The Peter Attia Drive - #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.

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

00:00:15.500 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

00:00:19.820 into something accessible for everyone. Our goal is to provide the best content in health and

00:00:24.780 wellness, full stop. And we've assembled a great team of analysts to make this happen.

00:00:28.900 If you enjoy this podcast, we've created a membership program that brings you far more

00:00:33.320 in-depth content. If you want to take your knowledge of this space to the next level,

00:00:36.860 at the end of this episode, I'll explain what those benefits are. Or if you want to learn more now,

00:00:41.760 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay,

00:00:47.780 here's today's episode. My guest this week is Dr. Mohit Kara. Mo is a professor of urology at

00:00:56.220 Baylor College of Medicine. He is also a renowned expert in male and female sexual dysfunction,

00:01:01.880 declining testosterone levels in aging men, and male infertility. This episode is a follow-up to

00:01:07.880 last week's episode with Dr. Sharon Parrish, which focused on sexual health and females. This episode

00:01:14.360 focuses on the other side of that conversation, all things related to male sexual health. We start by

00:01:20.180 talking about erectile dysfunction. We speak about the percentage of men who deal with this issue at

00:01:24.900 various ages, the way it is diagnosed, and what we know about erectile dysfunction and cardiovascular

00:01:29.820 disease. We then speak about various drugs, shockwave therapy, stem cells, PRP, and lifestyle

00:01:35.780 modifications that can help with erectile dysfunction. We then talk about Peyronie's disease,

00:01:41.020 which is a curvature of the penis, including its causes and treatments. The conversation includes

00:01:46.740 discussions around penile fractures and what is known about penile enlargement treatments. 0.98

00:01:51.640 From there, we speak about what happens when a person has an erection for over four hours, 0.92

00:01:56.940 why that's problematic, premature ejaculation, the causes and treatments, and anorgasmia,

00:02:02.320 or delayed orgasms, both causes and treatments. We then shift the conversation to talk about

00:02:07.340 testosterone, including the physiology of how testosterone, DHT, and estrogen work, and how we

00:02:12.920 should think about them and why they all matter. We talk about which blood panels you should use to

00:02:17.280 measure your testosterone and the difference between the blood levels and the symptoms that we might see

00:02:21.700 in the case of low testosterone. We talk about testosterone replacement therapy and the various

00:02:26.260 ways to increase testosterone, including the use of pellets, topical formulations, injectable

00:02:32.540 formulations, oral formulations, and intranasal formulations. We even discuss the role of testosterone in

00:02:39.200 patients with prostate cancer. We end the conversation talking about DHT and finasteride and some of the

00:02:46.300 concerns around post-finasteride syndrome. As you can hear, this conversation is really a tour de force

00:02:51.880 as it relates to various topics around sexual health in males. And I think anyone who listens to

00:02:57.780 this will walk away learning something as I did. So without further delay, please enjoy my conversation

00:03:03.180 with Dr. Mohit Kara. Mo, thanks so much for making the trip over here from Houston. Although I know you

00:03:13.820 didn't come to see me, you came for tennis, but I'll take what I can get. Anytime we can do one of these in

00:03:17.640 person, it's great. There's a lot we want to talk about today. I will admit my insane capacity for

00:03:24.700 ignorance in this domain. So when one of our analysts was working on, you know, sort of the topics we were

00:03:31.060 going to talk about, it turns out I know as little about this as I know about the contrapositive in women's

00:03:37.120 sexual health. So, you know, a lot of times I go into a podcast having more knowledge about a

00:03:41.580 substance and I can guide the discussion more thoroughly. So I'll be kind of leaning on you

00:03:45.800 heavily, but maybe we can just start by talking a little bit about your background, your training,

00:03:51.060 and how that leads you to doing what you're doing. So after medical school, what did you go and do?

00:03:55.820 Sure. So first of all, thank you for having me on the show. So after I went to college at Vanderbilt

00:03:59.400 and I first went to Boston University, got my MBA, got my MPH. I was a healthcare analyst

00:04:05.100 for about two years. I didn't like it very much, but I met my wife in Boston. She was at BU Medical

00:04:10.620 School at the time. So I had to change a course and career path. And I went to University of Texas,

00:04:15.180 San Antonio for medical school. Then after that, I went to Baylor College of Medicine,

00:04:19.460 did a one-year internship in general surgery, then did five years in urology, then I did a one-year

00:04:24.080 fellowship in male reproductive medicine surgery where I really got into sexual health and infertility.

00:04:29.680 And I've been at Baylor now since 2007 on faculty.

00:04:32.260 Tell me about what that means. So when I did my general surgery residency,

00:04:38.080 the urologists I was working alongside with, because one of my best friends, Ted Schaefer,

00:04:41.960 who you know, of course, is a urologist, a big emphasis in urology, at least as I saw it from

00:04:47.120 the outside, was of course on urologic cancers. So the big things that we saw the urologist doing

00:04:52.540 was removing prostate cancer, removing bladder cancers, removing kidney cancers. Those were big

00:04:57.320 parts of it. Because I was only limited in how much urology I did, I didn't really see much of

00:05:03.240 any of the other stuff. So I don't really know what constituted reproductive health or sexual

00:05:08.460 health for men. So what was that fellowship like? And what were the things that you sort of focused

00:05:12.000 on?

00:05:12.400 It was great. So listen, urology is multiple subspecialties. It could be stones, it could

00:05:16.340 be cancer, it could be female urology. But one subspecialty is sexual medicine and another one is 0.99

00:05:21.360 infertility. And usually they're combined. And so really what you're focusing on is reproductive

00:05:25.340 medicine in terms of vasectomy reversals, doing procedures to help men recover somatogenesis,

00:05:31.140 varicocele repair, sperm retrieval, but also sexual medicine, taking care of erectile dysfunction,

00:05:36.480 premature ejaculation, Peyronie's disease. And a big focus of that is also hypogonadism.

00:05:41.400 So that's really what I've focused my career on is really the sexual medicine side.

00:05:45.000 And that's where we have my research and my basic science lab.

00:05:47.860 Does it make sense to just quickly orient listeners to the anatomy of what we're talking about?

00:05:53.420 Sure. So when people think about the penis, they think just about one simple organ, but

00:05:57.580 there's actually a confluence of three different organs. It's really the urinary system, it's the

00:06:02.140 reproductive system, and it's the sexual system together. So the urinary system, meaning the

00:06:06.220 bladder, next to the bladder comes the prostate. From the prostate comes the urethra. Now in the

00:06:11.020 prostate, there are two ducts called the ejaculatory ducts. And from those ejaculatory ducts, the testicles 0.99

00:06:16.540 through the vas deferens will put some sperm into the ejaculatory ducts. Those ejaculatory ducts mix 1.00

00:06:22.540 with the seminal fluid from the seminal vesicles, and that gives a man his ejaculate.

00:06:26.940 Above the urethra are two, what we call them tubes, if you will. These are called the

00:06:31.500 corpora cavernosa. Essentially what it is, it's just smooth muscle inside. So those two

00:06:36.080 smooth muscle bodies, corpora cavernosa, are responsible for erections. Below the tube, 0.94

00:06:40.520 called the urethra, are responsible for urinary. So again, you just have three systems all coming

00:06:45.060 together. And so do you, in your mind, because I'd rather do this through the lens of your framework,

00:06:52.460 do you think about this by problem or by age or by some other metric? How do you go about thinking

00:06:58.040 through these issues? It's a holistic system. You think about it because each of these can affect

00:07:02.120 the others. For example, let's talk about the testicles. When you talk about infertility, that 0.99

00:07:06.500 can also affect hypogonadism. Hypogonadism can also infect fertility. So patients also, when you think

00:07:11.900 about the urinary system, patients can have retrograde ejaculation by taking medication for

00:07:16.620 BPH. Well, that may affect fertility and that may affect their sexual function. So all three

00:07:21.200 are interrelated. So you think about it as a whole. Does it make sense to start with a certain set of

00:07:27.040 problems and then maybe talk about how they change temporally over in terms of prevalence by age? And

00:07:32.540 if so, where would it make sense to start? Do you want to start with premature ejaculation, 0.50

00:07:35.860 erectile dysfunction? Start with ED. And I think about sexual health in general. I think,

00:07:39.440 I just want to put this into context. Why don't you think about this? So we know that 52% of men

00:07:44.560 over the age of 40 suffer from erectile dysfunction, to some degree. 52% of men, even if you take

00:07:49.840 conservative numbers, that's 30 million men in the U.S. suffer from this disease.

00:07:55.200 And how are we defining it? Is it one time I had too much to drink and I couldn't get an

00:07:59.500 erection? Or how do we think about it? So what we use is we use a questionnaire,

00:08:02.620 a validated questionnaire called the IIEF. And this questionnaire, there's several forms,

00:08:06.840 but there's a shorter version with six questions. And essentially, based on those numbers,

00:08:11.460 you can tell if someone has mild, moderate, or severe ED. So when they gave the original study

00:08:16.540 in 1994, when it came out, 52% of men over the age of 40 had some degree of erectile dysfunction.

00:08:22.740 And you talked about aging, but it's very interesting. On that graph, 40% of men at 40

00:08:27.560 had some degree of ED, 50% at 50, 60% at 60, 70% at 70. So it's an easy way to remember

00:08:33.260 what percentage of men suffer from ED. Now, it's not necessarily aging, I think,

00:08:38.100 that causes the ED. I think it's the acquisition of comorbid conditions as we get older, and we'll

00:08:41.900 talk about that. But again, it's a prevalent condition. I think about women. I treat a lot 1.00

00:08:46.680 of women for sexual dysfunction. 43% of women in the United States suffer from some degree of

00:08:51.240 sexual dysfunction. 30% of men in the U.S., some have some degree of premature ejaculation or

00:08:56.620 ejaculatory dysfunction. 7% to 9% of men have Peyronie's disease.

00:09:00.460 How many?

00:09:01.900 7% to 9% of men in the U.S. have Peyronie's disease.

00:09:05.520 We should set aside time to talk about it.

00:09:07.180 The problem is that this population, I call it suffer in silence.

00:09:10.640 Yeah, that's what I'm going to ask you.

00:09:11.660 They never talk about it. They never talk about it. In fact, there are many studies showing they're

00:09:14.760 completely silent. They don't seek care. And the issue is it has a significant impact on their

00:09:20.300 quality of life. So we know that a third of men who have ED have suffered from depression because

00:09:25.100 of their ED. 37% of men who have ED have anxiety because of their ED. We know that it causes

00:09:30.340 impairment in quality of a relationship between a couple. And if you look at quality of life

00:09:34.640 scores, they're significantly impaired in men who suffer from sexual dysfunction.

00:09:37.600 And so when you said suffering in silence, you weren't just referring to Peyronie's disease.

00:09:42.200 You're talking about all sexual dysfunction. 0.77

00:09:43.540 All sexual dysfunction. So there's reasons for that. So one is if you look at surveys, 0.89

00:09:48.580 it was actually, I got to bring this up because it was in a great survey that came out last year.

00:09:52.120 1,500 men surveyed between the ages of 18 and 80. And they asked about their mental, physical,

00:09:58.740 and sexual health. So in my world, it's mental, physical, and sexual health. It's a triad,

00:10:03.420 not mental and physical. And they're all related. But the survey found that roughly 40% of men in the

00:10:09.500 survey had some degree of sexual dysfunction. 50% of those men said, I would love to get treatment,

00:10:14.780 but I don't know where to go. But what was very interesting, the clincher was only 51% of those men

00:10:20.580 told their doctor about it. Only 44% of those men told their partner or their wife about it.

00:10:27.500 That's suffering in silence. And the main reason was they were embarrassed.

00:10:32.360 Also, clinicians don't ask about it. When you go to a doctor's office, and my wife is guilty, 1.00

00:10:36.460 my wife's a family practitioner. She said to me, look, I have to take care of diabetes, hypertension,

00:10:41.480 OSA, and all these conditions in X amount of time. And ED tends to be the bottom of the list.

00:10:46.560 I don't have the time to ask about it. So clinicians don't ask about it. Patients are

00:10:50.500 embarrassed to ask about it. And that's the suffering in silence.

00:10:54.240 Well, one of the desired outcomes of this podcast, of course, is to empower people of

00:10:58.980 both sexes, plus their physicians, to hopefully take a more active role in this. Not to put you

00:11:03.800 on the spot and ask you what those six questions are, but just directionally, what are the criteria

00:11:09.260 for ED in terms of severity, frequency, and such?

00:11:12.600 Sure. So I think one of the easiest ways to look at it is to use a question called the

00:11:16.400 SEP2 and the SEP3. So there's just two simple questions you have to ask the patient.

00:11:20.980 Are you able to get an erection sufficient for penetration? It's either yes or no. And are you 0.99

00:11:25.660 able to maintain that erection till orgasm? It's either yes or no. If they answer no to either one 0.98

00:11:30.460 of those questions, they have ED.

00:11:32.040 Under any condition, even if it happens just once, or if it says, well, you know,

00:11:36.320 eight times out of nine, I'm okay, but one time out of nine, I can't.

00:11:40.320 Then they had one episode of ED. So it's graded. But by definition, if someone says,

00:11:44.960 and the number one cause of ED typically is I can't maintain it. That's the first sign.

00:11:49.160 They say, doc, I can get it, but I can't maintain the erection. They're telling you I have venous 0.77

00:11:53.600 leak, which is the first sign of some kind of erectile dysfunction.

00:11:57.340 To be clear, this is not confused with something I do hear quite a bit of from patients, which is

00:12:02.720 I can get an erection. I can maintain an erection. I can't ejaculate. 0.80

00:12:06.380 We're going to talk about- 0.95

00:12:06.720 That's a separate problem.

00:12:07.720 That's right.

00:12:08.380 Yeah.

00:12:08.620 That's not ED. Okay. So let's talk about the pathophysiology of this, again, at the risk

00:12:14.060 of sounding and demonstrating my ignorance. How much of this is physiologic, i.e. neurovascular?

00:12:19.660 How much of this is psychological?

00:12:21.820 So the mnemonic I teach in medical students is vent. What are the etiologies? Vascular,

00:12:27.280 endocrine, neurologic, and trauma. And peroneus reads can be trauma as well. So vascular,

00:12:32.900 endocrine, neurologic trauma. Don't forget medications. We'll talk about those. Beta

00:12:37.000 blockers, for example, antiandrogens, finasteride. There's a lot of medications that can cause

00:12:41.700 impaired erectile function. And then there's psychogenic ED. Now, psychogenic ED typically

00:12:46.740 is in younger patients. It's not common that a young patient has organic ED, but they have

00:12:51.840 psychogenic ED. And psychogenic ED is treated very differently than organic ED. You want to ask

00:12:56.860 them some questions. Are you able to get an erection with masturbation? If they say, yeah, 1.00

00:13:00.120 no problem. That's psychogenic. They're telling you they have psychogenic ED. Do you get morning

00:13:04.080 erections? Oh yeah, I get morning erections, but I have difficulty having sex. You're telling you 0.99

00:13:07.620 you have psychogenic ED. So you want to probe for that because psychogenic ED is treated with sex

00:13:12.500 therapy. I use daily Cialis in these patients. It's very effective, I think. There's ways to treat

00:13:16.520 that that's very different than organic ED. Tell me a little bit more about what that means.

00:13:21.000 So do you refer out to sex therapy? What are sex therapists doing in these situations? How are they

00:13:25.180 helping people? Sure. So sex therapy, I do use sex therapists and I think they're very effective. The

00:13:29.400 problem is that many men don't want to see a sex therapist. They say, I want the pill. That's

00:13:34.080 typically. And if they do want to see a sex therapist, now it's getting a little bit easier

00:13:37.500 because telehealth. So they can do televisits. And before they have to go into the sex therapist

00:13:42.380 office and they're a little bit more likely to use the telehealth. But what has been very effective

00:13:47.080 for young patients is we will give them daily Tadalafil. So when they take daily Cialis, what they'll

00:13:53.120 notice is that their erections are starting to get better. And you'll do this at five milligrams daily.

00:13:56.300 Five milligrams. Now, what's interesting is that when a young person or anyone has erectile 0.61

00:14:01.460 dysfunction one time, we call it the vicious cycle. What happens is the next time they engage

00:14:06.780 in sex productivity, they say to themselves, as they're having sex, I hope I don't lose my 0.95

00:14:11.020 erection. I hope. And they will lose their erection guaranteed because they're so fixated. 1.00

00:14:15.080 Sort of like in driving, we say, if you're trying to not drive off the track as you're exiting a

00:14:20.900 corner, looking where you don't want to go is exactly where you're going to go.

00:14:24.540 Right. That's the same philosophy. The car follows the eyes.

00:14:26.680 Same philosophy. So what happens is, and then when they engage it the next time,

00:14:30.120 the next time they say, I can't believe it's happened two or three times.

00:14:32.620 And then it's just a total vicious cycle.

00:14:34.120 So they get anxious and they also undergo subconscious aversion. They start avoiding

00:14:38.220 sex because they're scared it's going to happen. Their partner thinks they have a low libido. 0.86

00:14:42.020 Is it really a low libido or are they really anxious about getting an ED? So typically daily Cialis,

00:14:48.060 when they engage in sexual activity, they start noticing, hey, things are working.

00:14:51.040 Things are fine. It's okay. And then you can many times wean it off, but you just want to show them

00:14:56.100 that everything's working great again. We use a lot of penile ultrasound in my office and it helps me 0.58

00:15:00.860 look at the peak systolic velocity and diastolic velocity. Many times getting an ultrasound and

00:15:05.540 showing them that everything is perfect is therapeutic.

00:15:08.640 Interesting.

00:15:09.260 You know?

00:15:09.980 So I want to come back to the penile ultrasound and to the, like some of the, what's the gains?

00:15:14.840 Yeah. So that's different. So that's the ultrasound for diagnostic purposes. What I do in the office,

00:15:18.600 we put an injection in the penis, induce an erection. The other ultrasound you're referring 0.99

00:15:22.480 to is shockwave therapy to treat erectile dysfunctions. There's three areas here. There's

00:15:27.380 stem cells, PRP, and shockwave, and that's a treatment option.

00:15:30.580 We'll come back to that in a second, but let's go back to this. Maybe just for folks,

00:15:34.040 explain briefly how Cialis, Viagra work. What's the mechanism?

00:15:38.240 The erections are caused or induced by the parasympathetic nerves and you can get stimulation

00:15:42.540 oral, I mean, excuse me, ocular vision, hearing, sensory, any kind of sensory stimuli or tactile

00:15:48.820 can induce the nerves to secrete nitric oxide, which will then go to the endothelium. This is

00:15:54.260 the key. The endothelium will secrete nitric oxide, which is really the on-off switch. Once

00:15:58.720 the nitric oxide goes up, we get an increase in something called cyclic GMP. Cyclic GMP causes

00:16:03.900 intracellular calcium to go down. It causes the dilation of the sinusoids and increases the blood

00:16:08.860 vessel diameter and the blood comes in. Now there's a bad thing there. There's something

00:16:12.520 called phosphodiesterase and phosphodiesterase eats up the cyclic GMP and therefore you will

00:16:18.680 lose the erection. So how does Viagra, Cialis, Levitro work? It's a phosphodiesterase inhibitor.

00:16:25.140 So it blocks phosphodiesterase so you have more cyclic GMP so you can keep the erection around.

00:16:30.760 Now there's 11 different phosphodiesterases in the body. So for example, type 5 is in the penis,

00:16:35.920 6 is in the eye, 11 is in the back. So some of these medications have cross-reactivity with the

00:16:42.120 other phosphodiesterases so you get side effects. For example, Cialis has more side effects with

00:16:47.700 phosphodiesterase type 11 so you may get more back pain. Viagra has more cross-reactivity with type 6

00:16:53.560 so you may get changes ocular vision. So ideally you want one that only affects 5 and nothing else.

00:17:00.220 And is there one to date that does that?

00:17:02.040 In my opinion, the newest one, Avanaphil, has the least cross-reactivity with the other

00:17:07.400 phosphodiesterases. So I think it has less side effects. The only difference is that it is not

00:17:13.420 generic yet so it's expensive.

00:17:15.040 Much more expensive.

00:17:15.780 Yeah. So the generics now, if you go to Cost Plus or Mark Cuban's or you go to GoodRx,

00:17:20.320 it is so cheap to get Cialis today. But Avanaphil is still not generic.

00:17:26.340 Do you want to tell people the story of how Viagra was developed?

00:17:31.220 So Viagra was developed to be a blood pressure medication to control the blood pressure. And

00:17:36.340 they started noticing that everyone was getting, or cardiovascular medication, everyone was getting

00:17:40.080 erections in the trial.

00:17:42.280 Everyone who got the Viagra as opposed to the placebo.

00:17:44.740 Very interesting. Other drugs were the same way. You may have heard of the drug Adi. We use this to

00:17:49.100 treat female sexual dysfunction or flibanzarine. That was used as a medication for depression. It was by

00:17:54.780 Borough in England in Germany. And so they give it to women for depression and they noted these 0.81

00:17:58.220 women wanted to have sex. And that's how we got the development of Adi. 1.00

00:18:02.020 And my recollection is Viagra was not successful as a systemic reducer of blood pressure. In other

00:18:06.980 words, that trial failed.

00:18:08.880 Right.

00:18:09.220 And what I read, I don't know if it's true, but what I read was the trial failed. It was Pfizer,

00:18:13.680 I believe, that had developed the drug. So as their kind of tail is between their legs and they're

00:18:17.340 saying, well, that sucks. We just lost all this money on a drug that doesn't treat blood pressure.

