Endopat, I'd be like, oh yeah, the Endopat, that's pretty cool.

49:19But Endopat 2000 just sounds like nonsense. It was endothelial 2000. That's when we came out. It was by an Israeli company, but we used to put a blood pressure cuff in one arm and then it would have a probe on the finger and then a probe on the contralider finger. And we put super physiologic pressures, we'd release it and you would measure the dilation in the finger as a marker for endothelial function as a ratio between the two fingers. So in the Mayo Clinic in 2004, they were using this device, and then they would take the patient directly into the cardiac cath, and then they would look at cardiovascular blockage.

49:49And so they found that if you had poor endothelial function in the finger, it was a marker for potentially occult blockage. So as a fellow, I did the same thing. I would do the machine, take these results, then I'd take them into the ultrasound room and do a penile ultrasound. And if they had poor endothelial function on the endopat, you would see a poor inflow of blood on the peak systolic artery. So there is a correlation between the endothelial function and cardiovascular disease, but it's not common. We see much more end-diastolic dysfunction than systolic dysfunction. Now let's talk to some of those therapeutic options you mentioned.

50:25When is a man a candidate for an injection and how long does it last? So let's think about it. We used to have in 2018, the guidelines came out in terms of therapies. And we used to think of therapies as first level, second level, third level. We don't think of that anymore. But the old level, first level was we start out with the pill. See how the pill works. The pill could be Viagra, Levitra, Cialis, or Stendra is the newest. A PD5 inhibitor. In that level, you should think about sex therapy. You should talk about lifestyle modification, which is very important. And then the second level was injections.

51:00So if the medications no longer worked, we would go into penile injections. And these injections are extremely effective. It's just that - What are you injecting? So either Trimix, which is papavirin, fentolamine, and prostaglandin, it's three medications, into the penile tissue, and it dilates the arteries. And it's very effective. And - Lasts for how long? It's dose dependent. So you got to be very careful because if you inject too much, you have a priapism. They have to go to the ER, and I may have to surgically bring it down. So the first injection should always be in the office and taught how to inject.

51:33And usually I ask to bring the partner because 50 % of the partners inject for their partners. Oh, I see. So this is something where you inject, use it, and it should go away and you're done. So you inject every time you need the treatment. You inject every time you want to have sex. I got it. You inject every time you want to have sex within five minutes. At the base of the penis. At the base of the penis, two and 10 o 'clock position. And what we teach you how to do it, and we have you slowly titrate up to finally get to 80 % rigidity because we get the other 20 % rigidity with foreplay. Once you find your number, whether it be 0.2 mls, 0.25 mls, you use that number.

52:02The problem, again, remember, is ED is a progressive disease. So many men will start having to use higher and higher doses. Then they'll have to go to a higher strength solution, to a higher strength solution. And finally, the third level is a penile implant. Now, in today's new paradigm, we don't have the first, second, and third. We offer the patients all the options. We use something called shared decision making. If a patient says, I don't want to start with a pill, I want to start with an injection, that's fine. We don't use the urethral suppositories anymore. We used to use them quite a bit in the past.

52:33It's a prostaglandin suppository that you place into the urethra, and it causes a vasodilation in the penis. In my opinion, they didn't work very well. They were good for combination therapy with - Isn't that uncomfortable? It can cause significant urethral burning. That is true. Some bleeding as well. And it cause a little bit of hypotension in some patients as well. So we stopped using those. But the penile prosthesis has been around now for 50 years. This year was 50 years, invented a Baylor in 1973, and it is a phenomenal treatment option for ED. And what does it look like in its current form?

53:04There's been many iterations. There are two main suppliers. There's Boston Scientific and Coloplast. And this device essentially is a procedure where we place two cylinders or balloons inside those casings, the copra cavernosa. There's a small pump in the scrotum. And there's a small reservoir behind the pubic bone typically or underneath the rectus muscle that holds normal saline. And all you're doing is when you want to engage in sexual activity, you reach down, you press the pump, and it brings normal saline into those cylinders and induces an erection. And when you finish engaging in sexual activity, you release it and all the fluid goes back.

53:36And so just to be clear, a man would still ejaculate normally. Still has pleasure. But he would still have an erection after ejaculation because he's not getting the signal to turn it off. He turns it off when he wants to turn it off. Meaning physiologically the erection's not going to go away until he defleets. Exactly. So some men find that very favorable. So essentially you have the erection whenever you want, as long as you want. So in other words, even if he ejaculates prematurely, he can still finish. And the same goes with the injections. So a man who uses an injection. Oh, the injection just goes away when it wears off.

54:08When the drug wears off. When the drug wears off. So some men do use that recreationally. So what happens is even if you ejaculate with an injection, you're not going to detumes. How risky is that surgery? I would say it's not very risky at all. How long does it take you to do this operation? About 45 minutes. Under general anesthesia? General anesthesia. Every surgery has risks. So let's be clear. There are some risks associated with it. There's a small percent of risk for infection. There's malfunction. But again, relatively very safe procedure in my opinion. But it has to be with someone who has done a lot of these procedures.

54:36Yeah. So if someone's listening to this and they think that, hey, I might be a candidate for that, How many procedures do they want that surgeon doing? Like, you know, you don't want to see somebody who does one a year. How many of these are you doing? I'm doing about 60 a year. I think at least 50 or greater. I mean, their partner patients, at least 50 to 60 a year, I think is very reasonable just to make sure that there are no issues. When you do this for a first-time patient, what's the reoperation rate? Or what's the malfunction rate? Or the rate of complication where you have to do something else?

55:06Typically, the infection rate's less than 2%, but now typically we'll say closer to 1%, so it's not very common. Do you use a prophylactic antibiotic? I do. So typically I use several things. I use Vank, Gent, and I'll use antifungal as well because we know that 10 % of these infections can be fungal. And then we use a new Arrogant called Aris. Vank and Gent. Why such big, big guns? Because we're so worried about getting a... If you get a prosthetic infection... Yeah, no, it's a disaster. It's over. So in other words, we're not going to just use first and second generation slothlosporins and cover the skin.

55:36We're going all in. So the vein cast would be in an hour before. If the vein cannot get in an hour before, I'm okay sometimes using ANSEF and GENT. I use an antifungal. But you're using GENT. Yep, and GENT for sure. And then what we'll do intraoperative is I now use Iricept. Iricept is what a lot of the orthopedic surgeons use. And Iricept is chlorhexidine essentially, but it's very good for fungal, anaerobe, aerob, and it's a very effective medicate and it's cheap. So we use Iricep intraoperatively. The benefit of some of these prosthetics is that they're antibiotic-coated. So the Boston Scientific was antibiotic-coated with minocycline rifampin.

56:08The Coloplast device is hydrophilic, and you can dip it into the antibiotic, and it takes it in. The key is a short operative time. There's many things in the operating room that we do to mitigate the risk of infection. Do you wear the space suit like the orthopods do for joints? We don't, but we limit the movement in the room. We tape the gloves. We make sure that there's no movement in the light handles above. I don't have more than one person at the table across from me. It's very important because if they get an infection - It has to come out. It has to come out. You can do a salvage, which means if I catch it early, I can take it out and put a new one, but it's about an 86 % success rate.

56:41So if you catch it early, if they're septic, they have any kind of purulence, no salvage. You're not going to do it. I mean, God forbid, just thinking worst case scenario. So if a guy is septic doing this, you're pulling the whole thing out. Do you get another chance to put one in when he's recovered? That's a really good question. You wait three months to make sure everything, but it is much more challenging to get another one in and it's going to be shorter, typically, maybe even thinner also. Sometimes you call this a penile cripple. So you just have to be very careful. You want to really mitigate the risk of infection.

57:14The same thing goes with someone who has priapism. After 36 hours, the new guidelines will suggest that you can put a penile implant in and I strongly suggest. Let's tell folks what priapism is. Yeah, so priapism is a prolonged erection that lasts greater than six hours. So we tell patients if it's longer than four hours, you should start seeking medical attention. The best example I can give you is this. If I take a rubber band and put it around your finger numerous times, I'm cutting off the blood supply. Well, how long does it take for that finger to start having necrosis and damage? In the penis, at 36 hours, we say the chance of recovery is extremely low.

57:49So if someone says, I've had an erection now and it happened on Friday and shows up on Monday, I'm very worried. I'm safe. The chances of you recovering. Let me understand what that guy is going through. Wouldn't he be in pain having had an erection from Friday till Monday? But is he just not seeking care because he's ashamed? He's ashamed or he thinks it's going to go down, which is the worst thing that could happen. And so majority of the patients are astute. They've been taught, hey, if you get erection greater than four hours, you need to come in. But very rarely, they sometimes will not. And then we're in trouble.

58:20because that patient now is, in my opinion, you have three months, if you want to help him, three months to get a penile prosthesis in because if you try to get that in later on down the road, I cannot tell you how much fibrosis and scarring is in that tissue. And for me to get the penile implant in - You do it on the day of admission. So for example, if that guy comes in having been 72 hours with an erection and you're basically willing to make the call at 72 hours, we're not going to even wait to see if you recover. Let me put the implant in right now before there's fibrosis, you have a better outcome?

58:51You can't, but you'll have almost a similar outcome if you do it within at least the first three months. It doesn't have to be 72 hours. So sometimes we think it's better, especially, so the problem is a lot of times the first thing that'll happen is they'll get a shunt. A shunt means someone will stick a needle or a knife down the glands or in the corpora and try to determess them. And then you get arterial to venous connection. Right, so if that happens, I don't want to put an implant in right away because you have a risk of erosion slightly and you have a slight price for affection possibly because someone's manipulating the tissue.

59:20So I said, let it calm down, come back in three weeks. And this gives us more time to get the implant. Do you do an ultrasound to make sure there's no shunt? I do. So what's interesting is if you do a shunt, most of the time the patient the next day will have an erection and the resident will call me and say, doc, it failed. It didn't fail. Now they have a reactive hyperemia. They have a high flow. And if you ultrasound them, you'll find that they have a high flow. So I said, wait a minute. It's the exact opposite. He presented with a low flow venous outflow obstruction. Right. and you converted them, but the resident will call me and say, he's got a high flow.

59:51I said, no, he doesn't. Get the ultrasound. Let's look. You get the ultrasound. It's a high flow. You leave them alone. So high flows treated a little bit different. High flows, typically someone had trauma. What is the etiology of priapism? I know it's a side effect. So there's many causes. Of phosphodiesterase inhibitors, right? But it's extremely rare. It's extremely rare. The most common cause typically is when someone is injecting a Trimix or an agent and injected too much. But you can get medications like trazodone, cocaine. I mean, there's a lot of medications that can induce an erection that won't go down.

1:00:21Interesting. Trazodone. Trazodone. Which is ubiquitous now as a sleep agent. Right. And it can cause priapism. Is it dose dependent? I don't know if it's dose dependent. Typically, most patients like 50 milligrams when they go to bed, but I would assume that it could be. Interesting. So the moral of the story here is if you have erection for four hours, go to the ER. Absolutely. And when that patient comes to you in the ER, you make an incision. Good point. So there's two things. The first thing I do is I put in phenylephrine. So if it's less than four hours, I'll inject the antidote. So phenylephrine, and it'll usually work if it's less than four hours.

1:00:53If the hours are greater and greater out, what I'll do is some aspiration irrigation to try to get the old blood out and phenylephrine. If that doesn't work - Sorry, aspiration irrigation off the base of the penis. Of the base of the penis. So we're using an 18-gauge butterfly needle, put it in, and I'm injecting normal saline, and I'm aspirating. Many times we'll use cool saline. We're just trying to get the sluggish blood out of the tissue. Wow. Do they ever develop like clot, venous clot? It is venous. That's what it is. Oh, it has already clotted. It's already clotted. It's already clotted.