00:18:21.940 But what they noticed was a difference in the samples being returned. So the patients who were

00:18:28.160 on the placebo were very happy to send their samples back. And somehow the majority of patients

00:18:33.100 on the treatment drug, Viagra, which wasn't called Viagra at the time, of course,

00:18:37.020 were disproportionately keeping it, which then prompted them to ask follow-up questions and say,

00:18:41.340 why are you keeping it? And that's how they sort of backed into this unintended consequence,

00:18:45.680 which is amazing in that it went from a ho-hum blood pressure drug that would have had a market

00:18:50.780 size of this to a market size of this.

00:18:53.900 And it was a game changer in my field. So in our field, sexual medicines, I'm part of the

00:18:57.560 sexual medicine side in North America, game changer in the way we treat men for ED.

00:19:02.260 We'll come back to this, I suppose, but we'll put a pin in it. There isn't probably a single drug

00:19:07.400 that has had that effect on women's sexual health, is there?

00:19:10.260 You know, the first drug that ever came out was in 2015 called Adi. The second drug was called

00:19:15.520 Vilesi, but not even close to the impact that Viagra had in men. Both are excellent drugs.

00:19:21.840 And they're more about desire.

00:19:23.300 They're more about desire. And we are learning that they may have some other functions as well,

00:19:27.620 off-label like orgasmic function. Both are good drugs, but they just really never took off

00:19:31.920 like Viagra.

00:19:33.240 It might be that the single most potent agent for women's sexual health, at least as a woman is aging, 0.92

00:19:38.420 is actually HRT. It's probably that estrogen has the greatest single impact.

00:19:42.800 There is a synergistic effect because if you use HRT and you use these medications,

00:19:47.020 because of different mechanisms of action.

00:19:48.180 That's right. They're accretive in their-

00:19:49.620 Yes.

00:19:50.540 Okay. So this phosphodiesterase inhibitor, which now we're into our third generation of them,

00:19:55.720 basically solve a physiologic problem.

00:19:58.360 Right.

00:19:59.000 So what is at the root of that problem? I mean, I understand that by inhibiting phosphodiesterase,

00:20:04.960 you keep around more cyclic GMP. You maintain the flow of blood in the smooth muscle. But what is it

00:20:12.380 about the aging process and or its comorbidities that is leading to that venous leak in the first

00:20:18.020 place?

00:20:18.600 You nailed it. So the main issue is venous leak, or we call a veno-occlusive dysfunction.

00:20:23.520 You have to think of anatomy. So it's actually very clever how the system was designed.

00:20:27.640 So if you think of the two tubes I was talking about earlier, inside those two tubes are muscle

00:20:31.740 and sinusoids. Down the center of the tube is an artery. And think of the wall of the tube as a

00:20:37.620 thick casing called the tunica albigenia. Right under the tunica albigenia are veins. We call

00:20:43.820 it subtunical veins. So as the blood comes in, it presses against the wall and prevents the blood

00:20:51.440 from coming out. So very clever system. The more blood comes in, the muscle can get pressed against

00:20:55.880 the wall and prevent the blood from coming out of the penile tissue. The problem is as we age,

00:21:01.620 we get atrophy of the muscle and we get fibrosis of the muscle. So as we get atrophy and fibrosis

00:21:07.100 of the muscle, we are able to get the blood in, but we can't keep the blood in.

00:21:12.140 Because we can't maintain enough pressure on the venous wall.

00:21:15.260 That's right. And so how do you overcome that? There's several ways. One is that you can actually,

00:21:21.400 so it's a simple outflow-inflow game. So if the inflow is 10 and the outflow is 15,

00:21:26.480 you're not going to get an erection. But if you give someone Viagra and you make the inflow 25,

00:21:32.180 you can overcome the venous leak by increasing the inflow. That's one way.

00:21:36.360 The second way is actually some people use something called a penile band.

00:21:39.780 Like a tourniquet.

00:21:40.480 Like a tourniquet. Because if you use a tourniquet, you can actually compress the veins

00:21:45.180 and still allow the inflow. So if a man-

00:21:47.460 So you haven't fixed the inflow problem, but you've increased the back pressure on the outflow.

00:21:51.120 That's exactly right. So if a man took his hand while he's having an erection and placed his hand 0.75

00:21:55.100 and grabbed the penis at the five and seven o'clock position, put pressure, you'll notice that you'll get 0.98

00:21:59.360 better and better erection because you're blocking the outflow. But you can't keep your hand- 0.98

00:22:03.120 And tell people why you said five and seven o'clock.

00:22:05.360 Well, it's circumferential.

00:22:06.640 Oh, it is. Okay.

00:22:07.360 It's circumferential.

00:22:08.120 I thought the veins were disproportionately-

00:22:09.500 Yeah, it's circumferential. But if you put your hand there and it gives you almost a 180

00:22:12.360 protection.

00:22:12.900 I see. Okay.

00:22:13.640 So it's circumferential, but-

00:22:14.840 So it's not like the fingers where at about five and seven-

00:22:17.660 No, it's all the way around.

00:22:18.520 We have the majority of our venous occlusion.

00:22:20.180 Okay, got it.

00:22:20.600 That's why if you apply a tourniquet, you actually prevent venous leak. But most people say,

00:22:25.320 I don't want to use a tourniquet. I say, it's fine. Just increase the inflow. That's why we use

00:22:29.000 intracalvinoso injections. We'll use Viagra. I mean, there's ways we can significantly increase

00:22:33.160 the inflow to overcome the outflow. But aging, aging does cause a venous leak. We know that lower

00:22:39.300 testosterone levels have been implicated for causing venous leak because it's atrophy of the

00:22:43.060 penile muscle. I do a lot of a procedure called a penile prosthesis, and I have a lab. So what I

00:22:47.240 do is we have a protocol where we can take the tissue, the penile tissue at that time, we send

00:22:50.960 it to the lab, and then we'll look at it. High, high density of androgen receptors within the penile

00:22:55.160 tissue. As the androgens go down, you can start getting atrophy of the penile muscle. 0.64

00:22:59.240 That is very interesting. And I do want to come back to the intracellular and nuclear

00:23:05.920 distribution of androgen receptors, testosterone, and DHT. So again, I'm trying to keep track in my

00:23:11.240 mind of all the things I want to come back to. If you said to me, Peter, how can an aging person

00:23:16.320 prevent atrophy of their muscle? The most obvious thing that comes to my mind is use it. It's a use

00:23:21.340 it or lose it system. Is the same true of the penis? It's very true. So if you look at patients who 0.99

00:23:27.700 are not using the penile muscle, for example, let's look at patients who have a radical prostatectomy.

00:23:32.480 Very unfortunate. Young man, say he's 52 years old, and right after that surgery, he's not using the

00:23:39.460 penile tissue, you will start getting atrophy of the muscle just if I put your arm in a cast today.

00:23:44.480 So regular erections, so nocturnal erections are very important also. So that's how we get our

00:23:49.500 oxygen into the penile tissue through the nocturnal erections, through sexual activity. There are studies 0.93

00:23:54.300 suggesting that daily PD-5 inhibitors, Cialis, Viagra, can help with hypertrophy of the cavernosal

00:24:00.480 smooth muscle. So that's why I particularly like to give patients daily Cialis because-

00:24:05.480 Even if they don't have ED?

00:24:06.860 So let's think about this for a second. I just mentioned earlier that 40% of men have ED at 40,

00:24:11.440 50% at 50. It's an aging process, right, to some degree. So when you take Viagra, you are not curing

00:24:18.600 your ED. You're just covering it that night while the disease continues to progress. But daily Cialis has

00:24:25.600 been shown to cause hypertrophy of the cavernosal smooth muscle, keep the tissue healthy. So in many

00:24:30.920 ways, I look at daily Cialis as a preventative measure to keep the tissue healthy. Now, I tell

00:24:36.260 patients, when is the best time to start? When you start noticing if there's a mild degree of ED,

00:24:40.980 something starting to show up for ED, that's when I want you to start taking the daily Cialis,

00:24:45.520 not only to help you with what your issue is, but I look at, to me, as a preventative measure.

00:24:50.300 You talked about daily Cialis. My recollection is that there were basically two dosing strategies,

00:24:56.680 right? There was 20 milligrams. The idea, I think it was, you know, hey, take 20 milligrams on Friday

00:25:02.620 and it'll hold you through till Sunday and you can basically, you know, have sex on demand.

00:25:07.480 Alternatively, it's having five in your system every single day produces the same tissue level. Is that

00:25:12.140 directionally right? Close. So the conversion is 1.6 is the multiplier. Okay. So if you take five

00:25:17.860 milligrams every day, it's like having almost like eight milligrams in your system, eight,

00:25:22.780 that's the conversion is 1.6. So eight is obviously less than 20, but some men really don't need 20.

00:25:28.160 So that five daily, and remember, there's other benefits. Five daily has been FDA approved for BPH

00:25:33.120 and we'll talk about BPH and ED. Oh, didn't know that.

00:25:35.800 FDA approved. So you can give someone Flomax or you can give them daily Cialis.

00:25:39.320 Well, the problem with Flomax is retrograde ejaculation.

00:25:41.500 Got it. So the young men, if they had a choice, he'll say, I'll take the Cialis and a side effect

00:25:45.500 there'll be better erections. So FDA approved for BPH.

00:25:49.800 Why? What's the mechanism?

00:25:50.640 So mechanism unknown. That's what's a little bit interesting.

00:25:53.520 Wow.

00:25:53.920 We do know, it even says in the packet, mechanism unknown, but we do know that IPSS scores,

00:25:58.980 these are urinary symptom scores, do improve in men who take daily PD5 inhibitors. That's true.

00:26:04.480 So you just have to be careful not to, if you do take Cialis and a Flomax medication,

00:26:09.700 not to take them too close together as a warning because you can get a little hypotensive.

00:26:12.600 So we have to separate them. But daily PD5 inhibitors are also FDA approved for pulmonary

00:26:17.960 hypertension.

00:26:18.820 That I knew.

00:26:19.280 And there were wonderful studies looking at daily Cialis versus on-demand Cialis showing

00:26:24.800 that the patients who took it for four weeks daily, significant improvement in endothelial

00:26:28.480 dysfunction. And we'll talk about that later, but endothelial dysfunction outside of the penis?

00:26:32.140 Outside of the penis. 0.99

00:26:32.880 Meaning systemic. 0.99

00:26:33.620 Systemic. And they were looking at blood markers, IL-6, C-reactive protein, not so specific.

00:26:37.900 They were looking at flow median vasodilation, brachial artery. And they were showing that

00:26:42.080 even if the patient stopped, this was a study by Aversa, even if the patient stopped the daily

00:26:46.340 Cialis versus the on-demand, those patients who took the daily still had persistent improvement.

00:26:50.820 So maybe, there may be something going on in the endothelium as well. So I think about

00:26:54.620 endothelium, I think about pulmonary hypertension, I think about BPH, I think about ED, it's five

00:26:57.780 milligrams daily, very affordable. Okay. Maybe we can-

00:27:00.660 What would you say is the biggest downside of Cialis?

00:27:02.600 I used to say cost, and it was unbelievably expensive.

00:27:05.560 How much did Cialis cost?

00:27:07.220 It was almost $15 to $20 a pill.

00:27:10.040 $15 or $20 for a five milligram?

00:27:11.780 Well, it was a 20 milligram pill, but it was still absorbent. It was almost $400 for a 30-day

00:27:16.640 supply of five milligrams, which was unbelievable. So then we started going to the compounding

00:27:20.820 pharmacies. We said, okay, the compounding pharmacies said we can make it for a dollar

00:27:24.260 a pill. That's great.

00:27:25.580 But it's hard to trust the quality, right?

00:27:27.180 Some are better than others, and some compounding pharmacies are FDA approved. So that makes it a little

00:27:30.740 bit better. But then the generics came out, and it was shocking. If I give a patient who goes to

00:27:35.960 HEB, they can get 90 pills of Cialis for $17 with no insurance. 90 pills, $5 million.

00:27:43.120 And are you concerned? I've become very concerned with the quality of generics and realizing that

00:27:48.300 not all companies are the same. Like Sandoz is a good company, but some companies are. Do you have

00:27:53.360 preferred brands of generics that you fancy?

00:27:56.480 I don't have a preferred brand, although I haven't seen the generics significantly less

00:28:01.760 effective than the brand when it comes to PD-5 inhibitors. That's one thing that I think I have

00:28:07.120 not seen it less effective.

00:28:08.680 That's great to hear. This is sort of indirectly related to ED, but what about refractory period?

00:28:14.080 So any guy listening to this can think back to being in his 20s where you seem to be able to 0.68

00:28:21.640 have an erection, ejaculate, and seven minutes later have another erection. You could have 0.99

00:28:26.440 intercourse 27 times in a day. And then something happens when you get older, those days are done.

00:28:31.720 Like you might get two a day.

00:28:32.920 Sure.

00:28:33.600 Is that considered a lagging or leading indicator of ED? Is the fact, like what's different about that

00:28:39.720 20-year-old versus the 50-year-old?

00:28:42.120 Yeah. So there's no question that the refractory period goes up as we age. One of the implications for

00:28:47.420 refractory time is prolactin. So when you have an ejaculate, your orgasm, your prolactin levels go

00:28:53.260 up. And that's been implicated as the reason for the refractory time. But as men get older, you're

00:28:59.100 right, ED is more prevalent. So it's harder to get the next erection and the refractory times go out.

00:29:05.840 And I'm sorry, is there anything different about the prolactin secretion?

00:29:09.540 I've never seen a study showing that, although I would intuitively think the prolactin may be

00:29:13.920 long for a longer period of time, but I have not seen any study showing that.

00:29:18.760 So that might be the indication basically that even if you don't have ED, things are changing.

00:29:24.000 Your physiology is changing.

00:29:25.360 Absolutely. And I think the majority of it is, it is more difficult to get an erection 0.98

00:29:30.280 as we get older. And therefore that contributes to the refractory time.

00:29:35.380 It's so interesting how evolution simply, you would argue that, you know, not that we want to spend too

00:29:40.480 much time speculating on evolution, given that as Andrew Huberman would say,

00:29:43.460 and neither of us were there for the design phase. But it's interesting in that you can

00:29:47.480 certainly understand, I think, in the case of women, why based on the change in reproductive 1.00

00:29:52.320 state, evolution didn't care as much about their sexual health as they got older. Is the same true 1.00

00:29:58.440 for us where evolution sort of thought, eh, the older you get, the more genetic mutations in your

00:30:04.540 sperm. I actually don't want you reproducing as much when you're 50 as you are when you're 20.

00:30:09.000 I don't know about that. We have patients who are older that have great semen parameters. I think

00:30:14.240 it's based on your quality of your health. Healthier men-

00:30:17.680 Which, by the way, would make sense.

00:30:18.980 It makes sense because you're more likely to reproduce. So if we look at men who are in their 0.83

00:30:22.300 80s, who are in great shape, they're having sex, no issues, no even unassisted.

00:30:27.100 Meaning they don't even require, they use a bit of eye growth.

00:30:29.580 Yeah. But some do, some don't. I mean, I have patients at 70, 80 years old, great shape,

00:30:34.380 no issues having erections. The patients that come to me who are older, 60, 70, who are also

00:30:40.160 trying to conceive, they marry someone younger. And you'll be surprised. Typically, sometimes you

00:30:44.840 will see patients with sperm or hepatogenesis, even at older ages. It's based on your quality of

00:30:49.820 your health. You know, I have younger patients who are 30 that are in terrible shape, poor quality

00:30:53.880 erections, terrible semen parameters. So I don't know if age is like the main driver.

00:30:58.200 No, I think that makes sense. And I think I talked about this with Sharon on the podcast,

00:31:01.840 but I almost wonder if the greatest motivation for a patient, especially a male patient,

00:31:07.440 with respect to insulin resistance is actually erectile function. Because definitely one of the

00:31:13.760 things I've seen in my practice is that patients who go from having a higher hemoglobin A1c to a

00:31:20.880 lower hemoglobin A1c will often notice an improvement in erections. Again, I'm not talking about a

00:31:26.660 one-point change. But if someone goes from having a hemoglobin A1c from 5.9 to 5, which represents

00:31:33.680 probably about a 25 milligram per deciliter reduction in average blood glucose, that's a

00:31:40.260 person who says, I used to need Cialis for every erection to, I'm totally fine.

00:31:44.560 So you bring up a really important point. It's lifestyle modification. Lifestyle modification has

00:31:49.060 a huge impact on the quality of a man's erections. And the four pillars that I stress all the time

00:31:53.980 for most sexual dysfunctions, diet, exercise, sleep, and stress reduction. If you chose to do

00:32:00.560 one of them, it would have an impact on your quality of erections and your quality of life. 0.99

00:32:04.500 And there's other manifestations that would improve as well. But you're talking about insulin

00:32:08.080 resistance. And when you improve insulin resistance, when you improve obesity, stop smoking, all of

00:32:13.400 these things improve. Now, I think there's a reason for this. There's a strong correlation

00:32:17.960 between cardiovascular disease and ED. If I made a column of the risk factors for ED and

00:32:24.560 cardiovascular disease, they're almost identical on both sides. So I say, what is the common link?

00:32:29.440 Why is ED? So many studies say that if you get ED today, within seven years, 15% of those men will

00:32:35.300 have a card attack or a stroke. 15%. It's the first sign of cardiovascular disease. Numerous studies

00:32:41.160 have shown that.

00:32:41.920 And just to be clear, this is not psychogenic ED.

00:32:44.880 Organic. Has to be.

00:32:45.780 So, and say that again. What percent? 15% of men-

00:32:48.640 So, in 2004, Ian Thompson had the prostate cancer prevention trial. Roughly 4,000 men did not have

00:32:54.320 ED, healthy men. He followed them prospectively. From the day they developed ED, 15% of them in seven

00:33:01.520 years had a cardiovascular event. That's significant. And he wasn't the first. Numerous studies have shown

00:33:06.880 a correlation between ED and cardiovascular disease. Montorsi that same year showed that

00:33:11.440 if you had a cardiovascular event, 50% of those men had ED 39 months prior to having the cardiovascular

00:33:16.720 event. It is the sentinel sign of cardiovascular disease.

00:33:20.100 So it's a real canary in the coal mine when it comes to microvascular health.

00:33:23.860 Particularly if it's arterial insufficiency. So the question is, what's the relation? So one

00:33:28.300 theory was arterial diameter theory. And it doesn't make a lot of sense, but this is the theory.

00:33:32.520 If you look at the penile arteries, they're one to two millimeters. The coronaries are three to four

00:33:36.740 millimeters. The peripheral arteries are six to seven millimeters. And if you get 50% occlusion of

00:33:41.180 an artery, you know you get an organ damage. So you're more likely to occlude the penile artery

00:33:45.040 before you occlude the coronary, coronary before the peripheral. So that was the theory. Now, 0.91

00:33:49.300 it doesn't work very well because most of ED is, you know, occlusive disease. And really,

00:33:53.400 it's the pudendal artery, not cavernosal artery. But that was one theory. The most prevailing

00:33:57.660 theory is endothelial dysfunction. That is the common link between ED and cardiovascular disease.

00:34:03.780 Well, the cardiologists were very clever before the urologist to show that if you improve

00:34:08.160 endothelial dysfunction, you can actually reverse cardiovascular disease. So if that's the common

00:34:13.760 link, as urologists, we just copy them. Well, two of the three biggest risk factors for

00:34:18.800 cardiovascular disease are taking aim at the endothelium. So the three big ones, ApoB,

00:34:24.140 that's not an endothelial issue, but smoking and blood pressure are, one being a chemical,

00:34:28.860 one being a mechanical disruption of the endothelium. And I suspect both blood pressure

00:34:32.520 and smoking- Are high risk factors.

00:34:34.140 Elimination would mediate ED.

00:34:36.500 For sure. Obese, diabetes is one of them also. This is called reversal. The best study I ever saw

00:34:42.300 was Esposito, 2004 in JAMA. She just simply said, I'm going to give you a diet and exercise program.

00:34:48.600 110 obese men, 55 went on a diet and exercise program, 55 went on nothing. And she followed

00:34:55.240 them for two years prospectively. If you simply had diet and exercise, you lost weight. It was a

00:35:00.500 Mediterranean diet, by the way. I really believe in the Mediterranean diet. If you lost weight and

00:35:04.200 took the Mediterranean diet, you saw three point, which was significant increase on the IIEF score.

00:35:09.740 This is on that six point scale?

00:35:10.960 On the six questions after 25, you know, but a three point and on the IIEF with no Viagra,

00:35:18.000 no intervention except diet and exercise alone.

00:35:20.420 Does that three point increase translate to a clinical meaningful improvement?

00:35:23.860 Close. Usually it's four. So it's pretty close. And the meaningful improvement is broken down into,

00:35:29.480 think of this as two, five, and seven. If you have mild AD, you want to see at least two,

00:35:34.220 moderate AD five, and severe AD seven.

00:35:36.380 Depends where they started.

00:35:37.300 It's the way they started, right? But typically you want to see about a four,

00:35:39.920 but even just a three, just on diet and exercise alone, they saw improvements in

00:35:43.660 endothelial function in terms of IL-6. They lost weight. I mean, just diet and exercise alone

00:35:48.180 reversed or had an improvement in AD. So lifestyle modification is very important

00:35:53.100 when we talk about sexual dysfunction.

00:35:55.560 So let's go back to what you were saying in the office, some of the diagnostic tests. So a guy comes

00:35:59.040 in, you quickly, or maybe not quickly, but you rule out psychogenic AD, and now you're realizing

00:36:04.640 this is something physiologic. So you mentioned a diagnostic ultrasound. So you're doing an

00:36:08.080 ultrasound of the penis. You inject something into the penis to induce an erection? 1.00

00:36:12.040 Yes. So we typically inject Trimix, which is a medication that's compounded. You can actually 0.99

00:36:16.580 also inject Alprosadil, which is commercially available, like EDEX.

00:36:20.720 And you're injecting this into the corpus?

00:36:22.240 Into the corpus, and it will cause a vasodilation.

00:36:24.840 And just because every guy listening to this is freaking out saying that you're sticking a needle 1.00

00:36:28.720 in my penis. 1.00

00:36:29.400 Right. But you'd be surprised. 1.00

00:36:30.580 Not in the urethra.

00:36:31.300 Not in the urethra. At the base of the penis, we inject it at the 2 or 10 o'clock position. 0.98

00:36:35.680 And within 5 to 10 minutes, it induces a very good erection. But what we're able to do with that 0.98

00:36:40.680 is we're able to look at something called the peak systolic velocity. If the peak systolic

00:36:44.800 velocity is less than 30, particularly if it's less than 25 millimeters per second, he has arterial

00:36:49.660 insufficiency. Now that's important. That means not enough blood flow is coming into the penile tissue.

00:36:54.020 If the end diastolic velocity is greater than 5 millimeters per second, then he has a venous leak.

00:37:00.420 So that's important. So I can now see if there's a hemodynamic problem going on in the penile tissue.

00:37:05.780 And just so folks understand this, right? Diastole, or let's start with systole. Systole is what's 0.97

00:37:11.000 happening when the heart is contracting. So you think about that as the flow out. Diastole is when the

00:37:18.400 heart is relaxing. In itself, it's filling. And so you're measuring kind of backflow through the

00:37:23.600 venous system. Right. And that venous leak is important because remember, that's the number

00:37:26.500 one cause. That's half the problem. The majority of the patients who have ED will start out with

00:37:29.820 venous leak. So, but then there's other- Just to be clear, the venous leak is usually

00:37:34.060 happening before you see arterial insufficiency. In most cases. And what's important is you can also

00:37:39.100 look at the corpora cavernosa. I can look at plaque. I can look at plaques. That plaque's important

00:37:44.000 because that's what causes an abnormal curvature. You actually see plaque in the muscle?

00:37:48.540 Not in the muscle. So in the wall, the tunica albiginia. So think about the two tunica albiginia

00:37:52.640 coming together. As they come together, in that V is where you see the plaque predominantly.

00:37:57.920 Most of the plaque happens in the V. So most curvature in the penis is dorsal. So it actually 0.88

00:38:02.800 goes upwards. So 80%. And so these patients will have a curvature of the penis when it's erect.

00:38:08.360 It's important when it gets greater than 60 degrees because that's prohibitive for intercourse. 0.77

00:38:13.300 And it is- 60 degrees.

00:38:15.000 So patients can have 90 degrees. They can have almost 180 degrees. It can be very significant.

00:38:19.880 Wow.

00:38:20.120 That is a very significant disease. Patients who have Peyronie's disease really suffer from

00:38:25.440 depression. They feel like there's a disfigurement. There's a treatment now. In 2015, the first FDA

00:38:30.160 approved treatment in the world came out for Peyronie's, which is called Xiaflex or collagenase,

00:38:34.500 where I can inject collagenase into the plaque and break it down so that I can improve the curvature.

00:38:40.680 So that's very important because historically, until 2015, we had no medical treatment. Everything was

00:38:45.740 off-label.

00:38:46.440 And what would that include?

00:38:47.480 So people used to give vitamin E and they used to give colchicine. So in 2015, I was involved in the

00:38:53.820 American Neurologic Association, Peyronie's guidelines, first guidelines. And we said,

00:38:57.800 do not give vitamin E. It's not indicated. Colchicine doesn't work. But the only medication

00:39:01.980 that's indicated are anti-inflammatories. The way Peyronie's works is-

00:39:05.760 This is administered locally or systemically?

00:39:08.440 Systemically. So that's what we give. Think about this. The way Peyronie's disease works,

00:39:12.440 there's an active phase and there's a quiescent phase. So the day you have an injury for about 12

00:39:18.420 months, it's constantly changing. We have the rule called the 15-40-45 rule. 15% of patients will get

00:39:25.380 better within the first year. That's awesome.

00:39:27.040 Sorry, does this mean that Peyronie's disease is always born of trauma?

00:39:31.100 It's the prevailing theory. And sex is trauma, by the way. And so when a patient engages in sexual

00:39:36.580 activity, if he has 100% rigid penis, less likely to injure. If he's 70, 80, or 90% rigid, he's going 0.74

00:39:43.700 to penetrate and he's going to injure. So ED many times precedes PD, Peyronie's disease.

00:39:49.060 Interesting.

00:39:49.580 But we do think it's due to trauma during intercourse. That buckling trauma will then

00:39:54.400 cause a plaque. So I tell patients, think about this. You have a balloon. I put a piece of duct

00:39:59.800 tape on the balloon. I blow up the balloon. What's going to happen? Everything's going to expand except

00:40:04.580 the duct tape and you're going to curve in the direction of the duct tape. And the greater the

00:40:08.900 duct tape, the greater the curve. So how can I treat this? I can use medications to remove the duct

00:40:14.100 tape or the plaque.

00:40:15.060 And you can't incise, you can't put a slit in the duct tape?

00:40:17.700 You can. So that's the surgical therapy. But in terms of medical therapy, you can actually put

00:40:21.600 the injection called collagenase. It breaks it up and it can help straighten the penis. 0.87

00:40:26.140 The second thing you can do is actually surgical. You can put stitches on the opposite side and 0.82

00:40:31.160 plicate it to make it straight. Or I can cut out the plaque and put a patch, a graft to the plaster,

00:40:37.980 human pericardium. So we put a patch. Or if they have some erectile dysfunction with it,

00:40:43.020 then I put in a penile prosthesis. Because what's the point of making the penis straight if you can't 1.00

00:40:46.560 get an erection? In that case, I'd put a penile prosthesis. 1.00

00:40:49.020 And does a patient know if trauma is the predisposing factor? Is it apparent to him 0.54

00:40:55.060 that he has induced trauma?

00:40:57.400 Sometimes. Majority, no.

00:40:59.080 Oh, wow. So you can't even say if you act quickly, you have a better chance of salvaging this.

00:41:04.480 The only way is when someone has something called a penile fracture. A penile fracture is when they're 0.97

00:41:09.500 engaging in sexual activity and there's a sudden pop, a sudden injury that occurs, significant swelling 0.99

00:41:14.740 that occurs in the penile shaft. And you should seek immediate medical therapy. And usually it's 0.99

00:41:18.960 surgical. So you'll go to the ER. They'll call me on the phone and say, doctor, could we think we

00:41:22.360 see a penile fracture? We'll go in and we'll take him to surgery and we'll sew up the fracture.

00:41:26.140 And the fracture is what?

00:41:27.900 A break in the tunica albiginia, in the casing I was talking about earlier.

00:41:30.920 And the swelling is now because fluid is leaking out.

00:41:33.200 It's all blood.

00:41:33.840 It's a hematoma that's-

00:41:34.820 It's a hematoma. So you want to act quickly. But majority of men, because we always ask them on the

00:41:39.080 intake, do you remember any trauma? 90% say no. I have no idea why this is happening.

00:41:43.600 I'm completely freaked out why this is happening. How did this happen to me? And then you have to

00:41:47.640 say, did you know that 7% to 9% of men have this? You're not alone. This is very prevalent. And it's

00:41:53.500 very, very concerning for these men.

00:41:56.000 Age?

00:41:56.680 Age does affect. It's more prevalent as men get older. But I do think so. In 2009, I wrote a paper

00:42:03.460 looking at testosterone as a possible implicator. So we found that 74% of men had low testosterone.

00:42:09.960 And that's interesting because, you know, when you have low testosterone, you have decreased 0.68

00:42:13.020 rigidity of the penis. So I think you're more likely to injure. But testosterone has been 0.95

00:42:16.880 implicated for wound healing, really in the dermatologic literature as well. So it's almost

00:42:21.000 like a double hit. You're more likely to be less rigid and injure. You're less likely to heal.

00:42:26.060 Because many people have trauma, but they don't have a plaque. And so there has to be something

00:42:30.540 going on with the healing process. So these patients will have an injury, but then the way

00:42:34.780 they heal is it's a plaque that forms.

00:42:38.480 15% of men have this, or sorry, 7% to 9% of men have this. Is it painful or is it just

00:42:43.700 disfiguring?

00:42:44.360 Yeah. So at the beginning, there's an active phase for 12 months. And in that 12 months,

00:42:48.940 it's the 15, 40, 45 rule. 15% of patients get better. They just get better. 40% of patients

00:42:55.140 stay the same. 45% of patients get worse. In the active phase, it's typically associated

00:43:00.920 with pain. Every time I get an erection, I'm having pain. The patient, you say, look,

00:43:05.360 I'm not going to operate on you. Because if I operate on you and you happen to be the 45% 1.00

00:43:09.540 that get worse, I'm going to have to operate on you again. It hasn't stabilized.

00:43:12.240 It hasn't remodeled fully.

00:43:13.220 It's not finished. So when I get to the quiescent phase-

00:43:16.080 Which is a year.

00:43:16.800 About a year, sometimes a little less, sometimes a little more, but about a year, I say,

00:43:19.680 have you noticed any changes that have occurred? No, doc, it's pretty stable. Is there any more

00:43:24.220 pain with an erection? No, there's no more pain. Okay. Now do you want to consider a surgical 0.95

00:43:29.360 option, which would be an option? The other treatment that's off-label for this, that's

00:43:34.160 gotten a lot of favor, is traction devices. So that's been very commonly used. And these

00:43:39.100 devices are devices that are- I use one on my neck, but I'm guessing it's different.

00:43:42.300 The same concept. Same idea, yeah.

00:43:43.500 Any part of the body is pliable. People wear braces because it changes. So constant traction

00:43:49.200 can make the penis longer, wider, but straighter. 0.99

00:43:53.100 How do you actually apply a traction device to the penis? 0.97

00:43:55.520 There is a portion of the device that goes around the glands and basically clamps the 0.92

00:43:59.160 glands. Then you have ability to extend the traction-

00:44:02.500 The glands is the head for folks listening, yeah. 0.99

00:44:04.900 And the base goes at the base of the penis as well. And you can extend it as far as is 0.97

00:44:10.120 comfortable. The one that I really like-

00:44:12.180 But this is on a flaccid penis. 1.00

00:44:13.440 Flaccid penis. The one that has gotten the most interest is the one out of the Mayo Clinic 1.00

00:44:18.060 called the Restorex. Because the Restorex, you actually bend it in the opposite direction

00:44:22.820 where you're curving in the flaccid state. It actually bends. So if you're curving up,

00:44:25.960 you can bend it down. If you're curing it left, you bend it right. And you hold it there for 30

00:44:29.680 minutes, at least twice a day, for three months, has been shown to have about 30 to 40% improvement

00:44:35.100 in curvature. So penis larger, wider, and straighter, but you got to do the work. They're 0.96

00:44:40.720 about $500, a little pricey, but they are effective.

00:44:44.220 And I know somebody listening is going to think, well, wait a minute. If you don't have

00:44:47.120 Peyronie's, can you still use this device to increase length or girth?

00:44:50.660 So these devices actually came from the porn sites. So before we started using them medically

00:44:54.720 in 2010, porn sites were using them to increase length and girth. And they do. And actually,

00:44:59.280 many patients will come to me-

00:45:00.380 By what percent?

00:45:01.220 Usually about any from one to one and a half inch you can get.

00:45:04.120 What?

00:45:04.600 Yeah, one inch. I mean, it's not like-

00:45:05.980 That sounds like a lot to me.

00:45:07.160 Two centimeters at the maximum.

00:45:08.800 And is that a permanent change or is that only a change that lasts as long as you continue to use

00:45:14.260 the device?

00:45:14.700 We know that patients have to, there has to be some continued therapy. So some patients,

00:45:19.260 when they finish using it, will have some periodic use, say every month or every, excuse me,

00:45:23.720 every once a week or twice a week just for periodic use. But some studies will show up to two centimeters

00:45:28.040 you can gain in length. So it's not negligible. So we get patients to come all the time and say,

00:45:33.360 can you do penis enlargement surgery? I don't do that surgery, but I think that the stretcher is a 0.90

00:45:39.080 safe way without doing surgery to gain some length.

00:45:42.360 And the guy will use this for how long?

00:45:46.420 It's every day, twice a day for at least 30 minutes up to three months. The old stretching devices

00:45:53.520 were two to six, even up to six hours a day, but they were not bent in the opposite direction.

00:45:59.980 They were just straight. And so it was two to six hours a day every day for at least three months.

00:46:04.880 But the Restorex, because it's the ability, I think, to bend in the opposite direction,

00:46:08.500 you could shorten the time that you have to wear it 30 minutes twice a day.

00:46:11.480 Wow. Is there a critical window in which that works going back to Peyronie's disease where

00:46:16.700 you have to do it during that 12-month period and thereafter it becomes very difficult for it to

00:46:21.360 be successful?

00:46:22.080 Yeah. So the people have looked at active versus quiescent phase, and I think you get benefit

00:46:25.560 in both phases. In my opinion, I think it's better to catch it in the active phase while it's trying

00:46:30.260 to prevent further progression of disease. So let's think about this. A guy comes in the active phase

00:46:35.500 and he has 30-degree curvature. How do I define success? If I get that 30 down to zero,

00:46:40.660 that is awesome. I'm very happy. But what if I'm able to prevent that 30 from going to 70?

00:46:46.380 That's also success in the active phase. So because if he's greater than 60, it's prohibited

00:46:50.800 for intercourse. So typically, I like to, at least the stretching device, now the AUA guidelines,

00:46:56.580 I want to be clear, will say we should probably wait until the patient is in the quiescent phase.

00:47:01.660 The treatment is to give them anti-inflammatories, have them come back when they're in the quiescent

00:47:05.080 phase, and then start therapy. And then the AUA guidelines, we did not put in any stretching

00:47:09.220 devices as well. It wasn't mentioned.

00:47:11.460 So the entire use of the stretching device is off-label?

00:47:13.640 It's off-label.

00:47:14.260 Got it. And it's expensive. It's 500 bucks, but potentially worth it depending on the extent of

00:47:19.540 the damage. So going back again to the diagnostics. So you induce the erection chemically,

00:47:27.020 you look for arterial inflow and venous outflow. You diagnose, let's just say the problem is purely

00:47:35.180 on the arterial side. So venous problem, no issue. You mentioned you can still use the

00:47:40.500 phosphodiesterase inhibitor to compensate.

00:47:42.800 You can.

00:47:43.380 So how does the ultrasound result change your management?

00:47:47.420 It lets me know where the problem is. So if it's a venous leak, you can offer a band. You wouldn't

00:47:52.320 really want to offer a band if you didn't have venous leak because it's arterial insufficiency.

00:47:55.220 And it tells you how bad it is also. So if I see that the venous leak is end diastolic of 10,

00:48:00.980 15, it just tells you the severity of ED, which is very important.

00:48:04.640 Tell me what normal is again.

00:48:05.640 So you want less than five on the end diastolic. You want at least greater than 25 or 30, 0.84

00:48:09.600 preferably on the peak systolic.

00:48:11.400 And so what would the typical numbers be? Not that you're doing this on guys that have no issues,

00:48:15.380 but if you did this on like a 20-year-old who had no issues whatsoever, what would you literally

00:48:20.540 see as the number?

00:48:21.200 Peak systolic of 40, end diastolic of less than one.

00:48:23.400 Yeah. So nothing. And what's important is that remember that each corpora cavernosa

00:48:26.920 will have a different number sometimes.

00:48:28.400 So you're doing both sides.

00:48:29.100 You have to do both sides.

00:48:30.080 How often do you see significant asymmetry?

00:48:32.080 Usually it's not that significant, but sometimes you can. So I just want to be very clear.

00:48:35.740 You know, look, you're having some low peak systolic on the right, but not on the left.

00:48:38.960 You know, so it just gives you another diagnostic. Remember what's interesting about the penis 0.99

00:48:42.440 is it's fenestrated. So that whatever you have on one side compensates on the other. 0.99

00:48:47.320 So if you inject a medication on the right, it also gets to the left. So it's fenestrated.

00:48:50.840 So it does make it very easy. But you mentioned something important. You know, this peak systolic

00:48:54.920 velocity, if it's low in a young man, I am worried because I think it's a marker for

00:49:01.680 cardiovascular risk. There was this machine I was using in my fellowship. I was a fellow

00:49:05.440 and we got this machine called the Endopat 2000 and it would check endothelial function.

00:49:10.400 What is it called?

00:49:11.180 Endopat 2000.

00:49:12.160 I love that it has the 2000 at the end of it, reduces any credibility of the machine,

00:49:16.540 right? If it was just the Endopat, I'd be like, oh yeah, the Endopat, that's pretty

00:49:19.420 cool. But Endopat 2000 just sounds like nonsense.

00:49:23.320 It was Endopat 2000 and that's when we came out. It was by an Israeli company, but we used

00:49:26.940 to put a blood pressure cuff in one arm and then it would have a probe on the finger and

00:49:30.860 then a probe on the contraria finger. And we put super physiologic pressures, we'd release

00:49:34.220 it and you would measure the dilation in the finger as a marker for endothelial function

00:49:39.280 as a ratio between the two fingers. So in the Mayo Clinic in 2004, they were using this

00:49:43.420 device and then they would take the patient directly into the cardiac cath and then they

00:49:47.780 would look at cardiovascular blockage. And so they found that if you had poor endothelial

00:49:52.040 function in the finger, it was a marker for potentially occult blockage. So as a fellow,

00:49:57.740 I did the same thing. I would do the machine, take these results, then I'd take them into

00:50:01.600 the ultrasound room and do a pen ultrasound. And if they had poor endothelial function on 0.75

00:50:06.480 the Endopat, you would see a poor inflow of blood on the peak systolic artery. So there

00:50:12.380 is a correlation between the endothelial function and cardiovascular disease, but it's not common.

00:50:18.640 We see much more end-diastolic dysfunction than systolic dysfunction.

00:50:22.340 Now let's talk to some of those therapeutic options you mentioned. When is a man a candidate

00:50:27.480 for an injection and how long did it last?

00:50:30.860 So let's think about it. We used to have, in 2018, the guidelines came out in terms of therapies.

00:50:36.740 And we used to think of therapies as first level, second level, third level. We don't think of that

00:50:42.240 anymore. But the old level, first level was we start out with the pill, see how the pill works.

00:50:46.780 The pill could be Viagra, Levitra, Cialis, or Stendra is the newest, a PD5 inhibitor. In that

00:50:52.520 level, you should think about sex therapy. You should talk about lifestyle modification,

00:50:56.640 which is very important. And then the second level was injections. So if the medications no

00:51:02.220 longer worked, we would go into penile injections. And these injections are extremely effective. 0.84

00:51:07.620 It's just that-

00:51:08.100 What are you injecting?

00:51:08.640 So either Trimix, which is papavirin, fentolamine, and prostaglandin, it's three medications

00:51:14.260 injections into the penile tissue and it dilates the arteries. And it's very effective.

00:51:20.220 And-

00:51:20.540 Lasts for how long?

00:51:21.240 It's dose dependent. So you got to be very careful because if you inject too much, you

00:51:24.800 have a priapism. They have to go to the ER and I may have to surgically bring it down. 0.94

00:51:29.140 So the first injection should always be in the office and taught how to inject. And usually

00:51:34.160 I ask to bring the partner because 50% of the partners inject for their partners.

00:51:37.420 Oh, I see. So this is something where you inject, use it, and it should go away and you're

00:51:41.420 done. So you inject every time you need the treatment.

00:51:43.140 You inject every time you want to have sex. 0.98

00:51:44.260 I got it. 1.00

00:51:44.760 You inject every time you want to have sex within five- 1.00

00:51:46.280 At the base of the penis. 1.00

00:51:47.080 At the base of the penis, two and 10 o'clock position. And what we teach you how to do 0.99

00:51:50.700 it, and we have you slowly titrate up to finally get to 80% rigidity because we get the other

00:51:55.760 20% rigidity with foreplay. Once you find your number, whether it be 0.2 mls, 0.25 mls,

00:52:01.720 you use that number. The problem again, remember, is ED is a progressive disease. So many men will

00:52:06.500 start having to use higher and higher doses. Then they'll have to go to a higher strength solution

00:52:10.500 to a higher strength solution. And finally, the third level is a penile implant. Now in 0.94

00:52:17.000 today's new paradigm, we don't have the first, second, and third. We offer the patients all

00:52:21.940 the options. We use something called shared decision making. If a patient says, I don't

00:52:25.920 want to start with a pill, I want to start with an injection, that's fine. We don't use

00:52:29.480 the urethral suppositories anymore. We used to use them quite a bit in the past. It's a prostaglandin

00:52:34.500 suppository that you place into the urethra, and it causes a vasodilation in the penis. In 0.97

00:52:39.420 my opinion, they didn't work very well. They were good for combination therapy with-

00:52:43.500 Isn't that uncomfortable?

00:52:44.460 It can cause significant urethral burning. That is true. Some bleeding as well. And

00:52:48.020 they cause a little bit of hypotension in some patients as well. So we stopped using those.

00:52:52.360 But the penile prosthesis has been around now for 50 years. This year was 50 years, invented

00:52:57.000 a Baylor in 1973. And it is a phenomenal treatment option for ED.

00:53:02.160 And what does it look like in its current form?

00:53:03.820 There's been many iterations. There are two main suppliers. There's Boston Scientific

00:53:08.440 and Coloplast. And this device essentially is a procedure where we place two cylinders

00:53:13.300 or balloons inside those casings, the copra cavernosa. There's a small pump in the scrotum. 0.72

00:53:18.260 And there's a small reservoir behind the pubic bone typically, or underneath the rectus muscle

00:53:22.680 that holds normal saline. And all you're doing is when you want to engage in sexual activity,

00:53:26.580 you reach down, you press the pump, and it brings normal saline into those cylinders and 0.74

00:53:31.160 induces an erection. And when you finish engaging in sexual activity, you release it and all 0.58

00:53:35.560 the fluid goes back. 0.68

00:53:35.780 And so just to be clear, a man would still ejaculate normally.