1:01:21I didn't realize that. Okay. So you're basically trying to get all that clot and sluggish blood out. Do you ever run heparin in it or anything like that? We don't run heparin in it. Although if I do a shunt, sometimes people have advocated starting him on heparin or Plavix to keep the shunt open. I usually typically use low-dose aspirin, but that's one thing you can do. So we aspirate, irrigate, then we put the phenylephrine. If it doesn't work, then my favorite is a T-shunt. And a T-shunt is where I take an 11 blade through the glands into the corpora, and then we have to sometimes use a Hagar dilator and put it down.

1:01:53You're doing this under local? Well, this time I'll take them to the OR. It hasn't been described under local, but I think it's just better to take them to the OR. Less traumatic. Less traumatic. And you have to counsel them. If I do this Hagar and disrupt the muscle, there's a high chance you're going to have erectile dysfunction and we'll have to deal with it. How often do you induce Peyronie's in treating priapism? After treating the priapism, there's now going to be a scar that results in this asymmetry. I think the question is when we use Trimix, if you use Trimix regularly, that is a risk factor for Peyronie's because any repetitive trauma to the corporal cavernous is going to actually injure the tissue.

1:02:31When a man is injecting for ED, do you tell him to vary the site as much as possible to avoid that trauma? Yes. We tell him to inject opposite sides every other day. So you can't do it every day. Inject opposite sides to mitigate the trauma that you're causing to the corporate cavernosa. Okay. Last thing on ED I wanted to talk to you about is this device that a couple of my patients have talked about. I think it's called Gaines Wave. What is it? So Gaines Wave is just a company that uses devices for shockwave therapy. So I just have to give you a little bit of history about shockwave therapy. In 2010, Dr.

1:03:07Vardy, European study, was the first to start using shockwaves to treat ED. Shockwaves are not new to urologists. We use high-intensity shockwave for kidney stones. That's what lithotripsy is, right? Lithotripsy is. It's called high-intensity shockwave. This is called low-intensity shockwave therapy, or LIST. And when I first saw that, I'll be honest with you, I thought it didn't make a lot of sense. I said, this is ridiculous. He's shocking the penis two to three times a week, three weeks, 2 ,500 shocks. What is he doing? But the science is actually quite clever. The science is you're inducing trauma.

1:03:39When you induce trauma, you bring in neoangiogenesis. You actually recruit stem cells. You help with nitric oxide synthase. So it actually is helping improve the condition. We weren't the first. Cardiologists have been doing it for years. If you look at cardiologists, they were shocking the heart and they look at the reperfusion and it was reperfusing the heart. Orthopedics do it for joints and they use it for plantar fasciitis and it's used for a lot of conditions. But this was shocking the penis in 2010. So since then... Again, pardon my ignorance, how is the device applied? Think of it like a probe.

1:04:12And what happens, you have to have someone performing the procedure. We divide the penis in six zones. So it's shaft, hilum, and cruce in two sides. So six zones. And we will typically - And so just explain where each of those is. The shaft is obviously the shaft of the penis. The hilum is where the, at the base of the penis. And the cruces underneath the scrotum because the penile tissues go underneath the scrotum. So we will deliver 2 ,500 shocks in these six areas. And it takes about 25, 30 minutes. And the patients will come in and they'll come in at least one or two times a week for three or six weeks.

1:04:46And they may have to have a booster. So when Vardy did it, he showed that - And the probe is just right on the - Right on the skin. Is it painful? It's not painful. It's well-tolerated, no anesthetic necessary. When Vardy did it, he showed that there was improvement in penile blood flow and men were having better erections. So the issue is that there are two types of machines. There are machines that have a focal shock and those that have a radial shock. And the radial shock is 100 times less in terms of pressure. It's over 1 ,000 times over in terms of time. So it's a longer shock and it's less penetration.

1:05:20And quite frankly, this is like a pneumatic machine. The pneumatic machine, they do nothing, but they're not dangerous. So the FDA has called this a type one medical device, low risk. Anybody can buy it. So you could be any profession, anyone on the street. The going rate for these is$500 to$1 ,000 a shock cash. Sorry,$500 to$1 ,000 for the machine? One treatment. For one treatment? One treatment. One treatment machine costs. But you said a guy needs two of these a week for three months. Three weeks. Oh, okay. So six treatments, let's say. So anywhere from$3 ,000 to$6 ,000 for a machine that's a pneumatic that does nothing, in my opinion.

1:05:59But the patient doesn't - That can be bought by somebody at Costco. You got it. You could go to the gas station and the guy could fill your tank and give you a little scrotal zap. You nailed it. And he can make$500 to$6 ,000. And the problem is that the ED population is very vulnerable. Because they don't want to go and ask somebody for help to think about this problem. Right. And they're almost desperate. They want treatment. And the other problem is that the ED population has a very high placebo response rate. If I gave a hundred men a sugar pill and I told them that this sugar pill would give you the best erections of your life, 30 % of men will get the best erections of their life off the sugar pill.

1:06:37And then of course they're going to tell their buddies that this is the best sugar pill you've ever had. So what you've seen now is an explosion of shockwave clinics throughout the country. Explosion. Everywhere you go, shockwave, shockwave. Now, look, there are certain shock waves that are very effective. The machines, these are called electrohydraulic machines, electromagnetic machines. These are called class type three machines. They do work. Now, I have to be very careful. They don't work in all patients. And we're still learning. And the class three machines, like Gaines Wave is a class three where you - Gaines Wave is the company.

1:07:07So the device, I don't know exactly what device they're using. Well, I just remember this because again, I've got two patients who are receiving or have received this treatment who both swear by it. But I know that at least one of the patients mentioned to me, only a doctor's office can have this thing. So I assumed it was a class three. Class three. Whatever the device they were using. But those machines are more expensive. The electrohydraulic is exactly what the shock wave is for the kidney stone, but it's a low intensity. Electromagnetic is by Stortz. But again, I just want to be fair. This is where the device took off greater than the science.

1:07:38The science is coming up. And I would say that it may be beneficial for patients who have mild to moderate ED, but be careful on the ads that are given on. If you look at these ads, they say you'll get a great erections today. You'll have great erections by tomorrow. The ads are unbelievable. So I'm part of the sexual medicine side of North America. We put out a position statement in 2018. Should be used investigationally at this time at the AUA, the guidelines for ED, investigational. Both were put out in 2018. It's been five years. There's been new data but I just want to say use it with caution.

1:08:08Don't tell everyone it's the best thing since sliced bread. it has potential and more studies need to be done. So we talked about ED. Does it make sense to now talk about premature ejaculation? Sure. I just want to mention two more things on ED. It's stem cells and PRP because that finishes the circle. And so stem cells, the problem with stem cells, and we published a paper, we did use stem cells. We had an IDE. There's no FDA approval for this, is there? There's no FDA approval for stem cells for ED. So many patients will have to go to Costa Rica, Panama, outside the country to get the stem cells for ED.

1:08:41Are there people doing it in the United States off-label? They used to, but you are not supposed to because the FDA has said you cannot use stem cells. Oh, I see. So just in general, for any therapy, I use a machine that had an IDE by the FDA, so an investigational device exemption. And this was, the exemption was for specifically ED for stem cells. So we conducted 30 patients. We used adipose-derived stem cells. We take the fat. We wanted to use it fresh, so we put them in a machine. We would get 37 to 50. So you would literally, this was autologous. You would take a man's adipose tissue, get the stem cells, and then re-infuse.

1:09:14You got it. But because I wanted a large amount of fat, I actually had a plastic surgeon do the liposuction under some mild sedation. So it was a little labor intensive. Then I would take the fat, it was 120 cc's of fat, and put it into a machine that had the IDE for making stem cells. So the machine after two hours would give me anywhere from 37 to 50 million stem cells, and then I would inject those stem cells into the penile tissue. At the base of the penis? At the base of the penis with a tourniquet for two minutes, and you have to inject slow or you'll damage the stem cells. So we let them sit there for 30 minutes, and we take the tourniquet off.

1:09:46And did you have 30 placebo men? This was non-placebo controlled, and this is important because up to today, there's not a single placebo controlled trial with stem cells for ED, not one. So given the placebo effect being so high, what was the effect you saw in these 30 men? We saw that they had an increase maybe of four on the IIEF, no placebo control, but it was only durable for six, maybe nine months and started tapering off. So it wasn't a lasting effect, but it was some effect that was going on. But we need a placebo control. So we're going to start a placebo control trial because people swear by stem cells.

1:10:17And some companies will say 15 ,000 will give you stem cells for ED. Where's the placebo control trial? It doesn't exist. So you have to be careful. Well, the other thing I guess is at$15 ,000 in Costa Rica, we would have to believe it's significantly better than daily Cialis at, what,$70 a year. So I would say, look, there may be some benefit. I do think there's some benefit in stem cells for ED. The number 15 ,000, I don't know, some people have different numbers, but Costa Rica, there are certain places I think that are doing it better than others, and they have more science behind it, but we still need more science.

1:10:52So do I think that stem cells have potential for ED? Yes, I do. Do we need more studies? Absolutely, to show the efficacy. And the question is, if I'm spending a lot of time doing liposuction and it lasts for six months, I can't do this for life. I mean, that's not a practical way to do it. Although one might argue, oh my God, that's fantastic. I'm getting free liposuction every six months. At some point, you're going to take all the subcutaneous fat on my body. But no, that's not a viable solution. But exosomes may be the next way. What are exosomes? That's basically the secretome, what's coming out of the stem cells.

1:11:25So people are looking at exosomes, and I think that may be another alternative to look in the future. How are they harvested? You can look at placental. Also, you're looking from the patient's own tissue, typically fat, but mostly from bone marrow. So they get it from the bone marrow. But again, you have to believe that the durability of this is much longer to justify this. Can you imagine saying, we're going to take a bone marrow biopsy on you every six to nine months to get your stem cells to give us your exosomes to do this procedure? some people will take the stem cells and they'll multiply them and they'll get billions and then they'll give you pieces of that now remember every time you multiply them every time you get past four the efficacy starts going down so that'd be a little careful you know so i do think there's some potential promise but we still are lacking in the science with the stem cells prp now that's interesting until the last year we got our first randomized placebo controlled trial first one until 2020, 21.

1:12:18Before then, there was one case report, one case report with five patients out of Wake Forest showing that there may be some benefit. And this was sold like it was the best thing since sliced bread. They call it the P-shot, which is the priapus shot. Basically, take stem cells. It costs about$1 ,500 to$3 ,000. Now, honestly, to really make it, it costs$50. You take blood, you spin it, you get the supernatant, you spin it again, add some calcium chloride, you have PRP. And they inject it. Now, there may be some benefit as well, but this is the one that lacks the most science as well. So there's an excellent study at the University of Miami right now looking at PRP and shockwave combination.

1:12:56Dr. Robinson - With placebo arms? With placebo arms. So that's going to be very interesting. When is that expected to be published? I think there's going to be some preliminary results at the AUA this year in April, next month. So that's going to be interesting. I think it came out as a late breaking. So hopefully next month, we'll know more. Yeah. Well, by the time this podcast comes out, it'll be in the past 10, so we'll link to that. Sure. So my takeaway from everything on ED, just to summarize, is easy way to remember the prevalence is it's matched by age. So amazing to think that at 40, which is pretty young, 40 % of men are impacted.

1:13:29At my age, 50 % of men at 60, 60%, et cetera. Second thing to consider is if men listening to this or their partners are listening, go and get help. Don't suffer in silence. The third thing to consider is that daily phosphodiesterase inhibitor I took away from you is a very viable solution, that there shouldn't be a stigma attached to that and there shouldn't be a fear that I'm becoming dependent on it or something like that in the sense that these are valuable drugs. They can also sometimes break the vicious cycle if there's a psychogenic component. You want to rule out psychogenic before you proceed to pharmacologic as the only therapy.