00:53:39.520 Still has pleasure. 0.76

00:53:40.320 But he would still have an erection after ejaculation because he's not getting the signal 0.98

00:53:44.000 to turn it off. 0.92

00:53:44.920 He turns it off when he wants to turn it off.

00:53:46.680 Meaning physiologically, the erection's not going to go away.

00:53:49.500 It's not going to go away.

00:53:49.780 Until he defleets.

00:53:51.680 Exactly. So some men find that very favorable. So essentially, you have the erection whenever

00:53:56.680 you want, as long as you want. 0.94

00:53:58.680 So in other words, even if he ejaculates prematurely, he can still finish.

00:54:02.620 And the same goes with the injections. So a man who uses an injection-

00:54:06.480 Oh, the injection just goes away when it wears off.

00:54:08.780 When the drug wears off.

00:54:09.080 When the drug wears off.

00:54:09.580 So some men do use that recreationally. So what happens is even if you ejaculate with an 0.72

00:54:14.040 injection, you're not going to detumes.

00:54:16.580 How risky is that surgery?

00:54:18.080 I would say it's not very risky at all.

00:54:20.360 How long does it take you to do this operation?

00:54:21.500 About 45 minutes.

00:54:22.360 Under general anesthesia?

00:54:23.120 General anesthesia.

00:54:24.240 Every surgery has risks. So let's be clear. There are some risks associated with it. There's

00:54:27.460 a small percent of risk for infection. There's malfunction. But again, relatively very safe

00:54:32.720 procedure in my opinion. But it has to be with someone who has done a lot of these procedures.

00:54:36.940 Yeah. So if someone's listening to this and they think that, hey, I might be a candidate for

00:54:40.400 that, how many procedures do they want that surgeon doing? Like, you don't want to see

00:54:45.680 somebody who does one a year. How many of these are you doing?

00:54:48.580 I'm doing about 60 a year. I think at least 50 or greater. I mean, they're partner patients.

00:54:52.740 At least 50 to 60 a year, I think is very reasonable just to make sure that there are no issues.

00:54:59.120 When you do this for a first-time patient, what's the reoperation rate? Or what's the

00:55:03.180 malfunction rate? Or the rate of complication where you have to do something else?

00:55:06.420 Typically, the infection rate's less than 2%. But now typically, we'll say closer to 1%. So it's

00:55:10.980 not very common.

00:55:11.820 Do you use a prophylactic antibiotic?

00:55:12.860 I do. So typically, I use several things. I use vanc, gent, and I'll use antifungal as well.

00:55:18.820 Because we know that 10% of these infections can be fungal. And then we use a new arrogant called

00:55:23.640 aristocrat. 0.97

00:55:23.920 Vanc and gent. Why such big, big guns?

00:55:27.040 Because we're so worried about getting a... If you get a prosthetic infection...

00:55:30.260 Yeah, no, it's a disaster.

00:55:31.240 It's over.

00:55:31.900 So in other words, we're not going to just use first and second generation

00:55:35.020 slophilosporins and cover the skin. We're going all in.

00:55:38.520 So the vanc has to be in an hour before. If the vanc cannot get in an hour before, I'm okay with

00:55:42.420 sometimes using ANSEF and gent. But I use an antifungal...

00:55:45.520 But you're using gent.

00:55:46.020 Yeah, and gent for sure. And then what we'll do intraoperative is I now use Iricept. Iricept is

00:55:51.220 what a lot of the orthopedic surgeons use. And Iricept is chlorhexidine essentially,

00:55:55.160 but it's very good for fungal, anaerobic, aerobic, and it's a very effective medic. And it's cheap.

00:56:00.080 So we use Iricept intraoperatively. The benefit of some of these prosthetics is that they're

00:56:04.320 antibiotic-coded. So the Boston Scientific was antibiotic-coded with minocycline rifampin.

00:56:08.420 The Coloplast device is hydrophilic and you can dip it into the antibiotic and it takes it in.

00:56:13.600 The key is a short operative time. There's many things in the operating room that we do to mitigate

00:56:17.680 the risk of infection.

00:56:18.940 Do you wear the space suit like the orthopods do for joints?

00:56:21.380 We don't, but we limit the movement in the room. We tape the gloves. We make sure that there's no

00:56:25.460 movement in the light handles above. I don't have more than one person at the table across from me.

00:56:30.640 It's very important because if they get an infection...

00:56:33.400 It has to come out.

00:56:34.160 It has to come out. You can do a salvage, which means if I catch it early, I can take

00:56:38.140 it out and put a new one, but it's about an 86% success rate. So you just have, if you catch

00:56:41.980 it early, if they're septic, they have any kind of purulence, no salvage. You're not going to do it.

00:56:46.880 I mean, God forbid, just thinking worst case scenario. So if a guy is septic doing this,

00:56:51.020 you're pulling the whole thing out. Do you get another chance to put one in when he's

00:56:54.640 recovered?

00:56:55.420 That's a really good question. You wait three months to make sure everything's... But it is

00:56:59.480 much more challenging to get another one in, and it's going to be shorter, typically,

00:57:04.960 maybe even thinner also. Sometimes you call this a penile cripple. So you just have to be 1.00

00:57:10.000 very careful. You want to really mitigate the risk of infection. The same thing goes with someone who

00:57:15.020 has priapism. After 36 hours, the new guidelines will suggest that you can put a penile implant in,

00:57:21.180 and I strongly suggest... 0.66

00:57:22.480 Let's tell folks what priapism is.

00:57:23.940 Yeah. So priapism is a prolonged erection that lasts greater than six hours. So we tell patients 0.90

00:57:29.680 if it's longer than four hours, you should start seeking medical attention. The best example I can

00:57:34.380 give you is this. If I take a rubber band and put it around your finger numerous times, I'm cutting

00:57:38.480 off the blood supply. Well, how long does it take for that finger to start having necrosis and damage?

00:57:44.120 In the penis, at 36 hours, we say the chance of recovery is extremely low. So if someone says, 0.62

00:57:50.720 I've had an erection now and it happened on Friday and he shows up on Monday, I'm very worried. I'm 0.50

00:57:55.200 saying the chances of you recovering...

00:57:56.460 Let me understand what that guy is going through. Wouldn't he be in pain having had an

00:58:01.380 erection from Friday till Monday? 0.96

00:58:03.400 But is he just not seeking care because he's ashamed?

00:58:05.640 He's ashamed or he thinks it's going to go down, which is the worst thing that could happen.

00:58:09.580 And so majority of the patients are astute. They've been taught, hey, if you get an erection 0.98

00:58:13.860 greater than four hours, you need to come in. But very rarely, they sometimes will not. And then we're in 0.81

00:58:20.040 trouble. Because that patient now is, in my opinion, you have three months, if you want to

00:58:25.820 help him, three months to get a penile prosthesis in. Because if you try to get that in later on down

00:58:30.280 the road, I cannot tell you how much fibrosis and scarring is in that tissue. And for me to get the

00:58:35.860 penile implant in... 0.99

00:58:36.500 Can you do it on the day of admission? So for example, if that guy comes in having been 72 hours

00:58:41.120 with an erection and you're basically willing to make the call at 72 hours, we're not going to even

00:58:46.440 wait to see if you recover. Let me put the implant in right now before there's fibrosis. You have a 0.62

00:58:50.660 better outcome?

00:58:51.220 You can't, but you'll have almost a similar outcome if you do it within at least the first

00:58:54.480 three months. It doesn't have to be 72 hours. So sometimes we think it's better, especially...

00:58:58.880 So the problem is a lot of times the first thing that will happen is they'll get a shunt. A shunt

00:59:02.940 means someone will stick a needle or a knife down the glands or in the corpora and try to determess them. 0.58

00:59:08.200 And then you get arterial to venous connection.

00:59:10.000 Right. So if that happens, I don't want to put an implant in right away because you have a risk of

00:59:15.360 erosion slightly and you have a slight price for affection possibly because someone's manipulating

00:59:19.780 the tissue. So I said, let it calm down, come back in three weeks. And this gives us more time

00:59:24.180 to get the implant.

00:59:24.880 Do you do an ultrasound to make sure there's no shunt?

00:59:26.480 I do. So what's interesting is if you do a shunt, most of the time the patient the next day will

00:59:31.840 have an erection and the resident will call me and say, doc, it failed. It didn't fail. Now they

00:59:37.280 have a reactive hyperemia. They have a high flow. And if you ultrasound them, you'll find that they have

00:59:41.720 a high flow. So I said, wait a minute. It's the exact opposite. He presented with a low flow

00:59:45.180 venous outflow obstruction. Right. And you converted them, but the resident will call me and say,

00:59:50.160 he's got a high flow. I said, no, he doesn't. Get the ultrasound. Let's look. You get the ultrasound.

00:59:54.500 It's a high flow. You leave them alone. So high flows treated a little bit different. High flows,

00:59:58.460 typically someone had trauma. What is the etiology of priapism? I know it's a side effect.

01:00:02.600 So there's many causes. Of phosphodiesterase inhibitors, right?

01:00:05.600 But it's extremely rare. It's extremely rare. The most common cause typically is when someone

01:00:10.180 is injecting a Trimix or an agent and injected too much, but you can get medications like

01:00:15.580 Trazodone, cocaine. I mean, there's a lot of medications that can induce an erection

01:00:19.900 that won't go down. Interesting. Trazodone.

01:00:22.340 Trazodone. Which is ubiquitous now as a sleep agent.

01:00:24.960 Right. And it can cause priapism. And so- Is it dose dependent?

01:00:28.680 I don't know if it's dose dependent. Typically, most patients like 50 milligrams when they go to bed,

01:00:32.520 but I would assume that it could be. Interesting. So the moral of the story here is if you have

01:00:37.120 erection for four hours, go to the ER. Absolutely. 0.97

01:00:40.920 And when that patient comes to you in the ER, you make an incision.

01:00:44.100 Good point. So there's two things. The first thing I do is I put in phenylephrine.

01:00:47.600 So if it's less than four hours, I'll inject the antidote. So phenylephrine, and it'll usually work

01:00:52.900 if it's less than four hours. If the hours are greater and greater out, what I'll do is some

01:00:56.580 aspiration irrigation to try to get the old blood out and phenylephrine. If that doesn't work-

01:01:02.040 Sorry. Aspiration irrigation off the base of the penis. 1.00

01:01:04.460 Of the base of the penis. So we're using an 18-gauge butterfly needle, put it in, 0.99

01:01:07.560 and I'm injecting normal saline, and I'm aspirating. Many times we'll use coal saline.

01:01:11.400 We're just trying to get the sluggish blood out of the tissue.

01:01:14.560 Wow. Do they ever develop like clot, venous clot?

01:01:17.320 It is venous. That's what it is.

01:01:18.660 Oh, it has already clotted.

01:01:20.040 It's already clotted.

01:01:20.580 It's already clotted. I didn't realize that. Okay.

01:01:22.460 So you're basically trying to get all that clot and sluggish blood out. And so you'll aspirate-

01:01:27.580 Do you ever run heparin in it or anything like that?

01:01:29.300 We don't run heparin in it. Although if I do a shunt, sometimes people have advocated

01:01:33.860 starting him on heparin or Plavix to keep the shunt open. I usually typically use a low-dose

01:01:38.520 aspirin, but that's one thing you can do. So we aspirate, irrigate, then we put the

01:01:42.700 phenylephrine. If it doesn't work, then my favorite is a T-shunt. And a T-shunt is where

01:01:47.600 I take an 11 blade through the glands into the corpora, and then we have to sometimes use

01:01:51.500 a Hagar dilator and put it down.

01:01:53.500 You're doing this under local?

01:01:54.580 Well, this time I'll take him to the OR. It hasn't been described under local, but I

01:01:58.880 think it's just better to take him to the OR.

01:02:00.320 Less traumatic.

01:02:00.940 Less traumatic. And you have to counsel him, you know, if I do this Hagar and disrupt the 0.82

01:02:05.220 muscle, there's a high chance you're going to have erectile dysfunction, and we'll have

01:02:09.040 to deal with it.

01:02:09.960 How often do you induce Peyronie's in treating priapism? After treating the priapism, there's

01:02:15.540 now going to be a scar that results in this asymmetry?

01:02:17.980 I think the question is, when we use Trimix, if you use Trimix regularly, that is a risk

01:02:24.480 factor for Peyronie's. Because any repetitive trauma to the corporal cavernous is going to

01:02:29.660 actually injure the tissue.

01:02:32.140 When a man is injecting for ED, do you tell him to vary the site as much as possible to

01:02:38.140 avoid that trauma?

01:02:39.140 Yes. We tell him to inject opposite sides every other day. So you can't do it every day.

01:02:43.920 And inject opposite sides to mitigate the trauma that you're causing to the corporal cavernousa.

01:02:49.140 Okay. Last thing on ED I wanted to talk to you about is this device that a couple of my

01:02:53.800 patients have talked about. I think it's called Gaines Wave. What is it?

01:02:57.540 So Gaines Wave is just a company that uses devices for shockwave therapy. So I just have to give you

01:03:03.740 a little bit of history about shockwave therapy. In 2010, Dr. Vardy, a European study, was the first

01:03:09.680 to start using shockwaves to treat ED. Shockwaves are not new to urologists. We use high-intensity

01:03:17.040 shockwave for kidney stones.

01:03:18.740 That's what lithotripsy is, right?

01:03:19.360 Lithotripsy is. It's called high-intensity shockwave. This is called low-intensity shockwave

01:03:23.820 therapy or LIST. And when I first saw that, I'll be honest with you, I thought it didn't make a lot

01:03:27.880 of sense. I said, this is ridiculous. He's shocking the penis two to three times a week, three weeks, 0.98

01:03:33.380 2,500 shocks. What is he doing? But the science is actually quite clever. The science is you're 0.99

01:03:38.760 inducing trauma. When you induce trauma, you bring in neoangiogenesis. You actually recruit

01:03:44.600 stem cells. You help with nitric oxide synthase. So it actually is helping improve the condition.

01:03:50.680 We weren't the first. Cardiologists have been doing it for years. If you look at cardiologists,

01:03:53.720 they were shocking the heart. And they look at the reperfusion, and it was reperfusing the heart.

01:03:58.260 Orthopedics do it for joints, and they use it for plantar fasciitis. It's used for a lot of conditions.

01:04:02.940 But this was shocking the penis in 2010. So since then- 0.98

01:04:07.320 Again, pardon my ignorance, how is the device applied?

01:04:10.760 Think of it like a probe. And what happens, you have to have someone performing the procedure.

01:04:15.620 We divide the penis in six zones. So it's shaft, hilum, and cruce in two sides. So six zones. 0.97

01:04:22.800 And we will typically-

01:04:23.880 And so just explain where each of those is. 0.99

01:04:25.600 The shaft is obviously the shaft of the penis. The hilum is where the- at the base of the penis. 0.99

01:04:29.980 And the cruce is underneath the scrotum, because the penile tissues go underneath the scrotum. 0.96

01:04:33.840 So we will deliver 2,500 shocks in these six areas. And it takes about 25, 30 minutes. And 0.90

01:04:41.100 the patients will come in, and they'll come in at least one or two times a week for three or six

01:04:45.860 weeks. And they may have to have a booster. So when Vardy did it, he showed that-

01:04:49.440 And the probe is just right on the-

01:04:50.920 Right on the skin.

01:04:51.960 Is it painful?

01:04:52.480 It's not painful. It's well-tolerated. No anesthetic necessary. When Vardy did it,

01:04:57.300 he showed that there was improvement in penile blood flow, and men were having better erections. 0.82

01:05:02.040 So the issue is that there are two types of machines. There are machines that have a focal

01:05:06.820 shock, and those that have a radial shock. And the radial shock is 100 times less in terms of

01:05:13.880 pressure. It's over 1,000 times over in terms of time. So it's a longer shock. And it's less

01:05:20.080 penetration. And quite frankly, this is like a pneumatic machine. The pneumatic machine,

01:05:24.320 they do nothing. But they're not dangerous. So the FDA has called this a type 1 medical device,

01:05:29.940 low risk. Anybody can buy it. So you could be any profession, anyone on the street.

01:05:35.680 The going rate for these is 500 to $1,000 a shock cash.

01:05:40.800 Sorry, 500 to $1,000 for the machine?

01:05:42.620 One treatment.

01:05:43.260 For one treatment?

01:05:43.980 One treatment. One treatment. Machine cost-

01:05:46.160 But you said a guy needs two of these a week for three months.

01:05:48.700 Three weeks.

01:05:49.320 Oh, okay.

01:05:50.140 So six treatments, let's say. So anywhere from $3,000 to $6,000 for a machine that's a pneumatic

01:05:56.940 that does nothing, in my opinion. But the patient doesn't-

01:06:00.520 That can be bought by somebody at Costco.

01:06:02.900 You got it.

01:06:03.340 You could go to the gas station, and the guy could fill your tank and give you a little 0.97

01:06:06.940 scrotal zap. 0.98

01:06:07.700 You nailed it. And he can make $500 to $6,000. And the problem is that the ED population is 0.94

01:06:13.100 very vulnerable.

01:06:13.780 Because they don't want to go and ask somebody for help to think about this problem.

01:06:19.340 Right. And they're almost desperate. They want treatment. And the other problem is that

01:06:23.080 the ED population has a very high placebo response rate. If I gave 100 men a sugar pill, and I told

01:06:30.700 them that this sugar pill would give you the best erections of your life, 30% of men will 0.95

01:06:35.080 get the best erections of their life off the sugar pill.

01:06:37.020 And then, of course, they're going to tell their buddies, this is the best sugar pill

01:06:40.180 you've ever had.

01:06:40.680 So what you've seen now is an explosion of shockwave clinics throughout the country.

01:06:45.820 Explosion. Everywhere you go, shockwave, shockwave. Now, look, there are certain shockwaves that

01:06:50.460 are very effective. The machines, these are called electrohydraulic machines, electromagnetic

01:06:55.040 machines. These are called class type three machines. They do work. Now, I have to be very

01:06:59.780 careful. They don't work in all patients. And we're still learning.

01:07:02.720 And the class three machines, like Gaines Wave is a class three where you-

01:07:05.800 Shockwave is the company. So the device, I don't know exactly what device they're using.

01:07:09.540 Well, I just remember this because, again, I've got two patients who are receiving or

01:07:13.080 have received this treatment who both swear by it. But I know that at least one of the

01:07:18.320 patients mentioned to me, only a doctor's office can have this thing. So I assumed it

01:07:22.440 was a class three.

01:07:23.360 Class three.

01:07:23.760 Whatever the device they were using.

01:07:25.360 But those machines are more expensive. The electrohydraulic is exactly what the shockwave

01:07:29.480 is for the kidney stone, but it's a low intensity. Electromagnetic is by Stortz.

01:07:33.000 But again, I just want to be fair. This is where the device took off greater than the

01:07:37.460 science. The science is coming up. And I would say that it may be beneficial for patients who

01:07:42.300 have mild to moderate ED. But be careful on the ads that are given on. If you look at

01:07:47.100 these ads, they say, you'll get a great erections today. You'll have great erections by tomorrow. 0.91

01:07:50.980 The ads are unbelievable. So I'm part of the Sexual Medicine Society of North America. We put 0.94

01:07:55.580 out a position statement in 2018. It should be used investigationally at this time. At the AUA,

01:08:00.680 the guidelines for ED, investigational. Both were put out in 2018. It's been five years.

01:08:05.200 There's been new data. But I just want to say, use it with caution. Don't tell everyone it's

01:08:10.080 the best thing since sliced bread. It has potential. And more studies need to be done.

01:08:14.920 So we talked about ED. Does it make sense to now talk about premature ejaculation?

01:08:20.020 Sure. I just want to mention two more things on ED. It's stem cells and PRP. Because that

01:08:25.120 finishes the circle. And so stem cells, the problem with stem cells, and we published a

01:08:29.960 paper. We did use stem cells. We had an IDE.

01:08:32.740 There's no FDA approval for this, is there?

01:08:34.500 There's no FDA approval for stem cells for ED. So many patients will have to go to Costa Rica,

01:08:38.860 Panama, outside the country to get the stem cells for ED.

01:08:41.460 Are there people doing it in the United States off-label?

01:08:43.360 They used to, but you are not supposed to because the FDA has said you cannot use stem cells.

01:08:47.000 Oh, I see.

01:08:47.300 So just in general, for any therapy, I use a machine that had an IDE by the FDA. So an

01:08:53.980 investigational device exemption. And this was, the exemption was for specifically ED for stem

01:08:59.340 cells. So we conducted 30 patients. We used adipose-derived stem cells. We take the fat.

01:09:04.560 We wanted to use it fresh. So we put them in a machine. We would get 37 to 50.

01:09:07.980 So you would literally, this was autologous. You would take a man's adipose tissue, get the stem

01:09:12.800 cells, and then re-infuse.

01:09:14.740 You got it. But because I wanted a large amount of fat, I actually had a plastic surgeon do the 0.96

01:09:19.360 liposuction under some mild sedation. So it was a little labor intensive. Then I would take the

01:09:24.140 fat, it was 120 cc's of fat, and put it into a machine that had the IDE for making stem cells.

01:09:30.240 So the machine, after two hours, would give me anywhere from 37 to 50 million stem cells.

01:09:35.260 And then I would inject those stem cells into the penile tissue. 0.99

01:09:37.840 At the base of the penis? 1.00

01:09:38.660 At the base of the penis with a tourniquet for two minutes. And you have to inject slow or you'll 1.00

01:09:42.080 damage the stem cells. So we let them sit there for 30 minutes and we take the tourniquet off.

01:09:46.400 And did you have a 30 placebo men?

01:09:48.640 This was non-placebo controlled. And this is important because up to today, there's not

01:09:52.280 a single placebo controlled trial with stem cells for ED, not one.

01:09:56.200 So given the placebo effect being so high, what was the effect you saw in these 30 men?

01:10:00.440 We saw that they had an increase maybe of four on the IIEF, no placebo control, but it was

01:10:05.160 only durable for six, maybe nine months and started tapering off. So it wasn't a lasting effect,

01:10:09.680 but it was some effect that was going on. But we need a placebo controlled. So we're going to start

01:10:14.320 a placebo controlled trial because people swear by stem cells. And some companies will say,

01:10:18.980 15,000, we'll give you stem cells for ED. Where's the placebo controlled trial? It doesn't exist.

01:10:24.400 So you have to be careful.

01:10:26.000 Well, the other thing I guess is at $15,000 in Costa Rica, we would have to believe it's

01:10:31.420 significantly better than daily Cialis at what, $70 a year.

01:10:36.320 So I would say, look, there may be some benefit. I do think there's some benefit in stem cells for

01:10:41.720 ED. The number 15,000, I don't know, you know, some people have different numbers, but

01:10:45.440 Costa Rica, there are certain places I think that are doing it better than others. And they have

01:10:50.260 more science behind it, but we still need more science. So do I think that stem cells have

01:10:54.520 potential for ED? Yes, I do. Do we need more studies? Absolutely. To show the efficacy. And the

01:11:00.140 question is, if I'm spending a lot of time doing a liposuction and it lasts for six months,

01:11:04.580 I can't do this for life. I mean, that's not a practical way to do it.

01:11:09.520 Although one might argue, oh my God, that's fantastic. I'm getting free liposuction every

01:11:13.400 six months. At some point, you're going to take all the subcutaneous fat on my body. But no,

01:11:17.560 that's not a viable solution. But exosomes may be the next way. 0.83

01:11:21.120 What are exosomes? It's basically the secretome,

01:11:23.580 what's coming out of the stem cells. So people are looking at exosomes, and I think that may be

01:11:28.000 another alternative to look in the future. How are they harvested?

01:11:30.740 You can look at placental. Also, we look at it from the patient's own tissue, typically fat,

01:11:34.520 but mostly from bone marrow. So they get it from the bone marrow.

01:11:37.240 But again, you have to believe that the durability of this is much longer to justify this. I mean,

01:11:42.160 can you imagine saying, we're going to take a bone marrow biopsy on you every six to nine months

01:11:46.720 to get your stem cells to give us your exosomes to do this procedure? 0.95

01:11:51.340 Some people will take the stem cells, and they'll multiply them, and they'll get billions,

01:11:55.540 and then they'll give you pieces of that. Now remember, every time you multiply them,

01:11:58.720 every time you get past four, the efficacy starts going down. So that'd be a little careful,

01:12:02.940 you know? So I do think there's some potential promise, but we still are lacking in the science

01:12:07.840 with the stem cells. PRP, now that's interesting. Until last year, we got our first randomized placebo

01:12:14.840 controlled trial, first one, until 2020, 21. Before then, there was one case report, one case report

01:12:22.440 with five patients out of Wake Forest showing that there may be some benefit. And this was sold like it was

01:12:28.200 the best thing since sliced bread. They call it the P-shot, which is the priapus shot. Basically,

01:12:33.320 it takes stem cells. It costs about $1,500 to $3,000. Now, honestly, to really make it,

01:12:38.720 it costs $50. You take blood, you spin it, you get the supernatant, you spin it again,

01:12:42.180 add some calcium chloride, you have PRP. And they inject it. Now, there may be some benefit as well,

01:12:48.040 but this is the one that lacks the most science as well. So there's an excellent study at the University

01:12:52.840 of Miami right now looking at PRP and shockwave combination. With placebo arms?

01:12:57.580 With placebo arms. So that's going to be very interesting.

01:12:59.900 When is that expected to be published?

01:13:01.420 I think there's going to be some preliminary results at the AUA this year in April, next month.

01:13:05.720 So that's going to be interesting. I think it came out as a late breaking. So hopefully next

01:13:09.380 month we'll know more.

01:13:10.240 Yeah. Well, by the time this podcast comes out, it'll be in the past 10. So we'll link to that.

01:13:14.080 So my takeaway from everything on ED, just to summarize, is easy way to remember the prevalence

01:13:21.760 is it's matched by age. So amazing to think that at 40, which is pretty young, 40% of men are

01:13:28.720 impacted. At my age, 50% of men at 60, 60%, et cetera. Second thing to consider is if men listening

01:13:35.700 to this or their partners are listening, go and get help. Don't suffer in silence. The third thing

01:13:40.800 to consider is that daily phosphodiesterase inhibitor I took away from you is a very viable

01:13:47.080 solution that there shouldn't be a stigma attached to that. And there shouldn't be a fear that I'm

01:13:52.240 becoming dependent on it or something like that in the sense that these are valuable drugs. They

01:13:56.640 can also sometimes break the vicious cycle if there's a psychogenic component. You want to rule

01:14:00.440 out psychogenic before you proceed to pharmacologic as the only therapy. You have the diagnostic side on

01:14:06.040 the arterial venous. And then I think this idea about PRP, stem cells, exosomes, and shockwave,

01:14:12.860 it's still a little bit too soon to know.

01:14:14.380 A little bit too soon. Promising, but too soon.

01:14:16.740 And of the four, would you say the most promising is stem cells?

01:14:20.360 I like shockwave. You know why? Because when I do shockwave therapy, it recruits the stem cells

01:14:25.160 because stem cells go to area of damage. So essentially, I'm getting the stem cells. I'm

01:14:28.880 getting the neo-ingiogenesis. It's not invasive. It's quick. It's not-

01:14:32.320 So we're probably most optimistic on shockwave, least on PRP.

01:14:36.080 So far, maybe there's a combination, shockwave and PRP or shockwave and stem.

01:14:39.220 And we'll see that with the results of this area. Okay. Let's pivot now and talk a little

01:14:42.860 bit about the sort of states of ejaculation. So inorgasmia, delayed orgasm, et cetera.

01:14:48.200 How does the prevalence of this differ by age?

01:14:51.720 So ejaculatory dysfunctions are important. We know that 30% of men, 30% of men are likely to have

01:14:57.380 some degree of ejaculatory dysfunction. More prominent is premature ejaculation.

01:15:01.720 Premature ejaculation, 30% of men, up to 30% will have it. Only 9% of that 30% will seek therapy.

01:15:08.840 It's really small. And that's really because many men are embarrassed to seek therapy about this.

01:15:13.260 So basically, 30% of men have this. Only 3% of men in total are doing anything about it.

01:15:19.160 That's exactly right, which is very small. But two years ago, the guidelines came out. The new

01:15:24.040 guidelines came out. So what is a premature ejaculation? Two ways to think about it. And this

01:15:28.180 is really important how you break it up at the beginning. It's either lifelong or acquired.

01:15:32.160 That's your first step. Has this patient had it ever since they remember having sex and they can

01:15:35.960 always have premature ejaculation? Or was this acquired? In either case, you have to have three

01:15:41.040 variables. You must have these three. One, you have to have a decreased ejaculatory time. Now,

01:15:46.660 when it's lifelong, it's typically now less than two minutes. So it's less than two minutes. It used to

01:15:51.840 be less than one. Now it's less than two. They have to have a sense of loss of control. I couldn't

01:15:56.140 control it. And number three, they have to be bothered by it. If a guy comes in and says,

01:15:59.820 I ejaculate in 30 seconds and I'm happy, great. He doesn't have the problem. He has to be bothered

01:16:04.200 by it. So it's important. What if he's not bothered by it, but his partner is?

01:16:08.340 Well, he has to be bothered by it. So if he's bothered that she's bothered, fine,

01:16:12.340 but he has to be bothered by the condition. Now, acquired is a little bit different. So look,

01:16:16.360 things were great till I hit 40. And all of a sudden I developed premature ejaculation.

01:16:20.680 Same principles. You have to be bothered by the condition. You have to have a sense of loss of

01:16:25.300 control and you have to have a decrease in time. Now, how do you define time? That's a little bit

01:16:31.020 tricky on this one because it's anywhere from two to three minutes or it's 50% of your typical time.

01:16:37.020 So let's say I used to ejaculate in 10 minutes and now it's five. Okay. That qualifies. It's 50%

01:16:42.860 of what mine. So these are the two definitions of you want to break it down. Now, why is that

01:16:47.440 important? Because how I treat somebody is very different. If someone's acquired, we start looking

01:16:52.760 at hormones. That's important. We look at prolactin. We look at thyroid. We look at

01:16:57.060 testosterone. We look at some more diagnostic. If it's lifelong, we don't do a lot of diagnostic

01:17:02.180 workup. You're not supposed to. It's the acquired where you start figuring out, you know,

01:17:06.080 the four reasons for this premature ejaculation. One is the biological, the theory that there's increased

01:17:11.700 sensitivity of the glands. So if they're born with increased sensitivity, that's why one of the

01:17:16.520 therapies is using lidocaine or some of these numbing agents on the glands. They're over the

01:17:21.340 counter. They're sprays that actually lidocaine on the penis, 10 minutes prior to engaging in 0.94

01:17:25.020 sexual activity. But doesn't that then put lidocaine onto the partner? You wipe it off before you engage

01:17:29.240 in sexual activity. I see. But be careful because if you spray too much, it causes ED. So that's one.

01:17:34.600 So it's the biological, there's a neurobiological essentially meaning the neurotransmitters.

01:17:39.040 So essentially that there's too little serotonin, the neurotransmitters are causing an impairment

01:17:43.820 for the ejaculation. There's some belief on genetic. We don't have an assay right now,

01:17:48.540 but there are four genes that have been implicated. There's some gene.

01:17:51.340 But these genes are only implicated in lifelong or in acquired?

01:17:54.540 In acquired. So it'll be lifelong. I'm sorry. And there's polymorphisms of the,

01:17:58.160 and they're neurosteroid receptor genes. And there are four of them, but we don't use this clinically.

01:18:03.700 We don't look for the assay. We just know that more studies need to be done.

01:18:06.600 The last one's important. It's psychological. If you have a new relationship, stress,

01:18:12.280 any kind of, that causes some psychological impairment, that can actually cause premature

01:18:15.520 ejaculation. Do you have a sense of why stress can have opposite effects? Why is it that in

01:18:19.980 one man, stress might result in ED and in another man, it might result in no difficulty with an

01:18:26.140 erection, but premature ejaculation? I can't answer that. I don't know the answer. I do know that stress

01:18:30.560 though significantly affect you in all sexual function. I call it SAD. It's stress, anxiety,

01:18:35.920 and depression. Patients suffer from those. So stress can have a significant impact on all forms

01:18:40.940 of sexual dysfunction. But stress, stress has a huge impact when it comes to sexual dysfunction.

01:18:46.300 A lot of men, when the stress have difficulty getting an erection, but it does affect premature

01:18:50.260 ejaculation as well. So these are the reasons why men have it. So how do you treat it? There's some 0.54

01:18:54.820 treatment options. And the first line therapy typically is the spray I was talking about, lidocaine spray

01:19:00.080 that you can use. We use promescent. It's over the counter. It's easy to get. The second one you

01:19:04.640 can use typically is SSRIs. So antidepressants. But some men say, I don't want to take an antidepressant.

01:19:11.840 I say, okay, you don't have to take it every day, although it works best if you take it every day,

01:19:15.340 but you can take it on demand. The problem with on demand is you got to take it six to eight hours

01:19:19.520 ahead of time. Which is counterintuitive, right? Because one of the side effects of an SSRI is

01:19:25.760 reduction in libido, right? And ED, both, and erection in libido. So you're right. So you just

01:19:30.500 have to realize that those are, and then first line therapy should always be sex therapy. This is

01:19:34.700 one area where sex therapy is very effective. And sex therapists are what? What is the formality

01:19:39.620 of training to be a sex therapist? They are certified. You have to have a certification.

01:19:43.240 Typically psychologists or psychiatrists? Typically psychologists, not psychiatrists,

01:19:46.740 but psychiatrists can be certified in sex therapy. They're very helpful because there's two techniques, 0.92

01:19:51.620 the start-stop technique, the squeeze technique that teach patients how to

01:19:55.540 prolong the ejaculate. But again, a lot of times patients say, just give me the pill. I say,

01:20:00.080 fine. But if they did the work, that's a cure. That's a cure for PE. So those are the first line

01:20:05.100 therapies. There are second line therapies. The two second line therapies are tramadol,

01:20:10.320 a narcotic, and actually has been shown, if you look at the ejaculatory time, less than one minute,

01:20:14.900 a lot of studies are up to seven minutes. The problem is-

01:20:17.540 A narcotic?

01:20:18.100 Yes. And it's been used quite often as a treatment, and it's in the guidelines as a therapy.

01:20:23.640 What's the risk of addiction or exacerbation of-

01:20:26.860 Very high. I had a patient once that started using five a month, then he started asking for

01:20:31.540 10 a month. And then once he called for 30 a month, and I said, this is ridiculous. He goes,

01:20:35.340 well, I'm having sex every day. I could tell he was getting addicted. And I said, I can't do this 0.91

01:20:39.420 anymore. So you just have to be careful on the tramadol. And then actually, alpha blockers,

01:20:43.960 Flomax, second line therapy for premature ejaculation.

01:20:47.280 Now, does that sometimes convert premature into retrograde?

01:20:50.020 You can. So right, that's one of the risk factors for the alpha blockers, the retrograde,

01:20:53.580 but it prolongs the ejaculatory time. So these are the treatment options that we use for patients,

01:20:58.200 and they're quite effective. You just kind of go through the algorithm for PE.

01:21:01.360 Explain what a retrograde ejaculation is.

01:21:03.460 So as I mentioned earlier, in the prostate, there's something called the ejaculatory ducts.

01:21:06.900 So think of it like a T. So the ejaculatory ducts are coming up, moving forward is the urethra, 0.94

01:21:12.560 and it's coming out the urethra. Moving backward is the bladder. So when the sperm comes up,

01:21:17.480 and the seminal fluid comes up, the tendency is for the fluid to go back into the bladder.

01:21:21.720 But as the man has an ejaculate, he closes off the bladder neck. So the fluid cannot get into

01:21:26.740 the bladder. It's forced to go out. But when you take a medication like an alpha blocker or

01:21:31.740 certain other medications, it can actually open the bladder neck. So what happens is the sperm

01:21:36.420 comes up, seminal fluid then goes into the bladder. And so nothing comes out of the urethra.

01:21:41.500 And when the man urinates or voids, then the seminal fluid will come out.

01:21:46.400 Is there any harm of a retrograde ejaculation?

01:21:48.260 No harm at all. Just some patients find it annoying.

01:21:50.620 Obviously would impair reproduction. 0.59

01:21:52.760 For sure. So if someone's trying to have a child-

01:21:54.740 Huge problem.

01:21:55.260 Yeah.

01:21:56.040 Okay. At the other end of that spectrum is anorgasmia.

01:22:00.800 Sure.

01:22:01.540 And what's your workup for that? 0.81

01:22:03.360 So anorgasmia, and we put this in the same, is a delayed ejaculation. So sometimes patients

01:22:08.000 have delayed ejaculation taking a long time. And the same principles are the same. Is it

01:22:12.540 acquired or lifelong? And the same principles, are you bothered by it? Loss of control or inability

01:22:17.900 to control? And more importantly, the timing. So what is the average amount of time that a

01:22:22.040 man takes to ejaculate in the United States? Typically about six to seven minutes on average.

01:22:26.220 Six to seven minutes is the norm.

01:22:28.280 That's self-reported?

01:22:29.580 In numerous studies. And it's interesting how we do it.

01:22:31.660 How do you do that?

01:22:32.540 Great question. So we look at something called the intravaginal ejaculatory latency.

01:22:38.780 I-E-L-T. And it's typically self-reported, but when it's self-reported, it's inaccurate.

01:22:43.940 Yeah, it's got to be.

01:22:44.420 It's inaccurate because when-

01:22:45.420 Who's keeping track of time?

01:22:46.420 So what happens is when you ask a man who has premature ejaculation, he underestimates the time.

01:22:50.820 If he ejaculated in two minutes, he says, I had 30 seconds. If you ask a guy who doesn't

01:22:54.420 have premature ejaculation, he overestimates the time. If he ejaculated in eight minutes,

01:22:58.160 he says, yeah, it was 15 minutes. So it's a big discrepancy. So how we do it is we give

01:23:02.440 the partner a stopwatch. When he orgasms, she's supposed to click the clock. And that's the best 0.99

01:23:07.640 way to get intravaginal ejaculatory latency. I-E-L-T is best by stopwatch.

01:23:12.680 And based on that gold standard, it's six to seven minutes.

01:23:16.200 Six to seven minutes. Now look, certain countries have different numbers. So Asian countries,

01:23:20.200 lower numbers. European countries, higher numbers, longer ejaculatory latency.

01:23:23.820 What do you attribute that to?

01:23:24.900 There could be cultural differences as well, but there are some differences. But when you look at,

01:23:29.940 for example, these medications like SSRIs, they are very effective in prolonging the I-E-L-T,

01:23:36.140 very effective. And there was a study in 2004 by Waldinger. He was looking at the different

01:23:40.080 SSRIs. Paxil was number one by far. So Paxil is typically used the most. Zoloft was number two.

01:23:46.580 And you can see based on the dose, because it's dose dependent. So the higher the dose,

01:23:50.700 the greater the ejaculatory time. But at the end of the spectrum, it was 25X with Paxil.

01:23:56.460 So typically it's about 10X. You'll see a delay.

01:23:59.800 But without getting to the point of ED.

01:24:01.980 So remember, you can dose, if I'm using too much Paxil, I bring it down.

01:24:05.520 So one of the problems, we'll talk about this delayed orgasmia. A lot of these patients have it

01:24:09.940 because they're on an SSRI. That's why they have it. So if they're on 40 milligrams of Paxil,

01:24:15.040 maybe we just go to 30, we still get the benefits of depression,

01:24:18.380 but we improve the ejaculatory latency time because it's very sensitive on those doses.

01:24:24.080 There's no set number on delayed orgasmia. But typically someone will say greater than 15 to

01:24:29.520 20 minutes. If it's greater than 15 to 20 minutes, that could be considered delayed orgasmia. We have

01:24:34.520 no FDA-approved treatments for this condition. There are no FDA-approved treatments. So everything

01:24:39.520 I'm going to tell you today is off-label use for how we treat this condition.

01:24:43.800 And what about the role of 5-alpha reductase inhibitors here?

01:24:47.140 I would not use 5-alpha reductase inhibitors. I don't like to use them at all in my practice.

01:24:51.560 Oh, I mean as implicated in anorgasmia. In other words, is it possible that 5-alpha reductase

01:24:56.200 inhibitors are amplifying?

01:24:57.600 It is possible. There are patients that have had or taken 5-alpha reductase inhibitors that have had

01:25:02.060 impaired orgasm or anorgasmia because remember it blocks DHT. And DHT is four to five times more

01:25:08.740 potent than T when it comes to function for the receptor. So typically, and one of the treatments

01:25:13.600 for delayed orgasmia is testosterone. So that's how you treat it, right? And so if you're using

01:25:19.580 a 5-alpha reductase inhibitors, the same drugs we talked about to treat ED, how often do they

01:25:27.660 induce delayed orgasm?

01:25:29.680 They don't induce delayed orgasm.

01:25:32.100 They just expose it. They might make it such that you can appreciate it.

01:25:34.560 But you bring up a very important point. If a patient presents with ED and premature

01:25:40.800 ejaculation, you always treat the ED first. And that's a really important point because by truth-

01:25:47.020 Wow, that's an interesting thought. Let me wrap my head around it. A guy says,

01:25:50.760 I have ED and premature ejaculation, meaning either I can't get an erection or when I can, 0.91

01:25:56.760 I have premature ejaculation. Those are my only two states.

01:25:59.160 You got it.

01:25:59.880 How common do you see that in a 50-year-old or 60-year-old man?

01:26:02.680 It's not that common, but it does occur. I would be honest. But why do we treat the ED first?

01:26:08.560 We treat the ED first because if you treat the ED, you can actually treat the PE.

01:26:13.540 You can delay it. You can actually fix-

01:26:15.460 Fix the PE. And there's a reason for this. Subconsciously, whether it's conscious or

01:26:20.320 subconscious, it's a belief that the body's saying, if I don't ejaculate quickly, I'm going to lose 0.94

01:26:26.120 this erection. I'm going to lose the erection before I ejaculate. And so if you're able to maintain 0.97

01:26:31.120 your erection and not worry about it, you may prolong the ejaculatory time. So a board question 0.89

01:26:36.400 we ask on the exams, patient presents the ED and PE, you treat the ED first, and you can treat the PE at

01:26:41.720 the same time.

01:26:42.120 I kind of want to shift gears a little bit and talk about testosterone replacement therapy. So let's

01:26:50.620 maybe give folks a little bit of an explanation of how the hypothalamus, pituitary, testes, and adrenals

01:27:00.920 all play a role in the generation of the hormones that we're about to talk about, which means let's

01:27:06.460 talk about everything from LH and FSH to testosterone, SHBG, DHT, et cetera. And then

01:27:12.880 let's talk about what deficiencies mean and what the consequences are and how we might go about

01:27:17.040 addressing it.

01:27:17.740 Sure. So let's talk about the physiology because it's important. So GnRH secreted from the

01:27:21.580 hypothalamus. GnRH then goes to the pituitary, secretes two hormones, LH and FSH.

01:27:26.520 And what's the signal for GnRH? Is it estrogen?