1:14:04You have the diagnostic side on the arterial venous, And then I think this idea about PRP, stem cells, exosomes, and shockwave, it's still a little bit too soon to know. A little bit too soon. Promising, but too soon. And of the four, would you say the most promising is stem cells? I like shockwave. You know why? Because when I do shockwave therapy, it recruits the stem cells. Because stem cells go to area of damage. So essentially, I'm getting the stem cells. I'm getting the neo-ingogenesis. It's not invasive. It's quick. It's not - So we're probably most optimistic on shockwave, least on PRP.

1:14:35So far, maybe there's a combination, shockwave and fear of it or shockwave and stem. And we'll see that with the results of this area. Okay. Let's pivot now and talk a little bit about the sort of states of ejaculation. So inorgasmia, delayed orgasm, et cetera. How does the prevalence of this differ by age? So ejaculatory dysfunctions are important. We know that 30 % of men, 30 % of men are likely to have some degree of ejaculatory dysfunction. More prominent is premature ejaculation. Premature ejaculation, 30 % of men, up to 30 % will have it. only 9 % of that 30 % will seek therapy. It's really small.

1:15:10And that's really because many men are embarrassed to seek therapy about this. So basically 30 % of men have this, only 3 % of men in total are doing anything about it. That's exactly right, which is very small. But two years ago, the guidelines came out, the new guidelines came out. So what is a premature ejaculation? Two ways to think about it. And this is really important how you break it up at the beginning. It's either lifelong or acquired. That's your first step. Has this patient had it ever since they remember having sex and they can always have premature ejaculation or was this acquired?

1:15:39In either case, you have to have three variables. You must have these three. One, you have to have a decreased ejaculatory time. Now, when it's lifelong, it's typically now less than two minutes. So it's less than two minutes. It used to be less than one. Now it's less than two. They have to have a sense of loss of control. I couldn't control it. And number three, they have to be bothered by it. If a guy comes in and says, I ejaculate in 30 seconds and I'm happy. Great. He doesn't have the problem. He has to be bothered by it, right? So it's important. What if he's not bothered by it, but his partner is?

1:16:08Well, he has to be bothered by it, right? So if he's bothered that she's bothered, fine, but he has to be bothered by the condition. Now, acquired is a little bit different. So look, things were great till I hit 40 and all of a sudden I developed premature ejaculation. Same principles. You have to be bothered by the condition. You have to have a sense of loss of control and you have to have a decrease in time. Now, how do you define time? That's a little bit tricky on this one because it's anywhere from two to three minutes or it's 50 % of your typical time. So let's say I used to ejaculate in 10 minutes and now it's five.

1:16:40Okay, that qualifies. It's 50 % of what mine. So these are the two definitions of you want to break it down. Now, why is that important? Because how I treat somebody is very different. If someone's acquired, we start looking at hormones. That's important. We look at prolactin. We look at thyroid. We look at testosterone. We look at some more diagnostic. If it's lifelong, we don't do a lot of diagnostic workup. You're not supposed to. It's the acquired where you start figuring out. You know, the four reasons for this premature ejaculation. One is the biological, the theory that there's increased sensitivity of the glands.

1:17:13So if they're born with increased sensitivity, that's why one of the therapies is using lidocaine or some of these numbing agents on the glands. They're over the counter. There's sprays that actually lidocaine on the penis 10 minutes prior to engaging in sexual activity. But doesn't that then put lidocaine onto the partner? You wipe it off before you engage in sexual activity. I see. But be careful because if you spray too much, it causes ED. So that's one. So it's the biological. There's a neurobiological, essentially meaning the neurotransmitters. So essentially that there's too little serotonin.

1:17:42The neurotransmitters are causing an impairment for the ejaculation. There's some belief on genetic. We don't have an assay right now, but there are four genes that have been implicated. There's some gene. But these genes are only implicated in lifelong or in acquired? In acquired. So it'll be lifelong. I'm sorry. Right. And there's polymorphisms of the, and they're neurosteroid receptor genes, and there are four of them, but we don't use this clinically. We don't look for the assay. We just know that more studies need to be done. The last one's important. It's psychological. If you have a new relationship, stress, any kind of, that causes some psychological impairment, that can actually cause premature.

1:18:15Do you have a sense of why stress can have opposite effects? Why is it that in one man, stress might result in ED, and in another man, it might result in no difficulty with an erection, but premature ejaculation? I can't answer that. I don't know the answer. I do know that stress, though, significantly affect you in all sexual function. I call it SAD. It's stress, anxiety, and depression. Patients suffer from those, so stress can have a significant impact on all forms of sexual dysfunction. But stress has a huge impact when it comes to sexual dysfunction. A lot of men, when the stress have difficulty getting an erection, but it does affect premature ejaculation as well.

1:18:51So these are the reasons why men have it. So how do you treat it? There's some treatment options. And the first line therapy typically is the spray I was talking about, lidocaine spray that you can use. We use Promescin. It's over the counter. It's easy to get. The second one you can use typically is SSRIs. So antidepressants. But some men say, I don't want to take an antidepressant. I say, okay, you don't have to take it every day, although it works best if you take it every day, but you can take it on demand. The problem with on demand is you got to take it six to eight hours ahead of time. Which is counterintuitive, right?

1:19:21Because one of the side effects of an NSSRI is reduction in libido, right? And ED, both, and reduction in libido. So you're right. So you just have to realize that those are, and then first-line therapy should always be sex therapy. This is one area where sex therapy is very effective. And sex therapists are what? What is the formality of training to be a sex therapist? They are certified. You have to have a certification. Typically psychologists or psychiatrists? Typically psychologists, not psychiatrists, but psychiatrists can be certified in sex therapy. They're very helpful because there's two techniques, the start-stop technique, the squeeze technique that teach patients how to prolong the ejaculate.

1:19:56But again, a lot of times patients say, just give me the pill. I say, fine. But if they did the work, that's a cure. That's a cure for PE. So those are the first line therapies. There are second line therapies. The two second line therapies are tramadol, a narcotic, and actually has been shown, if you look at the ejaculatory time, less than one minute, a lot of studies are up to seven minutes. The problem is - A narcotic? Yes. And it's been used quite often as a treatment, and it's in the guidelines as a therapy. What's the risk of addiction or exacerbation of - Very high. I had a patient once that started using five a month.

1:20:30Then he started asking for 10 a month. And then once he called for 30 a month, and I said, this is ridiculous. He goes, well, I'm having sex every day. I could tell he was getting addicted. And I said, I can't do this anymore. So you just have to be careful on the tramadol. and then actually alpha blockers, Flomax, second line therapy for premature ejaculation. Now, does that sometimes convert premature into retrograde? You can. So right, that's one of the risk factors for the alpha blockers at retrograde, but it prolongs the ejaculatory time. So these are the treatment options that we use for patients and they're quite effective.

1:20:59You just kind of go through the algorithm for PE. Explain what a retrograde ejaculation is. So as I mentioned earlier in the prostate, there's something called the ejaculatory ducts. So think of it like a T. So the ejaculatory ducts are coming up, Moving forward is the urethra, and it's coming out the urethra. Moving backward is the bladder. So when the sperm comes up and the seminal fluid comes up, the tendency is for the fluid to go back into the bladder. But as a man has an ejaculate, he closes off the bladder neck. So the fluid cannot get into the bladder. It's forced to go out. But when you take a medication like an alpha blocker or certain other medications, it can actually open the bladder neck.

1:21:35So what happens is the sperm comes up, seminal fluid then goes into the bladder. And so nothing comes out of the urethra. And when the man urinates or voids, then the seminal fluid will come out. Is there any harm of a retrograde ejaculation? No harm at all. Just some patients find it annoying. Obviously would impair reproduction. For sure. So if someone's trying to have a child. Huge problem. Yeah. Okay. At the other end of that spectrum is anorgasmia. Sure. And what's your workup for that? So anorgasmia, and we put this in the same, is a delayed ejaculation. So sometimes patients have delayed ejaculation taking a long time.

1:22:10And the same principles are the same. Is it acquired or lifelong? And the same principles, are you bothered by it? Loss of control or inability to control? And more importantly, the timing. So what is the average amount of time that a man takes to ejaculate in the United States? Typically about six to seven minutes on average. Six to seven minutes is the norm. That's self-reported? In numerous studies. And it's interesting how we do it. How do you do that? Great question. So we look at something called the intravaginal ejaculatory latency time, IELT. And it's typically self-reported, but when it's self-reported, it's inaccurate.

1:22:43Yeah, it's got to be. It's inaccurate because when - Who's keeping track of time? So what happens is when you ask a man who has premature ejaculation, he underestimates the time. If he ejaculated in two minutes, he says, I had 30 seconds. If you ask a guy who doesn't have premature ejaculation, he overestimates the time. If he ejaculated in eight minutes, he says, yeah, it was 15 minutes. So it's a big discrepancy. So how we do it is we give the partner a stopwatch. When he orgasms, she's supposed to click the clock. And that's the best way to get intravaginal ejaculatory. So IELT is best why stopwatch.

1:23:12And based on that gold standard, it's six to seven minutes. Six to seven minutes. Now look, certain countries have different numbers. So Asian countries, lower numbers. European countries, higher numbers, longer ejaculatory. What do you attribute that to? There could be cultural differences as well, but there are some differences. But when you look at, for example, these medications like SSRIs, they are very effective in prolonging the IELT, very effective. And there was a study in 2004 by Waldinger. He was looking at the different SSRIs. Paxil was number one by far. So Paxil is typically used the most.

1:23:45Zoloft was number two. And you can see based on the dose, because it's dose dependent. So the higher the dose, the greater the ejaculatory time. but at the end of the spectrum, it was 25X with Paxil. So typically it's about 10X you'll see a delay. But without getting to the point of ED. So remember you can dose, if I'm using too much Paxil, I bring it down. So one of the problems, we'll talk about this delayed orgasmia. A lot of these patients have it because they're on an SSRI. That's why they have it. So if they're on 40 milligrams of Paxil, maybe we just go to 30, we still get the benefits of depression, but we improve the ejaculatory latency time because it's very sensitive on those doses.

1:24:23There's no set number on delayed orgasmia, but typically someone will say greater than 15 to 20 minutes. If it's greater than 15 to 20 minutes, that could be considered delayed orgasmia. We have no FDA-approved treatments for this condition. There are no FDA-approved treatments. So everything I'm going to tell you today is off-label use for how we treat this condition. And what about the role of 5-alpha reductase inhibitors here? I would not use 5-alpha reductase inhibitors. I don't like to use them at all in my practice. Oh, I mean as implicated in anorgasmia. In other words, is it possible that 5-alpha reductase inhibitors are amplifying?

1:24:57It is possible. There are patients that have had or taken 5-alpha reductase inhibitors that have had impaired orgasm or anorgasmia because remember, it blocks DHT. And DHT is four to five times more potent than T when it comes to function for the receptor. So typically, and one of the treatments for delayed orgasmia is testosterone. So that's how you treat it, right? And so if you're using a 5-alpha, you're actually going in the opposite direction. What about the phosphodiesterase inhibitors, the same drugs we talked about to treat ED, how often do they induce delayed orgasm? They don't induce delayed orgasm.

1:25:32They just expose it. They might make it such that you can appreciate it. But you bring up a very important point. If a patient presents with ED and premature ejaculation, you always treat the ED first. And that's a really important point because by truth - Wow, that's an interesting thought. Let me wrap my head around it. A guy says, I have ED and premature ejaculation, meaning either I can't get an erection or when I can, I have premature ejaculation. Those are my only two states. You got it. How common do you see that in a 50-year-old or 60-year-old man? It's not that common, but it does occur.

1:26:05I would be honest. But why do we treat the ED first? We treat the ED first because if you treat the ED, you can actually treat the PE. You can delay it. You can actually fix. Fix the PE. And there's a reason for this. Subconsciously, whether it's conscious or subconscious, it's a belief that the body's saying, if I don't ejaculate quickly, I'm going to lose this erection. I'm going to lose the erection before I ejaculate. And so if you're able to maintain your erection and not worry about it, you may prolong the ejaculatory time. So a board question we ask on the exams, patient presents the ED and PE, you treat the ED first, and you can treat the PE at the same time.