01:27:29.540 And that's a negative feedback. So estrogen can't have a negative feedback on it. It's a

01:27:32.820 pulsatile pulse, GnRH. We know that pulse goes down as we age. So that's an important part of

01:27:37.500 aging. We'll talk about it as well. The LH and FSH will then go to the testicles. I tell the

01:27:41.880 residents, remember that LH has an L, goes to the lating cells. FSH has an S, goes to Sertoli cells.

01:27:48.040 So LH goes to the lating cells and produces testosterone. FSH goes to the Sertoli cells and

01:27:53.300 produces sperm. The two functions of the testicle are basically sperm and testosterone. So essentially,

01:27:59.400 if a patient comes in and they have, remember that the majority of a man's testicles are comprised of 0.94

01:28:05.660 Sertoli cells. That's important because the exam is more of an indicator of his fertility status

01:28:12.420 than his hormonal status. So that's important.

01:28:14.660 When you say exam, you mean size?

01:28:16.160 Size. So they should be four centimeters in diameter, 20 cc's. And so when I'm looking at an

01:28:20.720 infertility workup, if the patient has small testicles, elevated FSH and LH, I say there's a

01:28:26.400 production problem. He's not making it. If he has normal FSH and LH and normal testicles and no

01:28:32.240 sperm, it's an obstruction problem. So that's very important. The exam's very important.

01:28:37.220 So we talked about the fact that the testicle's making testosterone, but there's a negative 0.66

01:28:41.220 feedback. That negative feedback, testosterone goes back and feeds back negatively on the pituitary

01:28:46.120 and also on the hypothalamus. But also estrogen goes back and feeds back negatively. Testosterone

01:28:52.320 can be broken down.

01:28:52.960 By the way, is one of those stronger than the other as a signal?

01:28:56.480 I don't know if one's stronger than the other. I know that both are. I mean, we'll talk about

01:28:59.660 SERMs and how SERMs work as they block that negative feedback on the estrogen. But remember

01:29:04.060 that testosterone then is converted into estrogen, 0.3%, not much, 0.3%, and 6% to 8% is converted

01:29:11.380 to dehydrotestosterone. So you get two conversions. So the higher the testosterone, you should get

01:29:17.160 greater estrogen and greater DHT. That makes sense. So what many clinics do is they try to block the

01:29:24.400 conversions. They'll use aromatase inhibitors and they'll use 5-alpha reductase and try to control

01:29:29.340 it. And I'm not a big fan of that, but they do it. So that's really the big picture here.

01:29:34.620 Let's double click on a few of those things and maybe just rehash that. So when you go to the doctor,

01:29:39.440 it's pretty common that if the doctor knows what they're doing, they're going to measure FSH and LH in

01:29:43.720 addition to testosterone, we're not measuring GnRH, right? It's pulsatile. Even if we had an

01:29:49.320 assay for it, it would be useless, sort of like growth hormone. Let's talk about where SHBG fits

01:29:54.280 into the mix because that is often measured. And let's talk about the concept of free testosterone

01:29:59.320 slash bioavailable testosterone slash free androgen index, all of these things that are not measurable,

01:30:06.720 but are estimatable. And I want to understand if they mean anything.

01:30:10.980 Most testosterone is bound. 2% is free. 50% albumin, 44% SHBG, 4% corticotropin binding

01:30:18.840 globulin. Oh, I didn't know that. I thought SHBG was the lion's share, but it's split relatively

01:30:23.400 equally with albumin as well. Albumin, 50% albumin, 44%, and then 4% corticotropin binding

01:30:27.420 globulin, a small percentage, and then 2% free. But the body only cures what's free. If you look at

01:30:33.080 correlates with symptoms, the free testosterone is the best correlate with symptoms, but we're so fixated

01:30:39.300 on this total testosterone. The best example, a guy walks in, his testosterone is 450, 500.

01:30:44.160 He says, I feel lousy. You say, what's going on? Check his SHBG. Get a calculated free testosterone.

01:30:48.880 If his SHBG is elevated, the free T is going to be low. And there you have it.

01:30:52.560 How accurate do you think the calculated free testosterone is?

01:30:55.720 I think it's much more accurate than the assay. So I calculate my own. So there are calculators

01:31:00.080 that are online and very simple. You put in the albumin, you put in the SHBG, you put in the T,

01:31:03.200 click, and it'll give you the calculated free T. It's more accurate, I think, than the assay.

01:31:07.320 The gold standard is LCMS, but it's expensive and it's hard to get.

01:31:11.120 So there is an LCMS assay for free testosterone?

01:31:14.620 I don't know. I know it's for total. It's for total.

01:31:17.240 LabCorp does a total LCMS.

01:31:19.380 Yes. I don't think there's one free, but I-

01:31:21.640 But you're saying if you have an LCMS, if you're cost insensitive and you have an LCMS assay for

01:31:27.080 total and you know albumin and SHBG, which are pretty easy to measure, you plug those three numbers

01:31:32.740 in, you'll get an estimate, a pretty good estimate that's a calculation, of course, of free T.

01:31:37.660 Yes.

01:31:38.400 And I'll tell you, one of the things that has been the bane of my existence is that we have

01:31:44.180 pretty good data age-wise for the distribution of total T over a man's life.

01:31:50.980 Yes.

01:31:51.220 What does the normal bell-shaped curve look like at 20, 30, 40, 50, 60? We don't seem to,

01:31:57.420 at least, I haven't found those data for free T. All I seem to find for free T is over 18.

01:32:03.580 Yeah.

01:32:04.080 Which is very difficult because when I have a 50-year-old man who says,

01:32:07.640 how do I stack up? I say, well, I can only tell you how you stack up to men over the age of 18.

01:32:13.460 I can't tell you how you stack up to other 50-year-olds.

01:32:15.520 Yes. So I think there's two important points here. One is, I always thought that this concept

01:32:19.980 called androproze was real, meaning as we get older, our testosterone get low and lower

01:32:24.800 due to age alone. That is not true. We know now that total testosterone levels don't decline

01:32:31.980 very much in healthy males. What makes that testosterone go down is the acquisition of

01:32:38.300 comorbid conditions. A 75-year-old really healthy male, he'll be having a normal testosterone,

01:32:43.940 a total T. What does change is the SHBG. So as we get older, the SHBG does go up. The total

01:32:50.620 testosterone should stay relatively flat if you're healthy, and the free T will start to go down.

01:32:55.740 So I've noticed, and I'm sure we'll talk about this, genetics seem to play a very big role in SHBG.

01:33:02.140 I'm someone who just seems to have a very low SHBG.

01:33:04.780 So you're lucky.

01:33:05.260 But I also have a very low testosterone. So my testosterone is maybe 400, maybe 500,

01:33:11.420 but my SHBG is in the 30s. So my free T is about 2.5% of my total T. I have lots of patients

01:33:20.360 who have very high T, but their SHBG is in the 80s or 90s.

01:33:25.440 But that's the body compensating. So the body is very clever. And that patient, if their T starts

01:33:30.300 going down, the body starts offloading and lowering the SHBG to keep that hemostasis. It's

01:33:35.360 almost like our reserves. It's pretty fascinating. It's the body's reserves. It knows when we have too

01:33:39.940 much. It binds it.

01:33:41.240 And what do you think is driving the age thing? Because we definitely see an amazing response

01:33:45.460 to insulin. So as insulin comes down, SHBG tends to go up. As T4 goes up, SHBG goes up. And as

01:33:54.740 estradiol goes up, SHBG goes up.

01:33:56.740 Yes.

01:33:57.400 Which of those things, if any, are driving the age change?

01:34:00.420 I can't tell you which one is, to be honest with you. All I know is that it goes up. I don't

01:34:04.460 know which factors-

01:34:05.580 Might be something unrelated to that.

01:34:06.900 But I think genetics is a big part of it. So it's definitely genetics.

01:34:09.940 Obesity has an effect on SHBG. There are comorbid conditions that affect the SHBG levels as well.

01:34:15.300 But it's interesting. Usually with obesity, we see it go down.

01:34:17.640 It's the opposite.

01:34:18.300 It comes with hyperinsulinemia and it goes down.

01:34:20.440 Okay. So you buy the idea that having a plasma measurement, pardon me, a plasma estimate of free

01:34:29.940 testosterone is valuable. One of the things that I've struggled with is trying to make the leap

01:34:37.860 between what we can estimate, which is plasma concentration of free testosterone, and what is

01:34:43.560 probably physiologically important, which is how much of that free testosterone gets into a cell,

01:34:48.320 how much then gets into the nucleus, how many androgen receptors do they have, how are they

01:34:52.900 saturated, how sensitive are they, and how do they lead to gene transcription? And I know that in the lab,

01:34:58.400 you can probably do those things. I've talked with Ted Schafer about that, but clinically I can't do any

01:35:03.060 of those things. I literally have this very crude estimate of free testosterone and I struggle

01:35:09.520 greatly to make the link between that and what's happening. So instead, I just sort of say to, and I

01:35:16.760 had this discussion with a patient yesterday, which was, this is a 55-year-old guy in pretty good

01:35:21.340 health. His free testosterone is estimated at seven nanograms per deciliter. So he says,

01:35:28.260 doc, is this high or low? And I said, it's low. You're about the 20th percentile for men over the

01:35:33.080 age of 18. Again, I can't actually tell him what he is for a 55-year-old because I don't have the data

01:35:37.920 and it drives me bananas that that isn't published. But I tell him, yeah, you're at about the 20th

01:35:42.100 percentile for all men over the age of 18. And he said, should we do anything about it? And I said,

01:35:46.160 well, I gave him my soliloquy that I just gave you. I don't actually know how much of that seven

01:35:52.540 is doing its job. And by the way, if your androgen receptors are already saturated,

01:35:56.320 I don't know that giving you more is going to do anything. So I said, let's go through the symptoms.

01:36:00.480 So I asked him a whole bunch of symptomatic questions. I want to hear yours. You're going

01:36:03.940 to share yours, not mine. And sure enough, to a T, he didn't have one symptom that I asked him about.

01:36:09.520 And I asked him about 10 things. And he said, I don't have one of those. And I said, well,

01:36:14.400 I would not treat you then. Let's revisit this in a year. And he said, great, no problem.

01:36:19.440 So first of all, I want to hear, what would you say to that patient if he said, Mo,

01:36:23.300 my free T is seven. It looks low. What should we do?

01:36:26.720 I'd say, first of all, I would completely agree with what you did because

01:36:28.940 why are we so fixated on the numbers? It's not about the numbers. It's about how he feels.

01:36:34.240 If a guy comes in with a level of 250, 200 total T, very low. And he says, I feel fantastic.

01:36:40.480 One could say, why are you treating him? Conversely, if he has a level of 500,

01:36:43.580 has all the symptoms, we don't treat. So if he comes in and he has symptoms,

01:36:49.280 then I will treat him.

01:36:50.240 And tell me the questions you would ask to a list of them.

01:36:52.820 So I say, these are the following. Low energy, low libido, erectile dysfunction.

01:36:57.400 I didn't ask that.

01:36:58.640 Increased fat deposition, decreased muscle mass, depression, poor sleep. Okay. Those are the big

01:37:03.680 ones.

01:37:04.260 I also asked about recovery from workouts.

01:37:06.200 Yeah, you could. That goes with the muscle. But you're right. Yes. Bone fractures are important

01:37:09.680 if they have bone fractures. And then just look at them. Just look at them. Are they obese?

01:37:13.420 Metabolic syndrome? No, this is a guy who's lost 25 pounds in the last year in our practice. He's

01:37:20.260 exercising more. His bone mineral density is fine. If I was going to be very critical,

01:37:26.620 I would say his appendicular lean mass index is only at about the 55th, 60th percentile. We want

01:37:33.060 to see our patients with an appendicular lean mass index above the 75th percentile. But I don't think

01:37:38.380 he needs testosterone to get there. A little more training and protein will probably get him there.

01:37:42.060 How old is he? 55.

01:37:43.360 Right. So he's young. So think about this. So I say, you don't need testosterone today. I don't

01:37:48.020 know about five or 10 years from now, but today I'm not going to put you on it because the reality

01:37:53.540 is if I do put you on it, it will suppress your endogenous access and you may need to be on it

01:37:57.840 for life and you don't need it today. You have no symptoms.

01:38:00.440 That's been my lazy excuse, which is I'm 50. I am a firm believer in the benefits of testosterone.

01:38:06.460 I wouldn't be prescribing it to patients if I didn't feel that way. I've spent not as much

01:38:10.420 time as you, but more time than most people in the literature. And I completely buy the efficacy

01:38:15.460 and safety of it, but I'm like, I don't need it yet. And I know that once I started, I'm going

01:38:20.740 to be on it indefinitely. So I'm going to hold out as long as possible until I need it.

01:38:24.840 That's what I wish most people would do. The problem is a lot of these young men go into the

01:38:28.100 T clinic at 30 years of age and they get started and they're on it. Then they come see me and they say,

01:38:34.200 I didn't know I could be infertile and now I have to reverse them, which is a protocol we use. 0.92

01:38:39.620 They never were informed that they could have fertility.

01:38:43.260 Let's talk about this. Maybe we'll talk about all the different ways that we can replace

01:38:48.120 testosterone. So the three ways that we have historically done it in our practice,

01:38:52.960 I guess technically four. One is, and we don't do this anymore. We used to use clomiphene. It had

01:38:58.240 the advantage of several things. One, it's a pill, very convenient. Take it three times a week.

01:39:02.920 Two, it preserved function, meaning you preserved both testicular volume and spermatic function.

01:39:09.180 So you preserved fertility. And actually it was quite efficacious because you could titrate the

01:39:13.260 dose and get to almost whatever you mean. The drawback is if the man didn't have testicular

01:39:17.880 reserve, he wasn't going to get much of a bump. There were some guys who had peripheral hypogonadism

01:39:25.360 as opposed to central. This was a great treatment for central, but you were at the limit of what the

01:39:30.040 testes could do. There were reasons we ended up stopping it that I won't necessarily get into,

01:39:34.040 but we basically haven't used that in a very long time. We then would use as the alternative to that

01:39:38.840 HCG. HCG is just a mimetic for LH, luteinizing hormone, which you talked about, of course, is the

01:39:45.220 direct stimulant of the Leydig cell, which makes testosterone. Lots of disadvantages. It's pretty

01:39:50.280 expensive. It's an injectable. It's a very delicate injectable. So it has to be refrigerated. If you drop the

01:39:55.980 bottle, the protein misfolds and it's crap. So lots of problems associated with it. But again, 0.96

01:40:01.760 it seems to preserve testicular volume, which young men care about. Maybe older men do it as well.

01:40:06.660 Not clear if it's as good as Clomid at preserving fertility. I would love to hear your opinion on that.

01:40:12.620 But again, it feels less problematic to men in the sense that it's less permanent. Of course,

01:40:19.140 we then use the mainstay is injectable testosterone cipionate or its derivatives. And again,

01:40:24.620 we'll talk about all the pros and cons of that. And then lastly, pellets. So testosterone pellets.

01:40:29.540 Don't do that anymore now that we've switched to being more of a remote practice. So I don't see

01:40:33.640 patients in person to put the pellets in them. And also for men, pellets are a much bigger deal than

01:40:39.740 for women. The pellets are so much bigger. For women, when you're putting little estrogen and 0.72

01:40:43.860 testosterone pellets in it, it's a walk in the park. They don't even notice you've done it. For men, 0.54

01:40:47.720 they notice it. Great topic. So this is really important. So you talked about two. So let's talk

01:40:51.660 about endogenous ways to raise testosterone first. And you can use Clomid. You can use HCG.

01:40:57.200 Some people use anastrozole. I don't recommend that, but we'll talk about that.

01:41:00.820 So Clomid first. It's a CIRM, negative feedback to the estrogen receptor.

01:41:05.120 The problem with Clomid is the following. We get a discrepancy effect. And this is what happens.

01:41:10.560 You get a very nice bump in the testosterone level. That's true. But roughly 40% of patients say,

01:41:16.100 I have no desire for sex. I have no erections. I don't feel any desire. Because the way the Clomid 0.82

01:41:21.600 works, it blocks estrogen receptor centrally. Men need estrogen. It is critical. You need estrogen 0.93

01:41:28.080 for libido and sexual function. So they have these beautiful 800, 900 levels. No desire for sex.

01:41:33.100 You take that same patient and put them on exogenous testosterone at 800. He says, it's working.

01:41:37.100 So the way Clomid works is that it blocks. And so that mechanism is not conducive for many men.

01:41:42.260 Yes, it's easy. There's a national backorder. So now we're starting to use a little bit more

01:41:46.120 N-Clomid. Is N-Clomid legal in the US?

01:41:49.740 It is compounded. Remember, reproced and tried to get it through in 2015 at the FDA. Never made

01:41:54.220 it through. It's the transisomer of Clomid, zooclomid. And essentially, it is available

01:41:59.420 compounded. And you can get it. But it's hard to get Clomid now even, because there's a national

01:42:04.880 backorder. Is this just due to all these tea shops opening up on every corner that are-

01:42:09.980 Well, they're different. So they're more into giving the tea and the injection. And you come

01:42:14.760 in and get the injection for a fee. But this still is on the endogenous side. Clomid's not bad. I

01:42:19.920 mean, it does-

01:42:20.560 Why is there such a run on this stuff?

01:42:22.320 Because what happened was HCG was, for many years, compounded. Recently, the FDA has said that HCG

01:42:30.460 cannot be compounded. So everyone dropped the HCG and went to Clomid. And now there's a mad rush to

01:42:35.560 get the Clomid. You can still get HCG commercially-

01:42:38.300 Yeah, Pregnel is the blend.

01:42:40.300 Pregnel, but it's through the roof. So what happened was that everyone started going to

01:42:42.740 Clomid. And so now we're backordered on Clomid. And you can still get HCG, but it's pricey.

01:42:47.420 And did the FDA say no more compounding HCG because it's too complicated and they couldn't

01:42:52.400 do quality assurance?

01:42:53.640 I think it was a patent infringement. I think it was more to the fact that I think Merck still had

01:42:57.740 rights to the patent on HCG. And it was too similar. Because a compounder can make something,

01:43:02.800 but it has to be different. That's my understanding. I think it's going to start coming back.

01:43:06.800 But there was a national shortage on HCG. And that's why people started going to Clomid.

01:43:12.440 But Clomid, it's not the 60% will say my T goes up. You got to give it every other day or you can

01:43:17.420 get a tachyphylaxis. So 7% can get tachyphylaxis if you give it daily. Some patients, they say,

01:43:22.660 I can't remember every other day. I say, fine, take it every day. And there's 7% chance you may

01:43:26.220 become resistant to the drug.

01:43:27.380 7%.

01:43:27.740 7%. Okay. So that's fine.

01:43:29.680 We tell people to get a pillbox when we used to use it. So it was just Monday,

01:43:32.800 Wednesday, Friday, and don't have to think about it. Load the pillbox.

01:43:35.460 If they forget, take it every day. And Clomid, we give it every day.

01:43:38.580 And what doses do you use?

01:43:40.200 50 for Clomid every other day. And Clomid, 25 a day. Or if they forget on 50 every other day,

01:43:45.200 we use 25 Clomid daily. Okay, fine. It's not a great, but it does help. We use it for fertility.

01:43:49.540 So patients who are coming to me for fertility to help them achieve a pregnancy, we use it.

01:43:53.720 You can use HCG. HCG is expensive and it is pricey. Typically, it depends on what dose you want to use.

01:43:59.400 But it's 1,500 three times a week, up to 2,000 three times a week. It can be effective.

01:44:04.120 It's nice for patients who have pituitary pathology, because I bypass the pituitary,

01:44:07.860 go straight to the testicle, and they can start making testosterone. 1.00

01:44:10.820 And then in patients who have an elevated LH and FSH, initially, Klinefelters,

01:44:16.040 can't really use HCG or Clomid because the way Clomid works-

01:44:18.580 Because they're already maxed out.

01:44:19.520 They're already maxed out. So you've got to use Nasterzol because I'm trying to increase

01:44:23.480 the T to E ratio, increase the T. And typically, I'm using this medication to improve

01:44:27.800 spermatogenesis so that I can then do a biopsy or a testy to achieve sperm.

01:44:32.480 I've never seen a man with Klinefelters. When a man presents with Klinefelters, 0.96

01:44:35.860 what are his typical T, DHT, and E levels?

01:44:39.260 So the E's are typically high. The T's are typically-

01:44:41.460 How high are the E's?

01:44:42.580 40, 30.

01:44:43.340 Oh, so not that high.

01:44:43.960 They're not super high, but they are. And it depends on how far along you see them along the way.

01:44:46.940 FSH and LH are typically already elevated, pretty high. So if the FSH and LH are already elevated,

01:44:51.680 I can't use Clomid or HCG.

01:44:53.520 What's the prevalence of Klinefelters? 0.96

01:44:55.080 1 in 500, so it's quite common.

01:44:56.320 Really? That high?

01:44:58.340 Yes.

01:44:58.940 Just tell people what Klinefelters is. 0.64

01:45:00.320 It's a genetic abnormality where you have an extra X chromosome, XXY.

01:45:04.860 So phenotypically, you're a man.

01:45:06.440 Phenotypically, you're a man, but there are issues. Infertility, you can have gynecomastia.

01:45:11.360 They're typically long stature in nature.

01:45:13.800 They have normal sexual function?

01:45:15.360 They have no issues with ED, but the T is low, so that may affect the ED. But we treat these men

01:45:20.340 with medications to raise the T. And so we see that-

01:45:22.820 And why can't you just give them testosterone? 0.98

01:45:24.120 We can, but what if they want to have a child? So that's the only thing. So what we may do is, 0.91

01:45:29.020 I see a lot of these patients when they're 14 or 15 when they're first diagnosed.

01:45:33.080 How are they usually diagnosed? I mean, I know the diagnosis is genetic,

01:45:35.620 but what brings them to presentation?