1:26:42I kind of want to talk, shift gears a little bit, and talk about testosterone replacement therapy. So let's maybe give folks a little bit of an explanation of how the hypothalamus, pituitary, testes and adrenals all play a role in the generation of the hormones that we're about to talk about, which means let's talk about everything from LH and FSH to testosterone, SHBG, DHT, et cetera. And then let's talk about what deficiencies mean and what the consequences are and how we might go about addressing it. Sure. So let's talk about the physiology because it's important. So GNRH secreted from the hypothalamus.

1:27:22GNRH then goes to the pituitary, secretes two hormones, LH and FSH. And what's the signal for GnRH? Is it estrogen? And that's a negative feedback. So estrogen can't have a negative feedback on it. It's a pulsatile pulse, GnRH. We know that pulse goes down as we age. So that's an important part of aging we'll talk about as well. The LH and FSH will then go to the testicles. I tell the residents, remember that LH has an L, goes to the lating cells. FSH has an S, goes to Sertoli cells. So LH goes to the lating cells and produces testosterone. FSH goes to the Sertoli cells and produces sperm. The two functions of the testicle are basically sperm and testosterone.

1:27:58So essentially, if a patient comes in and they have, remember that the majority of a man's testicles are comprised of sertoli cells. That's important because the exam is more of an indicator of his fertility status than his hormonal status. So that's important. When you say exam, you mean size? Size. So they should be four centimeters in diameter, 20 cc's. And so when I'm looking at an infertility workup, if the patient has small testicles, elevated FSH and LH, I say there's a production problem. He's not making it. If he has normal FSH and LH and normal testicles and no sperm, it's an obstruction problem.

1:28:34So that's very important. The exam is very important. So we talked about the fact that the testicle is making testosterone, but there's a negative feedback. That negative feedback, testosterone goes back and feeds back negatively on the pituitary and also on the hypothalamus, but also estrogen goes back and feeds back negatively. Testosterone can be broken down majority - By the way, is one of those stronger than the other as a signal? I don't know if one's stronger than the other. I know that both are. I mean, we'll talk about CIRMs and how CIRMs work as they block that negative feedback on the estrogen.

1:29:03But remember that testosterone then is converted into estrogen, 0.3%, not much, 0.3%, and 6 % to 8 % is converted to dehydrotestosterone. So you get two conversions. So the higher the testosterone, you should get greater estrogen and greater DHT. That makes sense. So what many clinics do is they try to block the conversions. They'll use aromatase inhibitors and they'll use 5-alpha reductase and try to control it. And I'm not a big fan of that, but they do it. So that's really the big picture here. Let's double click on a few of those things and maybe just rehash that. So when you go to the doctor, it's pretty common that if the doctor knows what they're doing, they're going to measure FSH and LH in addition to testosterone.

1:29:45We're not measuring GnRH, right? It's pulsatile. Even if we had an assay for it, it would be useless, sort of like growth hormone. Let's talk about where SHBG fits into the mix because that is often measured. And let's talk about the concept of free testosterone slash bioavailable testosterone slash free androgen index, all of these things that are not measurable, but are estimatable. and I want to understand if they mean anything. Most testosterone is bound. 2 % is free. 50 % albumin, 44 % SHBG, 4 % corticotropin binding globulin. Oh, I didn't know that. I thought SHBG was the lion's share, but it's split relatively equally with albumin as well.

1:30:2450 % albumin, 44%, and then 4 % corticotropin binding globulin, a small percentage, and then 2 % free. But the body only cares what's free. If you look at correlates with symptoms, The free testosterone is the best correlate with symptoms. But we're so fixated on this total testosterone. The best example, a guy walks in, his testosterone is 450, 500. He says, I feel lousy. You say, what's going on? Check his SHBG. Get a calculated free testosterone. If his SHBG is elevated, the free T is going to be low. And there you have it. How accurate do you think the calculated free testosterone is? I think it's much more accurate than the assay.

1:30:57So I calculate my own. So there are calculators that are online and very simple. You put in the albumin, you put in the SHBG, you put in the T, click, click. and it'll give you the calculated free T. It's more accurate, I think, than the assay. The gold standard is LC-MS, but it's expensive and it's hard to get. So there is an LC-MS assay for free testosterone. I don't know. I know it's for total. It's for total. LabCorp does a total LC-MS. Yes. I don't think there's one free. But you're saying if you have an LC-MS, if you're cost insensitive and you have an LC-MS assay for total and you know albumin and SHBG, which are pretty easy to measure, you plug those three numbers in, you'll get an estimate, a pretty good estimate.

1:31:35That's a calculation, of course, of free T. Yes. And I'll tell you, one of the things that has been the bane of my existence is that we have pretty good data age-wise for the distribution of total T over a man's life. Yes. What it means, what does the normal bell-shaped curve look like at 20, 30, 40, 50, 60? We don't seem to, at least I haven't found those data for free T. All I seem to find for free tea is over 18, which is very difficult because when I have a 50-year-old man who says, how do I stack up? I say, well, I can only tell you how you stack up to men over the age of 18. I can't tell you how you stack up to other 50-year-olds.

1:32:15Yes. So I think there's two important points here. One is I always thought that this concept called androproze was real, meaning as we get older, our testosterone get low and lower due to age alone. That is not true. We know now that total testosterone levels don't decline very much in healthy males. What makes that testosterone go down is the acquisition of comorbid conditions. A 75-year-old really healthy male, he'll be having a normal testosterone, a total T. What does change is the SHBG. So as we get older, the SHBG does go up. The total testosterone should stay relatively flat if you're healthy, and the free tea will start to go down.

1:32:55So I've noticed, and I'm sure we'll talk about this, genetics seem to play a very big role in SHBG. I'm someone who just seems to have a very low SHBG. So you're lucky. But I also have a very low testosterone. So my testosterone is maybe 400, maybe 500, but my SHBG is in the 30s. So my free tea is about 2.5 % of my total tea. I have lots of patients who have very high T, but their SHBG is in the 80s or 90s. But that's the body compensating. So the body is very clever. And that patient, if their T starts going down, the body starts offloading and lowering the SHBG to keep that hemostasis. It's almost like our reserves.

1:33:36It's pretty fascinating. It's the body's reserves. It knows when we have too much, it binds it. And what do you think is driving the age thing? Because we definitely see an amazing response to insulin. So as insulin comes down, SHBG tends to go up. As T4 goes up, SHBG goes up. And as estradiol goes up, SHBG goes up. Which of those things, if any, are driving the age change? I can't tell you which one is, to be honest with you. All I know is that it goes up. I don't know which factors - Might be something unrelated to that. But I think genetics is a big part of it. So it's definitely genetics. Obesity has an effect There are comorbid conditions that affect the SHBG levels as well.

1:34:15But it's interesting. Usually with obesity, we see it go down. It's the opposite. It comes with hyperinsulinemia and it goes down. Okay. So you buy the idea that having a plasma measurement, pardon me, a plasma estimate of free testosterone is valuable. One of the things that I've struggled with is trying to make the leap between what we can estimate, which is plasma concentration of free testosterone, and what is probably physiologically important, which is how much of that free testosterone gets into a cell, how much then gets into the nucleus, how many androgen receptors do they have, how are they saturated, how sensitive are they, and how do they lead to gene transcription?

1:34:56And I know that in the lab, you can probably do those things. I've talked with Ted Schaefer about that, but clinically, I can't do any of those things. I literally have this very crude estimate of free testosterone, and I struggle greatly to make the link between that and what's happening. So instead, I just sort of say to patients, and I had this discussion with a patient yesterday, which was, this is a 55-year-old guy in pretty good health. His free testosterone is estimated at seven nanograms per deciliter. So he says, doc, is this high or low? I said, it's low. You're about the 20th percentile for men over the age of 18.

1:35:33Again, I can't actually tell him what he is for a 55-year-old because I don't have the data and it drives me bananas that that isn't published. But I tell him, yeah, you're at about the 20th percentile for all men over the age of 18. And he said, should we do anything about it? And I said, well, I gave him my soliloquy that I just gave you. I don't actually know how much of that seven is doing its job. And by the way, if your androgen receptors are already saturated, I don't know that giving you more is going to do anything. So I said, let's go through the symptoms. So I asked him a whole bunch of symptomatic questions.

1:36:02I want to hear yours. You're going to share yours, not mine. And sure enough, to a T, he didn't have one symptom that I asked him about. And I asked him about 10 things. And he said, I don't have one of those. And I said, well, I would not treat you then. Let's revisit this in a year. And he said, great, no problem. So first of all, I want to hear, what would you say to that patient if he said, Mo, my free T is seven. It looks low. What should we do? I'd say, first of all, I would completely agree with what you did, because why are we so fixated on the numbers? It's not about the numbers. It's about how he feels.

1:36:34If a guy comes in with a level of 250, 200 total T, very low. And he says, I feel fantastic. One could say, why are you treating him? Conversely, if he has a level of 500, has all the symptoms, we don't treat. So if he comes in and he has symptoms, then I will treat him. And tell me the questions you would ask to a list of them. So I say, these are the following. Low energy, low libido, erectile dysfunction. I didn't ask that. Increased fat deposition, decreased muscle mass, depression, poor sleep. Okay. Those are the big ones. I also asked about recovery from workouts. Yeah, you could. That goes with the muscle, but you're right.

1:37:08Yes. Bone fractures are important if they have bone fractures. And then just look at them. Just look at them. Are they obese, metabolic syndrome? No, this is a guy who's lost 25 pounds in the last year in our practice. He's exercising more. His bone mineral density is fine. If I was going to be very critical, I would say his appendicular lean mass index is only at about the 55th, 60th percentile. We want to see our patients with an appendicular lean mass index above the 75th percentile. But I don't think he needs testosterone to get there. A little more training in protein will probably get him there.

1:37:42How old is he? 55. Right. So he's young. So think about this. So I say, you don't need testosterone today. I don't know about five or 10 years from now, but today I'm not going to put you on it because the reality is if I do put you on it, it will suppress your endogenous access and you may need to be on it for life and you don't need it today. You have no symptoms. That's been my lazy excuse, which is I'm 50. I am a firm believer in the benefits of testosterone. I wouldn't be prescribing it to patients if I didn't feel that way. I've spent not as much time as you, but more time than most people in the literature.

1:38:13And I completely buy the efficacy and safety of it, but I'm like, I don't need it yet. And I know that once I started, I'm going to be on it indefinitely. so I'm going to hold out as long as possible until I need it. That's what I wish most people would do. The problem is a lot of these young men go into the T clinic at 30 years of age, and they get started, and they're on it. Then they come see me, and they say, I didn't know I could be infertile, and now I have to reverse them, which is a protocol we use. They never were informed that they could have infertility. Let's talk about this. Maybe we'll talk about all the different ways that we can replace testosterone.

1:38:48So the three ways that we have historically done it in our practice, I guess technically four, one is, and we don't do this anymore, we used to use clomiphene. It had the advantage of several things. One, it's a pill, very convenient, take it three times a week. Two, it preserved function, meaning you preserved both testicular volume and spermatic function. So you preserved fertility. And actually it was quite efficacious because you could titrate the dose and get to almost whatever you mean. The drawback is if the man didn't have testicular reserve, he wasn't going to get much of a bump. There were some guys who had peripheral hypogonadism as opposed to central.

1:39:26This was a great treatment for central, but you were at the limit of what the testes could do. There were reasons we ended up stopping it that I won't necessarily get into, but we basically haven't used that in a very long time. We then would use as the alternative to that HCG. HCG is just a mimetic for LH, luteinizing hormone, which you talked about, of course, is the direct stimulant of the Leydig cell, which makes testosterone. Lots of disadvantages. It's pretty expensive. It's an injectable. It's a very delicate injectable, so it has to be refrigerated. If you drop the bottle, the protein misfolds and it's crap.

1:39:59So lots of problems associated with it. But again, it seems to preserve testicular volume, which young men care about. Maybe older men do it as well. Not clear if it's as good as Clomid at preserving fertility. I would love to hear your opinion on that. But again, it feels less problematic to men in the sense that it's less permanent. Of course, we then use the mainstay is injectable testosterone cipionate or its derivatives. And again, we'll talk about all the pros and cons of that. And then lastly, pellets. So testosterone pellets. Don't do that anymore now that we've switched to being more of a remote practice.

1:40:33So I don't see patients in person to put the pellets in them. And also for men, pellets are a much bigger deal than for women. The pellets are so much bigger. For women, when you're putting little estrogen and testosterone pellets in it, it's a walk in the park. They don't even notice you've done it. For men, they notice it. Great topic. So this is really important. So you talked about two. So let's talk about endogenous ways to raise testosterone first. And you can use Clomid. You can use HCG. Some people use anastrozole. I don't recommend that, but we'll talk about that. So Clomid first. It's a CIRM, negative feedback to the estrogen receptor.

1:41:04The problem with Clomid is the following. We get a discrepancy effect, and this is what happens. You get a very nice bump in the testosterone level. That's true. But roughly 40 % of patients say, I have no desire for sex. I have no erections. I don't feel any desire. Because the way the Clomid works, it blocks estrogen receptor centrally. Men need estrogen. It is critical. You need estrogen for libido and sexual function. So they have these beautiful 800, 900 levels, no desire for sex. You take that same patient and put them on exogenous testosterone at 800, he says, it's working. So the way Clomid works is that it blocks, and so that mechanism is not conducive for many men.

1:41:42Yes, it's easy. There's a national backorder. So now we're starting to use a little bit more N-Clomid. Is N-Clomid legal in the US? It is compounded. Remember, reprose and try to get it through in 2015 that the FDA never made it through. It's the transisomer of Clomid, Zuclomid. And essentially, it is available compounded, and you can get it. But it's hard to get Clomid now even, because there's a national backorder. Is this just due to all these tea shops opening up on every corner that are - Well, they're different. So they're more into giving the tea and the injection, and you come in and get the injection for a fee.

1:42:16But this still is on the endogenous side. Clomid's not bad. I mean, it does - Why is there such a run on this stuff? Because what happened was HCG was for many years compounded. Recently, the FDA has said that HCG cannot be compounded. So everyone dropped the HCG and went to Clomid. And now there's a mad rush to get the Clomid. You can still get HCG commercially, but the price is through the roof. So what happened was that everyone started going to Clomid. And so now we're backordered on Clomid and you can still get HCG, but it's pricey. And did the FDA say no more compounding HCG because it's too complicated and they couldn't do quality assurance?

1:42:53I think it was a patent infringement. I think it was more to the fact that I think Merck still had rights to the patent on HCG and it was too similar because a compounder can make something, but it has to be different. That's my understanding. I think it's going to start coming back, but there was a national shortage on HCG and that's why people started going to Clomid. But Clomid, it's not 60 % will say my T goes up. You got to give it every other day, or you can get a tachyphylaxis. So 7 % can get tachyphylaxis if you give it daily. Some patients, they say, I can't remember every other day. I say, fine, take it every day.

1:43:25And there's a 7 % chance you may become resistant to the drug. 7%. 7%. Okay. So that's fine. We tell people to get a pillbox when we used to use it. So it was just Monday, Wednesday, Friday, and don't have to think about it. Load the pillbox. If you forget, take it every day. Enclomid, we give it every day. And what doses do you use? 50 for Clomid every other day. Enclomid, 25 a day. Or if they forget on 50 every other day, we use 25 cloma daily. Okay, fine. It's not a great, but it does help. We use it for fertility. So patients who are coming to me for fertility to help them achieve a pregnancy, we use it.

1:43:53You can use HCG. HCG is expensive and it is pricey. Typically, it depends on what dose you want to use, but it's 1 ,500 three times a week, up to 2 ,000 three times a week. It can be effective. It's nice for patients who have pituitary pathology because I bypass the pituitary, go straight to the testicle and they can start making testosterone. And then in patients who have an elevated LH and FSH initially, Kleinfelters, can't really use HCG or Clomid because the way Clomid works - Because they're already maxed out. They're already maxed out. So you've got to use Nassar's all because I'm trying to increase the T to E ratio, increase the T.

1:44:25And typically I'm using this medication to improve somatogenesis so that I can then do a biopsy or a testy to achieve sperm. I've never seen a man with Kleinfelters. When a man presents with Kleinfelters, what are his typical T, DHT, and E levels? So the E's are typically high. The T's are typically - How high are the E's? 40, 30. Oh, so not that high. They're not super high, but they are. And it depends on how far along you see them along the way. FSH and LH are typically already elevated, pretty high. So if the FSH and LH are already elevated, I can't use Clomid or ACG. What's the prevalence of Klinefelters?

1:44:551 in 500, so it's quite common. Really? That high? Yes. Just tell people what Klinefelters is. It's a genetic abnormality where you have an extra X chromosome, XXY. So phenotypically, you're a man. Phenotypically, you're a man, but there are issues in fertility. You can have gynecomastia. They're typically long stature in nature. You can live in normal - They have normal sexual function? They have no issues with ED, but the T is low, so that may affect the ED. But we treat these men with medications to raise the T. And so we see that - And why can't you just give them testosterone? We can, but what if they want to have a child?

1:45:26So that's the only thing. So what we may do is, I see a lot of these patients when they're 14 or 15 when they're first diagnosed. How are they usually diagnosed? I mean, I know the diagnosis is genetic, but what brings them to presentation? A lot of times what you'll see is that there's no facial hair development. So there are delay in development. I see. No shaving. And so what you'll notice, and if there's a suspicion, long stature, small testicles on exam, the pediatrician may say, let me just check a curatype and just see what's happening. And then you see two X chromosomes. And then you know.

1:45:53One in 500. That means there's a lot of people listening to this podcast that have Kleinfelters. Presumably they know it, but they may not. And if they know it, they might be wondering, is testosterone an option? And what you're saying is not necessarily first line unless you can block estrogen as well. And of course, it depends on their fertility status. Right. And some of these patients will start testosterone. And then when they're ready to have children, we will do a procedure called a microtessi at that time. And what we'll do is we'll stop the testosterone. And so my reversal dose is HCG, 3 ,000 units, three times a week.

1:46:23And then we'll either give them gonal F or clomid with it. There's three ways to look at it. There's patients who've taken testosterone and they're abusers. And they've come in now and they want to have children. That's the type number one of patients. That patient stops the testosterone, HCG, 3 ,000 units, three times a week, plus recombinant FSH or gonol F, 75 units, three times a week. And that actually does help reverse. Anywhere from three to seven months, you can see recovery of somatogenesis in these patients who are azospermic. So that's great. And tell me, that guy shows up having been on testosterone for how long?

1:46:57To be in his - It could be years. And many times they may have gotten the testosterone from a gym or something, and they weren't getting monitored. And they're at super physiologic level. So this is how long have you been on it and how high was your dose? Dictates how far along. So for a year. We tell patients and we use physiologic doses. So a typical dose for us is 50 milligrams of cipionate twice a week. That's what we do. Okay. So we would say at physiologic dose, you don't want to be on this for more than two years. And we are really hypervigilant and say, I wouldn't be on this for more than a year unless you're willing to be on it.

1:47:29What do you say? You're talking about younger patients though? Yeah. Yeah, so someone who's like in his 40s. So in his 40s, I still try to, the second, so the category two is a young man who just wants to use HCG alone. And that's not 3 ,000 three times a week, that's 1 ,500 three times a week as a dose. And then there's the last one, and this is a study that we did at Baylor, where there's a patient who wants to take T and we give them HCG with it to protect the access. And that's 500, so 500, 1 ,500, 3 ,000. There's three different patients. the preservation of, you know, and this also preserves...

1:48:03Is the 500 of HCG three times a week, it's not doing anything to boost endogenous production? Protection. It's just protection. And the best study, this is the best study came out, a guy named Coviella. This is how we got the idea at Baylor. Coviella had a study in 2005 where he gave patients 200 milligrams of testosterone IM every week. That's a big dose. Big dose, every week. And what he was measuring was intratesticular testosterone levels. 200 IM every week, the intratesticular went down. 94 % of patients were down to zero in three weeks. So that's a good number to remember. 94 % decline in intratesticular testosterone in three weeks, 94 % decline.

1:48:38Then what he did was he gave these patients different doses of HCG, 250, 500, all the way, 1 ,000. And what he found was between 250 and definitely 500, there was no significant decline in intratesticular testosterone. Very interesting. So he's giving 500 every other show. In 2013, by partner, Larry Lipschultz said, okay, if that's true for intratesticular testosterone, what is it doing for fertility? So let's do the same thing. Let's give these patients testosterone, 500 units of HCG every other day. And what we saw was there was a decline, but it wasn't a significant decline. And now that was the median.

1:49:15So there are patients who can have it. I don't want people to think, hey, if I do this, it's completely safe. But it does help protect the decrease in somatogenesis. But why is that the case, given that HCG is acting on the Leydig cell? You would think you would need recombinant FSH to get the protection of spermogenesis. Because it has some FSH properties. If you give a man for fertility just HCG, you actually see some improvements in spermatogenesis. Now, there is some of the fact that some of the testosterone is being used by the Sertoli cells for production of sperm production. Has someone done the study of giving clomiphene or mcloniphene with testosterone to maintain sperm production?

1:49:52I have not seen that study, but people do it off-label. And it would seem to me that that would be even more efficacious. Yeah, people do it off-label. The only issue is that you got now two things working in opposite directions. Because you got the estrogen problem up top. Yeah. And also that you know that when you're giving the T, you're suppressing the LH and FSH, and Clomid's trying to raise the LH. But giving recombinant FSH would be the better thing to do there. How expensive is recombinant FSH? Extremely expensive. So I would say - It's really only used for fertility, right? If that's its on-label use is in fertility with - Yeah, up to$500 a month.

1:50:20I mean, it's very expensive. Wow. This is insanely expensive proposition once you start going. And what does HCG cost? It depends now because now you can't get a compounded. No, if you're getting Pregnil branded. About$300 a month. Insane. Yeah. You can understand why, unfortunately, men, especially younger men who might not have the disposable income, are basically just getting testosterone because it's very cheap. And especially if they're getting it in an illicit fashion, you're keeping them out of the doctor's office where they can't be monitored, and you're pushing them into the gym locker room where God only knows what they're getting.

1:50:54There's one thing I forgot to mention. On the fertility preservation side, besides the anastrozole, clomiphene, and HCG, there is some data that just came out suggesting that the intranasal testosterone does not significantly suppress somatogenesis. And this was interesting. So it's done three times a day. This was out of the group at a University of Miami. Three times a day? It's called Natesto. It's commercially available. You go to Walgreens, you can buy it. I've never even heard of this. I was just about to ask you about the oral testosterone, but we'll come back to that. So the testo is a nasal testosterone that's implied, it's 11 milligrams is applied in each nostril, and you do it three times a day.

1:51:30And essentially what happens is it has the fastest rapid onset, and then it declines. And I always thought when I - 11 milligrams TID. So 33 milligrams daily. So in other words, the bioavailability is much lower than an injection. Yes. But the interesting thing is this. I looked at the pharmacokinetics. I said, how can this be effective? It's in and out so quickly. And then doing some deeper work and talking to some endocrinologists said, look, Mo, you don't have to have it around. If it's bound to the receptor and it's doing its work, it doesn't have to physiologically be there all the time in the serum.

1:52:02And it's interesting. These patients do feel better. They feel better. And because of the rapid onset, some of them do say they take it before sex, they take it before a workout because it's very quick. They say they feel better when they take it. How has this not become the drug of choice? But no significant suppression in somatogenesis. That was interesting. Now, more studies need to be done, but that was - When was this approved? The testo, I think, has been out for at least six or seven years. It's been for a while. Is it cost prohibitive? Insurance does cover it. It can also be compounded, but it's used by a lot of young men.