01:45:37.120 A lot of times what you'll see is that there's no facial hair development. So there'll delay in

01:45:40.700 development.

01:45:41.260 I see.

01:45:41.760 No shaving. And so what you'll notice, and so if there's a suspicion, long stature,

01:45:46.080 small testicles on exam, the pediatrician may say, let me just check a curatype and just see 0.91

01:45:50.440 what's happening. 0.92

01:45:50.840 And then you see two X chromosomes.

01:45:52.260 And then you know.

01:45:53.060 One in 500. That means there's a lot of people listening to this podcast that have Klinefelters.

01:45:57.480 Presumably they know it, but they may not. And if they know it, they might be wondering,

01:46:01.300 is testosterone an option? And what you're saying is not necessarily first line unless you can block

01:46:07.080 estrogen as well. And of course, it depends on the fertility status.

01:46:10.100 Right. And some of these patients will start testosterone. And then when they're ready to

01:46:13.480 have children, we will do a procedure called a microtessi at that time. And what we'll do is

01:46:18.540 we'll stop the testosterone. And so my reversal dose is HCG, 3,000 units, three times a week.

01:46:23.640 And then we'll either give them gonal F or clomid with it. There's three ways to look at it.

01:46:27.380 There's patients who've taken testosterone and they're abusers. And they've come in now

01:46:31.480 and they want to have children. That's the type number one of patients. That patient stops

01:46:35.580 the testosterone, HCG, 3,000 units, three times a week, plus recombinant FSH or gonal F,

01:46:41.280 75 units, three times a week. And that actually does help reverse. Anywhere from three to seven

01:46:46.340 months, you can see recovery of somatogenesis in these patients who are azospermic. So that's great.

01:46:51.280 Right. And tell me, that guy shows up having been on testosterone for how long to be in his-

01:46:57.580 It could be years. And many times they may have gotten the testosterone from a gym or something,

01:47:01.240 and they weren't getting monitored. And they're at super physiologic level. So this is how long

01:47:06.200 have you been on it and how high was your dose? It dictates how far along. So for years-

01:47:10.360 We tell patients, and we use physiologic doses. So a typical dose for us is 50 milligrams of

01:47:15.860 cipionate twice a week.

01:47:16.760 That's what we do.

01:47:17.440 Okay. So we would say, at physiologic dose, you don't want to be on this for more than two years.

01:47:24.020 And we are really hypervigilant and say, I wouldn't be on this for more than a year unless

01:47:28.180 you're willing to be on it. What do you say?

01:47:30.120 You're talking about younger patients though?

01:47:31.340 Yeah. So someone who's like in his 40s.

01:47:34.420 So in his 40s, I still try to, the second, so the category two is a young man who just wants to use

01:47:40.340 HCG alone. And that's not 3,000 in three times a week, that's 1,500 three times a week as a dose.

01:47:47.420 And then there's the last one, and this is a study that we did at Baylor, where there's a patient who

01:47:51.780 wants to take T and we give them HCG with it to protect the access. And that's 500. So 500,

01:47:58.520 1,500, 3,000. There's three different patients. The preservation of, you know, and this also-

01:48:02.920 500 of HCG three times a week. It's not doing anything to boost endogenous production.

01:48:08.760 Protection.

01:48:09.240 It's just protection.

01:48:10.000 And the best study, this is the best study came out, a guy named Coviella. This is how we got

01:48:13.920 the idea at Baylor. Coviella had a study in 2005 where he gave patients 200 milligrams of testosterone

01:48:19.360 IM every week.

01:48:20.520 That's a big dose.

01:48:21.140 Big dose, every week. And what he was measuring was intratesticular testosterone levels. 200 IM every

01:48:27.120 week, the intratesticular went down. 94% of patients were down to zero in three weeks. So that's a good

01:48:32.220 number to remember. 94% decline in intratesticular testosterone in three weeks. 94% decline.

01:48:39.060 Then what he did was he gave these patients different doses of HCG, 250, 500, all the way,

01:48:45.780 1,000. And what he found was between 250 and definitely 500, there was no significant decline

01:48:50.920 in intratesticular testosterone. Very interesting. So he's giving 500 every other show in 2013.

01:48:56.860 Amazing.

01:48:57.160 In 2013, my partner, Larry Lipschultz, said, okay, if that's true for intratesticular testosterone,

01:49:02.980 what is it doing for fertility? So let's do the same thing. Let's give these patients testosterone, 1.00

01:49:07.940 500 units of HCG every other day. And what we saw was there was a decline, but it wasn't a

01:49:13.460 significant decline. And now that was the median. So there are patients who can have it. I don't want

01:49:17.700 people to think, hey, if I do this, it's completely safe. But it does help protect

01:49:21.880 decrease in somatogenesis.

01:49:23.300 But why is that the case, given that HCG is acting on the Leydig cell? You would think you

01:49:27.820 would need recombinant FSH to get the protection of spermogenesis. 1.00

01:49:31.460 Because it has some FSH properties. If you give a man for fertility just HCG,

01:49:36.140 you actually see some improvements in somatogenesis. Now, there is some of the fact that some of the

01:49:40.660 testosterone is being used by the Sertoli cells for production of sperm production.

01:49:45.120 Has someone done the study of giving clomiphene or mcloniphene with testosterone to maintain

01:49:51.040 sperm production?

01:49:52.220 I have not seen that study, but people do it off-label.

01:49:54.320 And it would seem to me that that would be even more efficacious.

01:49:56.620 Yeah. People do it off-label. The only issue is that you got now

01:49:59.220 two things working in opposite directions.

01:50:01.520 Because you got the estrogen problem up top.

01:50:03.180 Yeah. And also that you know that when you're giving the T, you're suppressing the LH and FSH,

01:50:07.040 and clomiphene is trying to raise the SLA. 0.98

01:50:08.640 So giving recombinant FSH would be the better thing to do there.

01:50:11.120 Yes.

01:50:11.820 How expensive is recombinant FSH?

01:50:13.520 Extremely expensive. So I would say-

01:50:15.240 It's really only used for fertility, right? If that's its on-label use is in fertility with what?

01:50:19.140 Yeah. Up to $500 a month. I mean, it's very expensive.

01:50:21.100 Wow. This is insanely expensive proposition once you start going. And what does HCG cost?

01:50:26.600 It depends now because now you can't get a compounded-

01:50:28.340 No. If you're getting Pregnil branded-

01:50:30.180 About $300 a month.

01:50:32.220 Insane.

01:50:32.800 Yeah.

01:50:33.160 You can understand why, unfortunately, men, especially younger men who might not have the

01:50:39.320 disposable income, are basically just getting testosterone because it's very cheap. And especially

01:50:44.700 if they're getting it in an illicit fashion, you're keeping them out of the doctor's office

01:50:48.800 where they can't be monitored, and you're pushing them into the gym locker room where

01:50:52.780 God only knows what they're getting.

01:50:54.340 There's one thing I forgot to mention. On the fertility preservation side, besides the

01:50:59.000 anastrozole, clomiphene, and HCG, there is some data that just came out suggesting that

01:51:04.020 the intranasal testosterone does not significantly suppress somatogenesis. And this was interesting.

01:51:10.100 So it's done three times a day. This was out of the group at a University of Miami.

01:51:14.560 Three times a day?

01:51:15.600 It's called Natesto. It's commercially available. You go to Walgreens, you can buy it.

01:51:18.480 I've never even heard of this. I was just about to ask you about the oral testosterone,

01:51:21.560 but we'll come back to that.

01:51:22.420 So Natesto is a nasal testosterone that's implied. It's 11 milligrams. It's applied in each nostril,

01:51:28.220 and you do it three times a day. And essentially what happens is it has the fastest rapid onset,

01:51:34.640 and then it declines. And I always thought-

01:51:36.460 11 milligrams TID.

01:51:37.920 So 33 milligrams daily.

01:51:38.960 So in other words, the bioavailability is much lower than an injection.

01:51:42.320 Yes. But the interesting thing is this. I looked at the pharmacokinetics. I said,

01:51:45.460 how can this be effective? It's in and out so quickly. And then doing some deeper work and

01:51:51.440 talking to some endocrinologists said, look, Mo, you don't have to have it around. If it's bound

01:51:56.100 to the receptor and it's doing its work, it doesn't have to physiologically be there all the time in

01:52:02.040 the serum. And it's interesting. These patients do feel better. They feel better. And because of the

01:52:06.700 rapid onset, some of them do say they take it before sex, they take it before a workout,

01:52:11.040 because it's very quick, they say they feel better when they take it.

01:52:13.700 How has this not become the drug of choice?

01:52:16.140 But no significant suppression in somatogenesis. That was interesting. Now,

01:52:20.980 more studies need to be done, but that was-

01:52:22.880 When was this approved? The testo, I think, has been out for at least six or seven years. It's

01:52:25.940 been for a while.

01:52:26.820 Is it cost prohibitive?

01:52:27.960 Insurance does cover it. It can also be compounded, but it's used by a lot of young men.

01:52:33.180 That's so interesting. So if a guy comes to you and you go down the path and decide you're going

01:52:39.480 to go down the exogenous route, not the endogenous route, how are you deciding between pellets,

01:52:45.380 which we should explain what they are, topical, like androgel or compounded, injectable,

01:52:51.040 such as Sipionate or Zyested or intranasal or oral now?

01:52:55.800 I go through all the options, first of all. Because a lot of times it could be cost prohibitive

01:52:58.960 and we find out which is the most affordable. Although, I would tell you that injectables,

01:53:03.300 cash price from a compounding pharmacy is $25 a month. We have them inject sub-Q,

01:53:08.080 either Ananthate or Sipionate. It's based on age. I use Sipionate for younger patients,

01:53:11.280 Ananthate for older patients. I think Sipionate is more anabolic, has more sodium retention.

01:53:15.860 And so I teach the residents, Sipionate has a C for child, Ananthate has E for elderly.

01:53:19.600 I typically use like 50 or 60, but I look at the patient, but I think that it has a little

01:53:23.660 more sodium retention. So I try to stay away from the swelling and the edema in older patients. So

01:53:28.180 that's how I make my decision. And where do you make that cutoff age-wise?

01:53:30.760 It's typically around 50 to 60 around there. I just, if they're using injectables. So I'll say,

01:53:36.020 okay. Now what I like about the injectables is, okay, we use sub-Q, always sub-Q.

01:53:41.460 So 25 gauge needle, short needle.

01:53:43.540 Yeah, 5 eighths inch, 1cc syringe, 25 gauge. It's big enough to draw it up. It's small enough to inject.

01:53:48.240 Outer part of the butt or belly? 0.75

01:53:49.760 Belly. And pinch the fat. Pinch the fat. And we do it Sunday, Thursday. Because these drugs peak 0.96

01:53:54.700 in 24 hours. So you do it Sunday, you're ready for Monday. You do it Thursday, you're ready for

01:53:58.360 Friday. And patients like it. It's $25 a month.

01:54:01.100 And tell me why you pinch. I know you want to get more tissue up, but don't you worry about

01:54:04.680 inducing trauma? You get more vasculature.

01:54:06.380 I think it decreases the pain. So the harder you pinch, the less pain you feel.

01:54:09.260 And why belly as opposed to upper outer gluteal fold?

01:54:11.800 I tell patients, you can do whatever you want.

01:54:13.200 Okay, okay.

01:54:13.620 Most patients just think fat and less pain in the fat. But some people, I have like 10,

01:54:19.020 20% say it's less painful in the muscle. I say, great, do it in the muscle. Wherever you prefer,

01:54:24.160 although there's a conversion. The conversion is the following, that you have a higher blood level

01:54:28.820 if it's in the fat. For example, I think the conversion is about 20%. So if you give someone

01:54:34.160 80 milligrams sub-Q, it's about giving 100 milligrams IM, roughly, is what I'm seeing.

01:54:39.800 So if you look at Zyastad, the starting dose is 75 milligrams, not 100. It's 75. So you do get a

01:54:45.520 slightly higher blood level, I think, when you give patients a sub-Q. So my favorite is Sunday,

01:54:51.180 Thursday, 0.25, $25 a month, no insurance. It's easy. But there are patients that are needle phobic.

01:54:56.140 I get it. So Zyastad's a great option.

01:54:58.200 And Zyastad, of course, is still a needle, but it's preloaded. They don't have to see it. It's just

01:55:01.520 a pen.

01:55:01.840 27 gates. It's unbelievably tiny. It has a high spring.

01:55:04.260 How do they get it out? Is the pressure just so...

01:55:06.160 So if you look at the gate, it's a high spring. So it's not a new drug. They're just using

01:55:10.800 enanthate. It's just enanthate in a very clever spring-loaded device.

01:55:15.440 Why haven't they come out with a cipionate equivalent?

01:55:17.720 I think enanthate's what they use to get through the FDA. It's a good point. So that's what they

01:55:21.540 use. But the ticket is the 27-gauge needle, which is unbelievably tiny, with a very powerful spring.

01:55:26.660 Very long spring.

01:55:27.540 So it gets it in with less pain, and the patients just throw it away.

01:55:30.620 They don't even know it.

01:55:31.160 For a month, it's easy.

01:55:32.300 And so at 100 milligrams, what's your monthly cost on...

01:55:36.000 Cash price on Zyested?

01:55:37.060 On Zyested.

01:55:37.640 On Zyested, $150. Cash price.

01:55:39.400 So considerably more than cipionate.

01:55:40.900 Considerably more than cipionate, but some people say it's worth it.

01:55:43.420 It's worth it because I don't have to deal with the pain.

01:55:45.020 I don't have to deal with it. I don't have to travel. I don't have to draw it up on my trip.

01:55:47.700 It's easy.

01:55:48.240 And there's no user error associated with how much you're drawing.

01:55:50.880 It's easy.

01:55:51.220 If I have a dollar for every time a patient made a mistake on the math.

01:55:54.340 Yeah. So it's easy. Now, the orals are very fascinating.

01:55:57.700 And just approved last year.

01:55:58.900 Well, 2019. So undecanoate has been approved all over the world since 1970.

01:56:04.180 It's been around for numerous years. It's called andriol.

01:56:06.780 So when I went to China, when I gave in Australia, Europe, andriol is available in Canada,

01:56:10.660 but never got approved in the US.

01:56:12.600 In 2019, the first testosterone undecanoate got approved.

01:56:16.080 Why is undecanoate important?

01:56:17.420 Because orals historically cause hepatotoxicity,

01:56:20.080 but these go through the lymphatic system.

01:56:22.300 So they don't cause hepatotoxicity.

01:56:23.940 Do you swallow them?

01:56:24.960 You have to take it with a fatty meal.

01:56:26.460 But the newer ones don't have to be with a fatty meal.

01:56:30.140 They just have to be with a meal.

01:56:31.620 If you take it fasting, no absorption. Zero.

01:56:34.720 So if you're intermittent fasting, it makes it a little tricky.

01:56:37.000 So you have to take it-

01:56:37.440 But you could just commit to taking it at dinner every night?

01:56:39.420 It's BID.

01:56:40.240 Oh boy.

01:56:40.880 So not bad.

01:56:41.820 So what happens is you're supposed to take it at breakfast and dinner.

01:56:45.240 So off-label, I do give my patients at breakfast and lunch.

01:56:48.660 Because what happens is you superimpose the first curve on the next.

01:56:51.220 So you get a really nice level in the day and it goes on.

01:56:53.760 It mimics the diurnal variation.

01:56:54.920 So I like it better breakfast and lunch.

01:56:57.340 Again, that's off-label.

01:56:58.200 And what's the dose?

01:56:59.840 So it depends.

01:57:00.660 So Jotenzo, which is the one that first came out in 2019, the first one, 237 milligrams BID.

01:57:07.280 Talando came out in 2022.

01:57:09.760 So now we have two, and that's 225 BID.

01:57:12.980 And-

01:57:13.300 225.

01:57:14.160 BID.

01:57:14.580 Which tells you how inefficient the oral conversion is relative to the injection, right?

01:57:19.640 Right.

01:57:19.900 But you're getting still the blood level.

01:57:21.440 Yes, yes, yes.

01:57:21.900 But now in 2022, the third one just got approved.

01:57:26.280 So Keisotrex, the new drug by Marius Pharmaceuticals, is now the third oral.

01:57:30.580 So now we have three orals that are FDA approved.

01:57:33.480 So it's getting very popular.

01:57:34.480 But all of BID, the only difference is Talando has no titration.

01:57:38.000 So essentially it's 225 and 80% of patients should be in the normal range, but there's

01:57:42.180 no titration.

01:57:42.760 The other two you can titrate if you're not high enough.

01:57:45.620 So orals are popular.

01:57:46.820 Look, Americans are used to taking pills.

01:57:48.200 They have pillboxes, they put them in their pillbox, but there are patients who are injectables

01:57:52.300 that just love doing it once a week or twice a week.

01:57:54.280 Very convenient.

01:57:55.580 I do do a lot of pellets, a lot of pellets in men and in women. 1.00

01:57:59.140 I think they're very effective.

01:58:00.420 But the only issue with pellets is that the falling, you'll peak in 72 hours, but by that

01:58:05.060 third to four month, and this was our paper, we showed that there's a sharp decline.

01:58:08.420 It actually just goes very quick.

01:58:10.540 So patients, it's kind of weird.

01:58:12.080 I live great for three months and kind of lousy for the fourth.

01:58:14.440 And then I come in, I live great.

01:58:15.940 So we can shorten the interval to three months, you know, that's fine.

01:58:19.020 So the key is, I call it putting the balloon in the air.

01:58:21.320 We want to put the balloon in the air and catch it before it gets too low and put it in

01:58:24.580 the air again.

01:58:25.480 But you know, it can do some logistic problems.

01:58:27.620 I mean, if you've got a trip and you've got to get into my clinic quickly.

01:58:30.240 So a lot of patients do like the injectables because they're autopilot.

01:58:33.240 I don't have to deal with it.

01:58:34.540 And you know, just show people how large a tract you're making for a male to put testosterone 1.00

01:58:40.660 in him.

01:58:41.200 Like it's not a trivial size.

01:58:42.480 It's not a trivial size, although I would tell you, so we were taught initially that

01:58:46.260 you should make a W go one, two, three, or a V.

01:58:48.500 Or a V, yeah, is what I used to do.

01:58:50.140 But I don't do that.

01:58:50.760 So we invented a technique called stacking.

01:58:52.720 So basically we put it in and basically it's just like a column.

01:58:55.520 We put them up and down together because you want to keep the distance far away from the

01:59:00.020 incision or you'll get expulsion.

01:59:01.800 And every time you do a V, it's a whole new track for blood or trauma.

01:59:05.760 So we would do a stacking technique and it's worked quite well.

01:59:09.040 And the pellets, you know-

01:59:09.660 Stacking vertically or stacking on top of each other?

01:59:12.000 On top of each other.

01:59:12.820 Literally like a column.

01:59:14.120 And so, you know, it works very well.

01:59:15.940 These patients, patients who do it like it.

01:59:17.960 And so they keep coming.

01:59:19.060 There's a lot of people that travel and they don't want to have the hassle or they're

01:59:22.260 needlophobic.

01:59:23.000 So they come in.

01:59:24.080 And how long is a guy inactive for you after putting pellets in?

01:59:27.480 No exercise for 72 hours.

01:59:29.180 A bandage stays on for 48 hours.

01:59:30.880 You can shower with it, but no exercise.

01:59:32.820 So some people say, I like to work out.

01:59:34.760 I now can't work out for 72 hours.

01:59:36.180 I got to come see you every three to four months.

01:59:37.820 I have pain, some discomfort, not much, but you have some.

01:59:40.820 And I say, what about the injectable?

01:59:42.660 It's once a week.

01:59:43.880 When you consider the track record of how long these drugs have been around in each of their

01:59:48.200 various forms and the challenges of using endogenous versus exogenous, if a man is committed

01:59:55.480 to being on testosterone therapy, so you're no longer worried about preserving endogenous

01:59:59.800 function, do you favor the injectable over all others right now?

02:00:04.160 I do.

02:00:04.420 So I worry about erythrocytosis also.

02:00:07.140 So we did a study showing that I think the worst thing you can do is give 200 milligrams

02:00:10.920 IM every two weeks.

02:00:11.900 That doesn't make a lot of sense to me.

02:00:13.920 And the drug will last about 10 days.

02:00:15.180 So for about four days, you're not even having any medication on board.

02:00:17.840 But you have a high erythrocytosis rate because it's the spiking that causes that erythrocytosis.

02:00:22.900 So if you have a man and you drop to 50 milligrams twice a week, the erythrocytosis rate goes

02:00:28.200 down.

02:00:28.600 It's more physiologic.

02:00:29.520 So as long as they don't mind doing it twice a week, it's my favorite.

02:00:33.240 It works the best and it's the cheapest.

02:00:35.040 And it produces a better physiologic level.

02:00:36.880 We didn't talk about topical.

02:00:38.420 I have never been a fan of topical for men.

02:00:42.400 I think it's acceptable for women because our options are limited. 1.00

02:00:45.660 But tell me what your views are on topical.

02:00:47.700 I don't favor topicals for several reasons.

02:00:49.700 So we did a paper in 2009 that showed that 20% of men won't even absorb a topical.

02:00:54.040 So that's poor absorption.

02:00:55.620 Same in women, by the way. 1.00

02:00:56.760 It's really problematic.

02:00:58.160 The formula is milligrams times percent penetrance.

02:01:02.960 And that's variable.

02:01:03.840 It's variable.

02:01:04.600 And it's even variable day by day on the same person.

02:01:07.400 So if I happen to get-

02:01:08.240 How clean is the skin?

02:01:09.320 What part of the skin do you apply it onto?

02:01:10.960 Has the skin been exfoliated?

02:01:12.640 Hair.

02:01:13.000 All of these things.

02:01:13.600 Yeah.