1:52:33That's so interesting. So if a guy comes to you and you go down the path and decide you're going to go down the exogenous route, not the endogenous route. How are you deciding between pellets, which we should explain what they are, topical, like androgel or compounded, injectable, such as Scipionate or Zyastad, or intranasal or oral now? I go through all the options, first of all. Because a lot of times it could be cost prohibitive and we find out which is the most affordable. Although I would tell you that injectables, cash price from a compounding pharmacy is$25 a month. We have them inject sub-Q, either enanthate or cipionate.

1:53:09It's based on age. I use cipionate for younger patients, enanthate for older patients. I think cipionate is more anabolic, has more sodium retention. And so I teach the residents that cipionate has a C for child, enanthate has E for elderly. I typically use like 50 or 60, but I look at the patient, but I think that it has a little more sodium retention. So I try to stay away from the swelling and the edema in older patients. So that's how I make my decision. And where do you make that cut off age-wise? It's typically around 50 to 60 around there. I just, you know, if they're using injectables.

1:53:35So I'll say, okay. Now, what I like about the injectables is, okay, we use sub-Q, always sub-Q. And we have - So 25-gauge needle, short needle. Yeah, 5-8 inch, 1cc syringe, 25-gauge. It's big enough to draw it up. It's small enough to inject. Outer part of the butt or belly? Belly. Pinch the fat. Pinch the fat. And we do it Sunday, Thursday. Because these drugs peak in 24 hours. So you do it Sunday, you're ready for Monday. You do it Thursday, you're ready for Friday. And patients like it. It's$25 a month. And tell me why you pinch. I know you want to get more tissue up, but don't you worry about inducing trauma?

1:54:05You get more vasculature. I think it decreases the pain. So the harder you pinch, the less pain you feel. And why belly as opposed to upper outer gluteal fold? I tell patients, you can do whatever you want. Most patients just think fat. You want to be able to see it. It's easier. And less pain in the fat. But some people, I have like 10, 20 % say it's less painful in the muscle. I say, great, do it in the muscle, wherever you prefer. Although there's a conversion, the conversion is the following, that you have a higher blood level if it's in the fat. For example, I think the conversion is about 20%.

1:54:32So if you give someone 80 milligrams sub-Q, it's about giving 100 milligrams IM, roughly, is what I'm seeing. So if you look at Zyastad, the starting dose is 75 milligrams, not 100. It's 75. So you do get a slightly higher blood level, I think, when you give patients a sub-Q. So my favorite is Sunday, Thursday, 0.25,$25 a month, no insurance. It's easy. But there are patients that are needle phobic. I get it. So Zyastad's a great option. And Zyus, that of course is still a needle, but it's preloaded. They don't have to see it. It's just a pen. 27 gauge. It's unbelievably tiny. It has a high spring.

1:55:04How do they get it out? Is the pressure just so? So if you look at the gate, it's a high spring. So it's not a new drug. They're just using enanthate. It's just enanthate in a very clever spring-loaded device. Why haven't they come out with a cipionate equivalent? I think enanthate is what they use to get through the FDA. It's a good point. So that's what they use. But the ticket is the 27 gauge needle, which is unbelievably tiny with a very powerful spring. Very long spring. So it gets it in with less pain and the patients just throw it away. They don't even know it. For a month. It's easy. And so at 100 milligrams, what's your monthly cost on?

1:55:36Cash price on Zyested. On Zyested,$150. Cash price. So considerably more than Sipionate. Considerably more than Sipionate, but some people say it's worth it. It's worth it because I don't have to deal with the pain. I don't have to travel. I don't have to draw it up on my trip. It's easy. And there's no user error associated with how much you're drawing. It's easy. If I have a dollar for every time a patient made a mistake on the math. Yeah. So it's easy. Now, the orals are very fascinating. And just approved last year. Well, 2019. So undecanoate has been approved all over the world since 1970.

1:56:04It's been around for numerous years. It's called andriole. So when I went to China, when I gave in Australia, Europe, andriole is available in Canada, but never got approved in the US. In 2019, the first testosterone undecanoate got approved. Why is undecanoate important? Because orals historically cause hepatotoxicity, but these go through the lymphatic system. So they don't cause hepatotoxicity. Do you swallow them? you have to take it with a fatty meal. But the newer ones don't have to be with a fatty meal. They just have to be with a meal. If you take it fasting, no absorption, zero. So if you're intermittent fasting, it makes it a little tricky.

1:56:36So you have to take it - But you could just commit to taking it at dinner every night? It's BID. Oh boy. So not bad. So what happens is you're supposed to take it at breakfast and dinner. So off label, I do give my patients at breakfast and lunch. Because what happens is you superimpose the first curve on the next. So you get a really nice level in the day and it mimics the diurnal variation. So I like it better breakfast and lunch. Again, that's off-label. Most people use it. And what's the dose? So it depends. So Jotenzo, which is the one that first came out in 2019, the first one, 237 milligrams BID.

1:57:07Talando came out in 2022. So now we have two, and that's 225 BID. 225? BID. Which tells you how inefficient the oral conversion is relative to the injection, right? Right. But you're getting still the blood level. Yes, yes, yes. wise. But now in 2022, the third one just got approved. So Kaisotrex, the new drug by Marius Pharmaceuticals is now the third oral. So now we have three orals that are FDA approved. So it's getting very popular, but all are BID. The only difference is Talando has no titration. So essentially it's 225 and 80 % of patients should be in the normal range, but there's no titration.

1:57:42The other two you can titrate if you're not high enough. So orals are popular. Look, Americans are used to taking pills. They have pill boxes. They put them in their pill box, but there are patients who are injectables that just love doing it once a week or twice a week, very convenient. I do do a lot of pellets, a lot of pellets in men and in women. I think they're very effective. But the only issue with pellets is that the following, you'll peak in 72 hours, but by that third to four months, and this was our paper, we showed that there's a sharp decline. It actually just goes very quick. So patients, it's kind of weird.

1:58:12I live great for three months, it kind of lousy for the fourth, and then I come in, I live great. So we can shorten the interval to three months, you know, that's fine. So the key is, I call it putting the balloon in the air. We want to put the balloon in the air and catch it before it gets too low and put it in the air again. But, you know, it can do some logistic problems. I mean, if you've got a trip and you've got to get into my clinic quickly. So a lot of patients do like the injectables because they're autopilot. I don't have to deal with it. And, you know, just show people how large a tract you're making for a male to put testosterone in him.

1:58:41Like it's not a trivial size. It's not a trivial size, although I would tell you. So we were taught initially that you should make a W, go one, two, three, or a V. Or a V, yeah, is what I used to do. But I don't do that. So we invented a technique called stacking. So basically we put it in and basically it's just like a column. We put them up and down together because you want to keep the distance far away from the incision or you'll get expulsion. And every time you do a V, it's a whole new track for blood or trauma. So we would do a stacking technique and it's worked quite well. And the pellets, you know.

1:59:09Stacking vertically or stacking on top of each other? On top of each other. Oh. Literally like a column. And so, you know, it works very well. These patients who do it like it. And so they keep coming. There's a lot of people that travel. and they don't want to have the hassle or they're needle phobic. So they come in. And how long is a guy inactive for you after putting pellets in? No exercise for 72 hours. A bandage stays on for 48 hours. You can shower with it, but no exercise. So some people say, I like to work out. Now I can't work out for 72 hours. I got to come see you every three to four months.

1:59:38I have pain, some discomfort, not much, but you have some. And I say, what about the injectable? It's once a week. When you consider the track record of how long these drugs have been around in each of their various forms and the challenges of using endogenous versus exogenous. If a man is committed to being on testosterone therapy, so you're no longer worried about preserving endogenous function, do you favor the injectable over all others right now? I do. So I worry about erythrocytosis also. So we did a study showing that I think the worst thing you can do is give 200 milligrams IM every two weeks.

2:00:11That doesn't make a lot of sense to me. And the drug will last about 10 days. So for about four days, you're not even having any medication on board. But you have a high erythrocytosis rate because it's the spiking that causes that erythrocytosis. So if you have a man and you drop to 50 milligrams twice a week, the erythrocytosis rate goes down. It's more physiologic. So as long as they don't mind doing it twice a week, it's my favorite. It works the best and it's the cheapest. And it produces a better physiologic level. We didn't talk about topical. I have never been a fan of topical for men.

2:00:42I think it's acceptable for women because our options are limited. But tell me what your views are on topical. I don't favor topicals for several reasons. So we did a paper in 2009 that showed that 20 % of men won't even absorb a topical. So that's poor absorption. Because there's a - Same in women, by the way. It's really problematic. The formula is milligrams times percent penetrance. And that's variable. It's variable. And it's even variable day by day on the same person. So if I have - How clean is the skin? What part of the skin do you apply it onto? Has the skin been exfoliated? Hair. All of these things.

2:01:13Yeah. So if a patient, I give him 1 ,000 milligrams of testosterone, he has 0 % penetrance, he gets nothing. So I said, patients, don't get fixated on how many milligrams I'm giving you. Let's look at the end result. What is your level? So the problem is that if you look at the attrition rate, if a man starts on a gel today, only 20 % are on that gel at the end of one ear. It's the convenience. It's having to do it every day. It's the levels. It's once a day, right? It's once a day. It's once a day, okay. Gels are once a day. You can do up to twice a day, but it's once a day. But the issue is this.

2:01:41I can't even get the levels that men want to be on sometimes on a gel that I can get on an injectable. So there's many reasons why. The cost, with insurance, right? The cost. You can get a compounded cream, which has even less penetrance. So I'm not going to go there. So I've never been, and don't forget about transference. It's a big problem with men because they're covering so much of their body surface area to get this stuff. If you have a pregnant woman at home, if you have a child at home, you want to be careful as well. Then if you have to travel for the TSA. So there's a lot of issues with the gels that I really, really don't think you should do.

2:02:12I mean, for women, you mentioned women, injectables and pellets work fantastic. Pellets are great. The injectable, you have to kind of compound it to get the dilution. But it's easy. So if we go 50 milligrams per ml, it's 0.1 cc. I usually go 20 per ml. And go 0.1 cc's a week. It's easy. And they find it very effective. Let's now talk about physiology. So how does testosterone work? How does DHTDHT work? How should we think about testosterone, DHT and estrogen and why do they all matter? So we talked about the breakdown, testosterone going into estradiol, testosterone going into DHT. Testosterone has numerous effects on different body parts at different levels.

2:02:51So we know that erectile function typically is around 200 nanogram per deciliter. When you start falling below 200 nanogram, you start losing nocturnal erections, right? Muscle tends to be higher. Bone tends to be higher. So different body parts, I guess, call it turn on at different levels. So in other words, what's the highest? What has the greatest sensitivity to falling testosterone? The way to cover yourself is just being the upper quartile. If I'm in the upper quartile, I know I'm covering because everyone's different. But again, you're saying when you said 200 nanograms per deciliter, that's total.

2:03:18How do we determine free the cutoffs? That's important. Everyone's different. So I have to say this. I never understood why we use this number 300. What are you telling me? 300 nanogram is a definition for hypogonadism. So are you telling me that 290, we must all feel bad, and at 310, we must all feel good? That is not true. Not even close. That's what it's come to. So the reality is that there are many patients at lower levels that feel good. It's based on the sensitivity of the antigen receptor. So when I was a fellow in my lab, very beginning, we would take the blood, we'd go back and count the CAG repeats.

2:03:50Patients who had longer CAG repeats would have more sensitive receptors. And why is that? And sensitive receptors, excuse me. Because everyone's different. Your receptors and my receptors have different sensitivities. Genetically, how we're made. So everyone has a different sensitivity of the receptor. So many have shown that people respond differently to different doses based on sensitivity. Dr. Zitzman in Germany showed that depression can be associated with sensitivity interceptor, sexual function. So sometimes people need more to feel better. And I think that's a misconception because a lot of times people say, well, you're in the normal range, you're at 400, something else may be going on.

2:04:27And invariably, if you can raise them to the upper quartile normal, cover them, you may see symptomatic improvement. Do you think we're ever going to get to the point where TRT can be customizable based on a more broad view where a patient comes to see you and you do an androgen receptor assay on them and you couple that with what their free T is and make decisions based on that as opposed to just sort of flying a little bit blind and having to guess? That would be amazing. So we did that in our lab. And so I had some of my colleagues say, hey, I have this patient I don't understand. Can you look at his sensitivity to androgen receptors?

2:05:00My lab is not CLIA certified, so I couldn't give you... You can't give advice. I can't give advice, but I can look at different assays. But I think that would be amazing. So there's got to be other factors I can predict. Because right now, it seems very archaic. How complicated is the assay? It's so easy to run. But the only thing is it does take a little bit of manual labor. My technician would have to sit there and he'd literally have to... Like it's an ELISA or what's the... It's an ELISA test that you see we have to count C-A-G and circle it. C-A-G and circle it. And then he would then say, hey, Kara, I have C-A-G repeat of 28.

2:05:29so you know he's extra. Do you not get the impression like LabCorp or somebody like this could generate that or even just a proprietary lab could get the CLIA certification and go ahead? What's the ROI? So the thing is, it's about how much money will they make if they do it? Yeah. And you're saying the market might not be there because the majority of the TRT market is wildly unsophisticated and their answer is just give more testosterone. And that's what they do. Not titrate testosterone to the right. Based on sensitivity, right. How dare I assume that people would care about the level of nuance I would, right?

2:05:59Now let's talk about DHT. So you mentioned that testosterone gets converted. I think you said about 6 % to 8 % of it gets converted. Presumably, there's quite a bit of genetic variability there. I mean, 5-valphabreductase activity is really quite genetic. And what is the purpose of DHT? So DHT is the most potent androgen we have on our body. In terms of sexual function, it's extremely important. When you remove the DHT, it can have a significant impact on someone's sexual function. So that's typically what I look at. Now look, DHT is implicated for prostate in terms of prostate growth. It's implicated for hair as well.

2:06:31So these are medications that are used to take away the DHT because they can cause alopecia. So 5-alpha reductase is located all over the body. There's type 1, there's type 2. So type 1 can be in the scalp, it can be in the brain, it can be in the prostate, it can be in the adrenals, it can be in the kidney. They're all over the body. The finasteride is predominantly type 2. Dutasteride is type 1 and type 2. We may talk about that later, but it's important to realize that these enzymes are throughout the body, have multiple functions throughout the body. Go over that type 1, type 2 again. So finasteride, was that the first drug used to treat BPH?

2:07:05Yeah, finasteride came out in 1992. As proscar. As proscar. Five milligrams of finasteride. You got it. To treat BPH. Yes. Then in 1997, the one milligram dose came out as Propecia. And then later on, I believe 2012, was dutasteride. And when you look at the graph - And dutasteride was brought out to treat BPH? Avodart. Avodart, but it was for BPH. BPH. Okay. So when you look at 5-alpha reductase activity, there's type 1 and type 2, two isoenzymes. If you look at where they are, type 1 and 2 is in the scalp. Type 2 is predominantly more in the prostate, but so is type 1. They're in the adrenal glands.

2:07:44They're in the brain as well. They're also located in the epididymis, all over the body. So it's not just affecting just one location. You're affecting numerous parts of the body when you're taking away the DHT, and that can have detrimental effects. About an hour ago, you said you do not like to use 5-alpha reductase inhibitors in your practice at all. I don't. So that means if a guy comes in with BPH and you want to treat him medically, not surgically, what would you use as first line? Alpha blocker or daily Cialis. That's it. And you're seeing as good a response with daily Cialis as you would see with Dutasteride or Proscar?

2:08:24I'm seeing a much better response with an alpha blocker. And then I would then use - And the alpha blocker of choice is - I usually use Alphizosin only because Alphizosin has the least rate of retrograde ejaculation. You can use Tamsulosin or you can use Solidosin, but Alphizosin has a - So for younger men - And what's the brand name on that one? Uroxatrol. So it tends to have the least rate. So for younger men, they prefer to have that. So typically that's the medication choice. I think finasteride is a very bad drug and I think it has very detrimental effects. You were the second very prominent urologist to raise this to me, the first being Ted Schaefer, which has got me and my team trying to wrap our minds around this thing called post-finasteride syndrome.

2:09:04Do you want to tell people what it potentially is? I know there's a ton of controversy and confusion around it. So finasteride, there are patients who have taken finasteride who develop irreversible sexual neurologic symptoms. For example, permanent ED, libido, psychological problems, depression, suicidal ideations. And I believe it's a real syndrome. I don't believe everyone who takes finasteride gets post-finasteride syndrome. But I do believe that there's a subset of patients who take finasteride who develop this condition. I'm the minority. Most people do not. And I accept that. So the official position of the American Urologic, what is it, AUA association is what?

2:09:45Well, if you look at the package, it states there are patients who have prolonged side effects with this drug. It says it. But the true definition of a statement on post-finasteride, there's no statement. Essentially, most clinicians don't believe it exists. I do believe that there's a subset of patients who take finasteride that have a significant adverse effect. There's a plausible mechanism for that. I want to explain what that is. but the key thing is this we were taught in medical school that finasteride blocks the conversion from testosterone to dihydrotestosterone and that's it that's all we were told but that is only one fraction of the story because each one of those steroids then goes into something called a neurosteroid dhc goes into enterzendol that's the neurosteroid then you multiply that by six so six steroids are blocked and those six steroids then have a decreased conversion into their neurosteroid.

2:10:37I'm sorry, the six steroids are blocked because 5-alpha reductase acts on more than one steroid? Exactly. Progesterone, aldosterone. There's a whole linear. It's not just testosterone. I see, I see. So the problem, the biggest problem is when you block progesterone, getting into its neurosteroid called allopregnanolone. Why is that important? Because allopregnanolone has been implicated for depression, anxiety, cognition, right? So some of those neuro steroids are very important when it comes to depression, anxiety, depression, and cognition. So much so that there has been an increase in suicide rates in men who've had this post-finasteride syndrome.

2:11:17If you had to guess, what percentage of men who take finasteride experience negative side effects that persist upon the cessation of the drug? I don't have a denominator, but I will tell you this. In the package insert, it says less than 5%. I think it's more than 5%. And I think many men get these symptoms, but they're taking it when they're 60 or 65 and they think it's a normal part of aging. They say, oh, I'm supposed to get ED. But a 30-year-old knows this is not normal. A 20-year-old knows this is not normal. But the key is this. Let's say you do or do not believe in post-finasteride. I believe in it.

2:11:51Let's say you don't believe in it. Okay, you say it's not true. What you cannot deny is that there's an increased risk of suicides in this population of men, irrespective whether you believe it's true or not. And I'm sorry, this is in all men who take finasteride or just young men? Certain men who have post-finasteride syndrome who take finasteride. So for example, I had a study. I had 25 men who had post-finasteride, 25 men who were controls. The controls are men who took finasteride but had no symptoms. Who never took finasteride at all. And the reason I did that was the reason because I was looking at gene variation.

2:12:25I would take skin biopsy of both populations. I was looking at genes, upregulation, downregulation of genes between the two populations, just normal controls and finasteride. But two patients out of my 25 committed suicide in my trial. And I'm sorry, the men who were taking finasteride in your trial were taking it for what reason? Predominantly alopecia. So you could technically argue that there's another issue going on, that whatever it is that's driving someone with alopecia to take finasteride for hair loss speaks to a difference in emotional state that might be predisposing them to some. In other words, it would be more interesting to see if you had 50 men who were all taking finasteride for the same indication, but you isolate the 25 who are experiencing negative symptoms.

2:13:12I think that would be very important. I agree. Or do a randomization. I agree. In either case, it has to bring some attention. 8 % suicide is an alarming rate. And that was over what period of time? It was over a five-year period, but my study was just a point in time. They'd come and visit, we would do that. But after they left, we follow up these patients, 8%. So if I told you any drug - And just to be clear again, to push back, because this is so important that we think through this rationally, do we know what the history was of mental illness in those patients? Did they have a history of depression before taking the drug?

2:13:42We don't have significant mental illness before they come in. They weren't on SSRIs. They weren't having a history of depression when they came in. So that's important to know that. They weren't diagnosed with depression prior. But any drug, if I told you drug X, it doesn't matter what you believe the cause or is, is associated with higher suicidal rates. I would say, okay, let's take a closer look and see what's happening. It doesn't matter. That's what I'm saying. I mean, it seems to me that a random assignment trial would address this. And if you didn't want to do randomization, you would at least be able to do a post hoc analysis in the way that I've described it.

2:14:15And it's amazing that that's not being done. Do we see the same effect of dutasteride? Patients who've taken dutasteride had symptoms, but it's not as prominent. And I think probably it's because A, a lot of the patients who were taking this were taking it for alopecia, so they were taking finasteride. But there have been reports of dutasteride symptoms the same way. I think that's important. So I think more attention has to be given to this condition. And that's why my personal bias, I do not give. So when men come to you on those products, you'll say, if the guy's coming to you on that product for BPH, we've got the alpha strategy and the Cialis strategy.

2:14:49If the guy's coming to you on that product for hair loss, you'll tell him what? I tell both men, if they're coming to you BPH or alopecia, I tell them that there is a condition that's been associated with this, men taking this medication that can cause an impairment in sexual function and actual depression and anxiety. Many countries, Canada, France, UK, have put on their package insert. Black box. Not black box, but this warning saying that, hey, there's an increased risk of suicidal ideation. This is not trivial. Technically, SSRIs have that warning as well. And it's never clear to me that SSRIs are causing an increase in suicide.

2:15:22It's in part, I think, that we're looking at a demographic that's more susceptible to suicide. I think that's the thing I'd always struggle with. What I find most interesting about this, and I'm not doubting that there's something there, is why does it linger after the drug stops? That's the part that is undoubtedly most disconcerting. It's if this is real, how is it that a guy can take this drug for a year, stop it, and two years later, he is still suffering the sexual side effects associated with it? That strikes me as epigenetic. I can't come up with another explanation. That's exactly right.

2:16:01So there many plausible mechanisms, one being that could be epigenetic, one is silencing of the 5-ARI gene through DNA methylation. So that's been the most common prevailing thought. Okay, but we don't know. But that's one of the most common thoughts. Again, it needs to be studied. Let's talk a little bit about the role of testosterone in prostate cancer. Because when I bring up testosterone replacement therapy for men, the question I get asked the most is about prostate cancer. Now, I've documented and discussed this in so much detail. I think I've probably done two, if not maybe three podcasts on the subject, including a dedicated AMA podcast on all things that relate to testosterone as far as risks and benefits.

2:16:47And I would say we've spent more time on this than just about anybody, perhaps not as much as you. We came away from this analysis with the belief that there was no evidence that exogenous testosterone application was increasing the risk of prostate cancer, and there was actually some evidence that hypogonadism may not be increasing the incidence of prostate cancer, but may have increased the incidence of high-grade prostate cancer. Furthermore, we saw virtually no evidence that exogenous testosterone therapy was leading to an increase in atherosclerotic cardiovascular disease, though there was one study that suggested in the short run, i.e.

2:17:29within one year, highly susceptible men might see an increase in the risk of ASCVD, but that risk decreased at two and three years post-treatment. So with that being my current state of understanding, can you fill in the gaps? This is a great topic. So this thought that testosterone causes prostate cancer started in 1941, Huggins and Hodges, Nobel Prize, based on one patient. One patient in 1941, when they gave exogenous testosterone, the prostate cancer got worse. If you look at the different paradigms, the American Urologic Association in 2018 came out with the testosterone guidelines, guideline on that intersection, patients should be informed there's no association between testosterone and prostate cancer, strong recommendation.

2:18:13So finally, patients say, I googled it, I heard I can get prostate cancer. So no, the guidelines are very clear. Based on the evidence, no data to support it. Contrast that for a moment with the guidelines on estrogen therapy and breast cancer in women, which we're not going to go down that rabbit hole because I get way too phosphorylated, but talk about the difference between men and women and how differently they're treated with respect to hormone therapy. I think a lot of that started with the WHI. The WHI, of course. 2003. So you get this big news and everyone's off hormones. And later on, you get a re-evaluation of the WHI and say, hey, maybe we made some mistakes.

2:18:45But all that noise - to talk about the TRAVERSE trial. So I've been one of the involved in the TRAVERSE trial. The TRAVERSE trial is coming out in June. This year will be coming out at the endo meeting about cardiovascular, but that was very similar. The impetus part of the TRAVERSE was, hey, we have no large trial in men. You know, we have something in women. We have nothing in men. The TRAVERSE, 6 ,000 patients, randomized placebo-controlled trial, largest of its kind, will be coming out pretty soon. But I want to finish about prostate cancer. So there's a paradigm shift, and the paradigm shift is that maybe testosterone may not only be safe, but it may be protective against the development of prostate cancer.

2:19:20So I just want to give you an example. In 2015, the Hopkins group published a very interesting study on a concept called bipolar androgen therapy. They called it BAT. Who was the lead on that? It's Schwarzscher and the senior was Denmead in 2015. And they did something very unconventional. You walk in with metastatic prostate cancer into Hopkins. And what they do is they give you high doses of testosterone to treat your metastatic prostate cancer. Which is mind-boggling because the standard care for that patient is the exact opposite. It's to give you androgen deprivation. It's to chemically castrate you.

2:19:53Right. And the way they would do it, they would give you Lupron first to shut you down, and then they would give you high doses, 400 milligrams every month, and it would go up and down. And it would basically convert the castrate-resistant prostate cancer to castrate-sensitive. And so essentially, the PSA went down by 50%, and what they saw was the radiographic disease, metastatic disease, went down by 50%. That is unheard of to give that metastatic prostate cancer patient testosterone. The same group published numerous really impressive studies, but my favorite was the one that came out in 2021 called the Transformer trial.

2:20:28This is mind-blowing. So they took about 200 patients who had castrate-resistant metastatic prostate cancer, and they said, okay. And if they became resistant to abiodarone, the treatment of care is enzalutamide, which is an androgen receptor blocker. They said, instead of giving everyone enzalutamide, we're going to give half the men high doses of testosterone. Okay, so let's see what happens. So they gave them enzalutamide or high dose of testosterone. They found that the overall survival between the two groups was the same, no different. But the difference in quality of life? Was significantly better on the patients.

2:21:00Of course. But it got even more interesting. You were allowed to, if you took bipolar antigen therapy, you were allowed to switch over to enzalutamide if you became resistant and vice versa. The patients who did bipolar antigen therapy and then did enzalutamide had significantly greater survival, 37 months versus 28 months, than enzalutamide, which is the standard of care. The cost of enzalutamide is$8 ,000 a month. The cost of 400 milligrams of testosterone is about$100 a month. And they had significantly greater survival. This was published in 21. 21. So we're two years after that. Yes. How many men with metastatic prostate cancer are receiving that care now?

2:21:40I think minuscule. Why? I don't know why attention was not given, more attention was given to this study. It's called the Transformer trial. It was really impressive as using a standard of care, which is enzalutamide versus bipolar endotherapy and then enzalutamide. So I think you're going to see a lot more of therapeutic use of testosterone. I also, you're going to see a lot of studies. There have been some recent studies suggesting that giving testosterone to men after radical prostatectomy may be potentially protective against biochemical recurrence. That was Tom Allering's group. Look, I'll tell you what.

2:22:09So I have a lab. In my lab, we do a lot of basic science work with testosterone and prostate cancer. One of the studies we did is we took Petri dishes. We put LYNCAP cells, prostate cancer cells in those Petri dishes. And we gave each one of those Petri dishes different amounts of testosterone. And it is true. When you initially give testosterone, you see prostate cancer cell growth. No question. but when you give higher and higher doses of testosterone, you see greater and greater suppression of prostate cancer cell growth. We call that the inverted U where maybe castrate may be protective, eugonadal protective, but hypogonadal is dangerous.

2:22:44So then we said, okay, let's do it in animals, 200 mice, castrated 50 mice. We gave castration, we gave 50 controls, we castrate and give low doses of testosterone and then we give castrate and high doses of testosterone. These are pellets in the mice. We published both these articles. What we found was that if you castrate the mouse, you get a decrease in prostate cancer growth. No question. It helps. Low doses of testosterone, you start getting increased in prostate cancer growth. High dose, you get a statistically significant decrease, an inverted use. So if I have prostate cancer - And the high dose compares how much to the castration?

2:23:18Essentially, it's a eugenadal range. Essentially, castration - So castration behaves almost the same as - slightly better, but in certain cases, in the animal case, in the Petri dish, it was better. It just varies. But the key is this. If I have prostate cancer, either castrate me or put me in the normal range, but do not, I think personally, put me in the hypogonadal range. I think it's the danger zone. Yeah. Except I would say having watched men get castrated chemically, it's awful. I mean, I generally advise men to undergo surgery whenever possible. If surgery is an option, if you're that Gleason 3 plus 3 or 3 plus 4 or whatever, and it's just a question of having the best surgeon operate on you, yes, there is a lot of downside of surgery, but I think it pales in comparison to the downside in what I see from men that undergo chemical castration, the metabolic syndrome and the metabolic derangement that follows from being hypogonadal, beyond hypogonadal.

2:24:13They're basically eugonadal, not to mention the complications of bleeding that follow with the radiation. So again, I'm sure there's lots of medical oncologists and radio oncologists that are listening to me now wanting to put arrows into the back of my head, but I don't think I'm speaking with just a surgeon's bias. I think I'm speaking from watching men in the years that follow undergo complete metabolic destruction. And even if they're still alive, their quality of life is so poor. So that's why I would say like, gosh, if there's a medical way to do this with high-dose testosterone. You're right.

2:24:45And certain patients do benefit better with radiation just based on Gleason score. But at the end of the day, yes, if it's moderate, we give them six months. If it's severe, we give them two years of androgen deprivation therapy. But we do, in my practice, treatment after radiation with testosterone. It's controversial. We'll get into this. And what dose are you using? 100 a week? So typically, I will use gel first. I want a short acting so I can stop it if the PSA. Then we'll move on to an injectable. But I treat them just like I normally would treat any other the patient. You treat them to a level of total T or free T at the top quartile?

2:25:14Just like I would at someone in the normal therapeutic range. But there's no data to support that it causes cancer. And what kind of consent form do these men sign to undergo something that is so radical? And do you need an IRB for this? If you look, most clinicians or urologists, there was a recent survey looking at urologists, 96 % of urologists will treat men after radical prostatectomy with testosterone. 86 % of urologists. Yes, after radical. After about 86 % after radiation therapy. Look, there has to be some consent here. There has to be some informed decision-making. The American Urologic Association made it very clear.

2:25:43The risk-benefit ratio after prostate cancer surgery or radiation is unknown. We don't have the randomized placebo-controlled trial. So I tell them, look, we don't have a randomized placebo-controlled trial. These are the risks. These are the benefits. And we have a shared decision-making model. But there's something important. You have to understand something called the prostate saturation model. It's really important. We were taught in medical school that the higher the testosterone, the greater the PSA. We were taught it was linear. And the higher the testosterone, the greater the growth. That is not true.

2:26:09At some point, it saturates. We did a study in 2011. We said the saturation was around 250 nanogram per deciliter. So if you take a guy who's at - That's pretty low. Pretty low, but that's where the inflection point was. And others have shown the same thing, roughly around 250, but we're all different. But why is that important? Because if you have a man who starts out with a testosterone level of 190, and you put him on testosterone, his PSA should go up. It should go up. If he's at 290 and you put him on testosterone, it should not go up. And if you take the guy from 290 and take him to 3000, should not go up because it's saturated.

2:26:41It plateaus. So that's why if I give someone Lupron, that testosterone goes down, but the PSA goes down. But if you raise the testosterone, it's not the more I raise it, the more the PSA goes up. So the tricky part for me is when patients come to me after radiation therapy, because they've been given androgen deprivation therapy, The testosterone is 50. Their oncologist spent all this time taking away the testosterone. That's right. And when you get it from 50 past 250, you're going to see that rise until you hit saturation. And so the oncologist says, what are you doing? Patient says, what's going on?

2:27:09I have to set the expectation. It's going to rise. It's going to plateau. I just have to have the understanding with you based on the saturation model. You just have to have this understanding. What about testosterone and breast cancer? This is a topic I have become very fascinated with. I want to do a dedicated podcast on breast cancer and all things that have to do with it because it's obviously such a comprehensive and such an important topic given its obvious impact on women. But while I have you here, does anything you do focus on from a research perspective, the effects of testosterone as an adjunct to therapy, especially in the estrogen-sensitive breast cancers?

2:27:46Yeah. So I do treat women who have a history of breast cancer. We may treat them with testosterone. It's working with the oncologist. Many times, though, I will typically use drugs that are not hormone-based, like Adi particularly, because that will give me the same benefit of libido, but with using dopamine. Oh, but you're using it for sexual function. Sexual function. I got it. No, I meant for, I've been reading a lot of case reports that have suggested that testosterone replacement therapy with aromatase blockade in women with breast cancer is a therapeutic option. In other words, testosterone is protective against breast cancer.

2:28:26And I don't know if the aromatase inhibitor is necessary. That's an even more controversial topic. But at least the thinking there would be you want to prevent testosterone from becoming estradiol. Sure. So the studies I've seen are giving testosterone without the aromatase inhibitor. And letting both go up. And showing that it's still protective. But I don't have a lot of experience in treating women with breast cancer. I'm going to hopefully find somebody that can. Well, we've covered a lot here today. This is a really interesting topic. And even though I came into it knowing very little, I feel like I've learned a lot, both in terms of pathology and the treatment.

2:28:58So Mo, I want to thank you very much for this. My pleasure. My hope, of course, is that everybody listening to this who's impacted by anything on the spectrum that we've talked about is at least a little more empowered to kind of realize that there are people like you out there. And presumably, do you have a sense of how many doctors in the country would have your degree of certification? So the urologists who have been subspecialized. Sure. So I'm part of an organization called the Sexual Men's Society of North America. And this is exactly what we do. It's a great organization. We're 1 ,200 strong and urge you to go to the website, look at it.

2:29:27Which is very interesting. That's almost, if I remember correctly, that's about the same number Sharon said, that there's about 1 ,200 or so doctors that are kind of doing what she's doing as well. In that group, there's a lot of APPs, nurse practitioners. So that 1 ,200 encompasses all of us. But all of us have the same passion and desire in this space. So sometimes someone's looking for a provider in their area. You can go to the website and find a provider in that area. Sometimes you work via telemedicine. In the state of Texas, it only can be in Texas. So I can only do telemedicine in Texas through Baylor.

2:29:58Yep. What percentage of those 1 ,200 are at major academic institutions like you are versus in private practice? Yeah. So I'd say the majority are in academic institutions. I'd say about the 1 ,200 or 400 or 450 are urologists. Majority are in academic institutions. Well, Mo, thank you very much. I hope you enjoy the rest of your weekend here in Austin playing tennis. The weather looks to be a little warm Thank you so much for the invitation. Thank you, peter. All right. That's awesome Thank you for listening to this week's episode of the drive If you're interested in diving deeper into any topics we discuss We've created a membership program that allows us to bring you more in-depth exclusive content without relying on paid ads It's our goal to ensure members get back much more than the price of the subscription Now to that end membership benefits include a bunch of things one totally kick-ass comprehensive podcast show notes that detail every topic, paper, person, thing we discuss on each episode.

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2:33:03Thank you.