02:01:14.060 So if a patient, I give him 1,000 milligrams of testosterone, he has 0% penetrance, he gets

02:01:18.580 nothing.

02:01:19.180 So I said, patients, don't get fixated on how many milligrams I'm giving you.

02:01:21.920 Let's look at the end result.

02:01:22.880 What is your level?

02:01:23.620 So the problem is that if you look at the attrition rate, if a man starts on a gel today,

02:01:28.820 only 20% are on that gel at the end of one ear.

02:01:31.920 It's the convenience.

02:01:33.060 It's having to do it every day.

02:01:34.320 It's the levels.

02:01:35.100 Twice a day, right?

02:01:35.980 It's once a day.

02:01:36.780 It's once a day, okay.

02:01:37.340 Gels are once a day.

02:01:38.220 You can do up to twice a day, but it's once a day.

02:01:40.240 But the issue is this.

02:01:41.280 I can't even get the levels that men want to be on sometimes on a gel that I can get on

02:01:45.960 an injectable.

02:01:46.920 So there's many reasons why.

02:01:48.160 The cost, you get insurance, right?

02:01:49.960 The cost.

02:01:50.500 You can get a compounded cream, which has even less penetrance.

02:01:53.600 So I'm not going to go there.

02:01:55.380 So I've never been, and don't forget about transference.

02:01:58.180 It's a big problem with men because they're covering so much of their body surface area 0.71

02:02:02.220 to get this stuff.

02:02:02.760 If you have a pregnant woman at home, if you have a child at home, you want to be careful 1.00

02:02:05.300 as well.

02:02:06.020 And if you have to travel with it, TSA.

02:02:07.960 So there's a lot of issues with the gels that I really, really don't think you should do.

02:02:12.280 For women, you mentioned women, injectables and pellets work fantastic. 0.99

02:02:15.860 Pellets are great.

02:02:16.840 The injectable, you have to kind of compound it to get the dilution.

02:02:19.380 But it's easy.

02:02:19.660 So if we go 50 milligrams per ml, it's 0.1 cc.

02:02:22.820 I usually go 20 per ml.

02:02:24.180 And go 0.1 cc's a week.

02:02:25.820 It's easy.

02:02:26.880 And they find it very effective.

02:02:28.880 Let's now talk about physiology.

02:02:31.480 So how does testosterone work?

02:02:34.240 How does DHT work?

02:02:36.020 How should we think about testosterone, DHT, and estrogen?

02:02:39.120 And why do they all matter?

02:02:40.280 So we talked about the breakdown, testosterone going into estradiol, testosterone going into

02:02:44.640 DHT.

02:02:45.680 Testosterone has numerous effects on different body parts at different levels.

02:02:51.280 So we know that erectile function typically is around 200 nanograms per deciliter.

02:02:55.360 When you start falling below 200 nanograms, you start losing nocturnal erections, right?

02:02:59.240 Muscle tends to be higher.

02:03:00.580 Bone tends to be higher.

02:03:01.340 So different body parts, I guess, call it turn on at different levels.

02:03:05.320 So in other words, what's the highest?

02:03:07.000 What has the greatest sensitivity to falling testosterone?

02:03:09.640 The way to cover yourself is just being the upper quartile.

02:03:12.140 If I'm in the upper quartile, I know I'm covering because everyone's different.

02:03:15.280 But again, you're saying when you said 200 nanograms per deciliter, that's total.

02:03:18.940 How do we determine free the cutoffs?

02:03:21.500 That's important.

02:03:22.280 Everyone's different.

02:03:23.160 So I have to say this.

02:03:25.120 I never understood why we use this number 300.

02:03:28.460 What are you telling me?

02:03:29.540 300 nanograms is a definition for hypogonadism.

02:03:32.340 So are you telling me that 290, we must all feel bad?

02:03:34.860 And at 310, we must all feel good.

02:03:36.560 That is not true.

02:03:37.660 Not even close.

02:03:38.340 That's what it's come to.

02:03:39.860 So the reality is that there are many patients at lower levels that feel good.

02:03:42.840 It's based on the sensitivity of the androgen receptor.

02:03:45.360 So when I was a fellow in my lab, very beginning, we would take the blood.

02:03:48.640 We'd go back and count the CAG repeats.

02:03:50.820 Patients who had longer CAG repeats would have more sensitive receptors.

02:03:54.560 And why is that?

02:03:55.500 Insensitive receptors, excuse me.

02:03:56.740 Because everyone's different.

02:03:58.040 Your receptors and my receptors have different sensitivities.

02:04:00.880 Genetically, how we're made.

02:04:01.980 So everyone has a different sensitivity of the receptor.

02:04:04.880 So many have shown that people respond differently to different doses based on sensitivity.

02:04:11.420 Dr. Zitzman in Germany showed that depression can be associated with sensitivity interceptor,

02:04:15.540 sexual function.

02:04:16.680 So sometimes people need more to feel better.

02:04:19.940 And I think that's a misconception because a lot of times people say, well, you're in the

02:04:23.700 normal range.

02:04:24.320 You're at 400.

02:04:25.640 Something else may be going on.

02:04:27.160 And invariably, if you can raise them to the upper quartile of normal, cover them, you

02:04:31.440 may see symptomatic improvement.

02:04:32.680 Do you think we're ever going to get to the point where TRT can be customizable based

02:04:39.220 on a more broad view where a patient comes to see you and you do an androgen receptor

02:04:44.140 assay on them and you couple that with what their free T is and make decisions based on

02:04:49.540 that as opposed to just sort of flying a little bit blind and having to guess?

02:04:53.740 That would be amazing.

02:04:54.580 So we did that in our lab.

02:04:55.660 And so I had some of my colleagues say, hey, can you have this patient I don't understand?

02:04:58.860 Can you look at the sensitivity to antireceptors?

02:05:00.860 My lab is not CLIA certified, so I couldn't give you...

02:05:03.600 You can't give advice.

02:05:04.260 I can't give advice, but I can look at different assays.

02:05:07.780 But I think that would be amazing.

02:05:09.220 So there's got to be other factors that can predict.

02:05:11.800 Because right now it seems very archaic.

02:05:13.500 How complicated is the assay?

02:05:15.020 It's so easy to run.

02:05:16.120 But the only thing is it does take a little bit of manual labor.

02:05:18.520 My technician would have to sit there and he'd literally have to...

02:05:20.480 Like it's an ELISA or what's the...

02:05:21.640 It's an ELISA test that you simply have to count C-A-G and circle it.

02:05:25.060 C-A-G and circle it. 0.99

02:05:26.740 And then he would then say, hey, Kira, I have C-A-G repeat of 28.

02:05:30.020 So you know he's extra.

02:05:31.260 Do you not get the impression like LabCorp or somebody like this could generate that?

02:05:35.020 Or even just a proprietary lab could get the CLIA certification and go ahead?

02:05:38.620 But what's the ROI?

02:05:39.420 So the thing is it's about how much money will they make if they do it?

02:05:42.360 Yeah.

02:05:42.620 And you're saying the market might not be there because the majority of the TRT market is wildly

02:05:47.620 unsophisticated.

02:05:49.300 And their answer is just give more testosterone. 1.00

02:05:51.300 And that's what they do.

02:05:52.080 Not titrate testosterone to the right...

02:05:54.200 Based on sensitivity.

02:05:55.300 Right.

02:05:55.480 How dare I assume that people would care about the level of nuance I would, right?

02:05:59.780 Now let's talk about DHT.

02:06:01.100 So you mentioned that testosterone gets converted.

02:06:03.360 I think you said about 6% to 8% of it gets converted.

02:06:05.960 Presumably there's quite a bit of genetic variability there.

02:06:08.240 I mean, 5-alpha reductase activity is really quite genetic.

02:06:12.120 And what is the purpose of DHT?

02:06:14.000 So DHT is the most potent androgen we have on our body.

02:06:17.560 In terms of sexual function, it's extremely important.

02:06:20.380 When you remove the DHT, it can have a significant impact on someone's sexual function.

02:06:24.200 So that's typically what I look at.

02:06:26.120 Now look, DHT is implicated for prostate in terms of prostate growth.

02:06:29.480 It's implicated for hair as well.

02:06:31.540 So these are medications that are used to take away the DHT because they can cause alopecia.

02:06:36.120 So 5-alpha reductase is located all over the body.

02:06:39.140 There's type 1, there's type 2.

02:06:40.760 So type 1 can be in the scalp.

02:06:42.340 It can be in the brain.

02:06:43.340 It can be in the prostate.

02:06:44.260 It can be in the adrenals.

02:06:45.220 It can be in the kidney.

02:06:46.040 They're all over the body.

02:06:47.620 The finasteride is predominantly type 2.

02:06:49.960 We do tasterides type 1 and type 2.

02:06:51.940 We may talk about that later.

02:06:52.940 But it's important to realize that these enzymes are throughout the body, have multiple functions

02:06:57.220 throughout the body.

02:06:58.380 Go over that type 1, type 2 again.

02:07:00.320 So finasteride, was that the first drug used to treat BPH?

02:07:05.260 So yeah, finasteride came out in 1992.

02:07:08.660 As proscar.

02:07:09.460 As proscar.

02:07:10.360 Five milligrams of finasteride to treat BPH.

02:07:13.260 Yes.

02:07:13.600 Then in 1997, the one milligram dose came out as propecia.

02:07:18.560 And then later on, I believe 2012, was dutasteride.

02:07:22.780 And when you look at the graph-

02:07:24.580 And dutasteride was brought out to treat BPH?

02:07:26.640 Avodart.

02:07:27.280 Avodart.

02:07:27.980 But it was for BPH.

02:07:29.100 BPH.

02:07:29.700 Okay.

02:07:30.260 So when you look at 5-alpha reductase activity, there's type 1 and type 2, two isoenzymes.

02:07:36.400 If you look at where they are, type 1 and 2 is in the scalp.

02:07:39.420 Type 2 is predominantly more in the prostate, but so is type 1.

02:07:43.220 They're in the adrenal glands.

02:07:44.520 They're in the brain as well.

02:07:46.580 They're also located in the epididymis, all over the body.

02:07:49.960 So it's not just affecting just one location.

02:07:54.280 You're affecting numerous parts of the body when you're taking away the DHT.

02:07:59.900 And that can have detrimental effects.

02:08:02.460 About an hour ago, you said you do not like to use 5-alpha reductase inhibitors in your

02:08:06.360 practice at all.

02:08:07.220 I don't.

02:08:07.700 So that means if a guy comes in with BPH and you want to treat him medically, not surgically,

02:08:13.600 what would you use as first line?

02:08:15.100 Alpha blocker or daily Cialis.

02:08:17.300 That's it.

02:08:18.020 And you're seeing as good a response with daily Cialis as you would see with dutasteride

02:08:23.620 or Proscar?

02:08:24.740 I'm seeing a much better response with an alpha blocker.

02:08:28.060 And then I would then use-

02:08:28.880 And the alpha blocker of choice is?

02:08:30.260 I usually use alfuzosin only because alfuzosin has the least rate of retrograde ejaculation.

02:08:35.740 You can use tamsulosin or you can use psilidocin, but alfuzosin has a-

02:08:39.020 So for younger men-

02:08:40.020 And what's the brand name on that one?

02:08:41.540 Uroxitrol.

02:08:42.100 So it tends to have the least rate.

02:08:43.240 So for younger men, they prefer to have that.

02:08:45.180 So typically that's the medication choice.

02:08:47.060 I think finasteride is a very bad drug.

02:08:49.420 And I think it has very detrimental effects.

02:08:51.220 You are the second very prominent urologist to raise this to me, the first being Ted Schaefer,

02:08:57.260 which has got me and my team trying to wrap our minds around this thing called post-finasteride

02:09:03.980 syndrome.

02:09:04.900 Do you want to tell people what it potentially is?

02:09:07.200 I know there's a ton of controversy and confusion around it.

02:09:09.400 So finasteride, they're patients who have taken finasteride who develop irreversible sexual

02:09:15.520 neurologic symptoms, for example, permanent ED, libido, psychological problems, depression,

02:09:22.700 suicidal ideations.

02:09:24.320 And I believe it's a real syndrome.

02:09:26.420 I don't believe everyone who takes finasteride gets post-finasteride syndrome, but I do believe

02:09:31.100 that there's a subset of patients who take finasteride who develop this condition.

02:09:36.020 I'm the minority.

02:09:37.360 Most people do not.

02:09:38.520 And I accept that.

02:09:39.800 So the official position of the American Urologic, what is it, AUA association is what?

02:09:45.520 Well, if you look at the package, it states there are patients who have prolonged side

02:09:49.360 effects with this drug.

02:09:50.200 It says it.

02:09:50.880 It's there.

02:09:51.420 But the true definition of a statement on post-finasteride, there's no statement.

02:09:55.820 Essentially, most clinicians don't believe it exists.

02:09:58.700 I do believe that there's a subset of patients who take finasteride that have a significant

02:10:03.820 adverse effect.

02:10:05.280 There's a plausible mechanism for that.

02:10:06.580 I want to explain what that is.

02:10:08.000 But the key thing is this.

02:10:09.860 We were taught in medical school that finasteride blocks the conversion from testosterone to

02:10:15.240 dihydrotestosterone.

02:10:16.200 And that's it.

02:10:16.680 That's all we were told.

02:10:17.880 But that is only one fraction of the story.

02:10:20.240 Because each one of those steroids then goes into something called a neurosteroid.

02:10:25.460 DHT goes into an entretendiol.

02:10:27.420 That's the neurosteroid.

02:10:29.040 Then you multiply that by six.

02:10:30.960 So six steroids are blocked.

02:10:33.300 And those six steroids then have a decreased conversion into their neurosteroid.

02:10:37.540 I'm sorry.

02:10:37.780 The six steroids are blocked because 5-alpha reductase acts on more than one steroid?

02:10:42.840 Progesterone, aldosterone.

02:10:44.540 There's a whole linear.

02:10:45.980 It's not just testosterone.

02:10:47.560 Oh, I see.

02:10:48.300 I see.

02:10:48.580 So the problem, the biggest problem is when you blocked progesterone getting into its

02:10:52.840 neurosteroid called allopregnanolone.

02:10:55.380 Why is that important?

02:10:56.500 Because allopregnanolone has been implicated for depression, anxiety, cognition, right?

02:11:03.200 So some of those neurosteroids are very important when it comes to depression, anxiety, depression,

02:11:08.540 cognition, so much so that there has been an increase in suicide rates in men who've had

02:11:16.120 this post-finasteride syndrome.

02:11:17.520 If you had to guess, what percentage of men who take finasteride experience negative side

02:11:24.240 effects that persist upon the cessation of the drug?

02:11:27.260 I don't have a denominator, but I will tell you this.

02:11:29.440 In the package insert, it says less than 5%.

02:11:31.920 I think it's more than 5%.

02:11:33.260 And I think many men get these symptoms, but they're taking it when they're 60 or 65 and

02:11:38.820 they think it's a normal part of aging.

02:11:40.740 They say, oh, I'm supposed to get ED.

02:11:41.980 But a 30-year-old knows this is not normal.

02:11:44.620 A 20-year-old knows this is not normal.

02:11:46.180 But the key is this.

02:11:47.620 Let's say you do or do not believe in post-finasteride.

02:11:50.740 I believe in it.

02:11:51.200 Let's say you don't believe in it.

02:11:52.560 Okay, you say it's not true.

02:11:53.940 What you cannot deny is that there's an increased risk of suicides in this population of men, irrespective

02:12:01.220 whether you believe it's true or not.

02:12:03.260 And I'm sorry, this is in all men who take finasteride or just young men?

02:12:06.760 Certain men who have post-finasteride syndrome who take finasteride.

02:12:11.580 So for example, I had a study.

02:12:13.640 I had 25 men who had post-finasteride, 25 men who were controls.

02:12:17.560 In my 25-

02:12:18.060 The controls are men who took finasteride but had no symptoms.

02:12:20.680 Who never took finasteride at all.

02:12:22.280 And the reason I did that was the reason because I was looking at gene variation.

02:12:25.420 I would take skin biopsy of both populations. 1.00

02:12:28.600 I was looking at genes, upregulation, downreaction of genes between the two populations.

02:12:31.660 Just normal controls and a finasteride.

02:12:34.080 But two patients out of my 25 committed suicide in my trial.

02:12:38.100 And I'm sorry, the men who were taking finasteride in your trial were taking it for what reason?

02:12:42.660 Predominantly alopecia.

02:12:43.600 So you could technically argue that there's another issue going on.

02:12:48.840 That whatever it is that's driving someone with alopecia to take finasteride for hair loss

02:12:53.580 speaks to a difference in emotional state that might be predisposing them to some.

02:13:00.080 In other words, it would be more interesting to see if you had 50 men who were all taking 0.51

02:13:04.600 finasteride for the same indication, but you isolate the 25 who are experiencing negative symptoms.

02:13:12.080 I think that would be very important.

02:13:13.600 I agree.

02:13:14.120 Or do a randomization.

02:13:15.260 I agree.

02:13:16.020 In either case, it has to bring some attention.

02:13:19.320 8% suicide is an alarming rate.

02:13:22.060 And that was over what period of time?

02:13:23.400 It was over a five period.

02:13:24.640 But my study was just a point in time.

02:13:26.280 They'd come and visit.

02:13:26.980 We would do that.

02:13:27.580 But after they left, we follow up these patients.

02:13:30.620 8%.

02:13:30.980 So if I told you any drug-

02:13:32.360 And just to be clear, again, to push back, because this is so important that we think

02:13:35.860 through this rationally.

02:13:37.500 Do we know what the history was of mental illness in those patients?

02:13:40.300 Did they have a history of depression before taking the drug?

02:13:42.780 We don't have significant mental illness before they come in.

02:13:46.260 They weren't on SSRIs.

02:13:47.700 They weren't to have a history of depression when they came in.

02:13:50.620 So that's important to know that.

02:13:52.080 They weren't diagnosed with depression prior.

02:13:54.320 But any drug, if I told you drug X, it doesn't matter what you believe the cause is, is associated

02:14:00.040 with higher suicidal rates.

02:14:02.300 I would say, okay, let's take a closer look and see what's happening.

02:14:05.740 It doesn't matter.

02:14:06.180 That's what I'm saying.

02:14:06.620 It seems to me that a random assignment trial would address this.

02:14:10.040 And if you didn't want to do randomization, you would at least be able to do a post hoc

02:14:13.600 analysis in the way that I've described it.

02:14:15.320 And it's amazing that that's not being done.

02:14:17.180 Do we see the same effect of dutasteride?

02:14:19.240 Patients who've taken dutasteride had symptoms, but it's not as prominent.

02:14:22.280 And I think probably it's because, A, a lot of the patients who were taking this were

02:14:25.640 taking it for alopecia.

02:14:26.780 So they were taking finasteride.

02:14:28.320 But there have been reports of dutasteride symptoms the same way.

02:14:32.860 I think that's important.

02:14:33.580 So I think more attention has to be given to this condition.

02:14:37.740 And that's why my personal bias, I do not give finasteride.

02:14:40.820 So when men come to you on those products, you'll say, if the guy's coming to you on

02:14:45.200 that product for BPH, we've got the alpha strategy and the Cialis strategy.

02:14:49.820 If the guy's coming to you on that product for hair loss, you'll tell him what?

02:14:53.160 I tell both men, if they're coming to you on BPH or alopecia, I tell them that there

02:14:56.560 is a condition that's been associated with this, men taking this medication that can

02:15:00.120 cause an impairment in sexual function and actual depression and anxiety.

02:15:04.760 Many countries, Canada, France, UK, have put on their package insert.

02:15:08.500 Black box.

02:15:09.200 Not black box, but this warning saying that, hey, there's an increased risk of suicidal

02:15:13.040 ideation.

02:15:13.860 This is not trivial.

02:15:15.040 Technically, SSRIs have that warning as well.

02:15:17.680 And it's never clear to me that SSRIs are causing an increase in suicide.

02:15:22.240 It's in part, I think that we're looking at a demographic that's more susceptible to

02:15:26.680 suicide.

02:15:27.280 I think that's the thing I'd always struggle with.

02:15:29.420 What I find most interesting about this, and I'm not doubting that there's something there,

02:15:34.720 is why does it linger after the drug stops?

02:15:38.860 That's the part that is undoubtedly most disconcerting.

02:15:42.940 If this is real, how is it that a guy can take this drug for a year, stop it, and two

02:15:50.900 years later, he is still suffering the sexual side effects associated with it?

02:15:55.420 That strikes me as epigenetic.

02:15:58.540 I can't come up with another explanation.

02:16:00.620 That's exactly right.

02:16:01.240 So there are many plausible mechanisms, one being that could be epigenetic.

02:16:05.480 One is silencing of the 5-ARI gene through DNA methylation.

02:16:09.880 So that's been the most common prevailing thought.

02:16:13.620 Okay, but we don't know.

02:16:15.620 But that's one of the most common thoughts.

02:16:17.400 Again, it needs to be studied.

02:16:19.420 Let's talk a little bit about the role of testosterone in prostate cancer.

02:16:23.220 Because when I bring up testosterone replacement therapy for men, the question I get asked the

02:16:29.220 most is about prostate cancer.

02:16:30.900 Now, I've documented and discussed this in so much detail.

02:16:33.660 I think I've probably done two, if not maybe three podcasts on the subject, including a

02:16:39.100 dedicated AMA podcast on all things that relate to testosterone as far as risks and benefits.

02:16:47.000 And I would say we've spent more time on this than just about anybody, perhaps not as much

02:16:51.320 as you.

02:16:52.300 We came away from this analysis with the belief that there was no evidence that exogenous

02:16:58.220 testosterone application was increasing the risk of prostate cancer.

02:17:01.540 And there was actually some evidence that hypogonadism may not be increasing the incidence of prostate

02:17:09.660 cancer, but may have increased the incidence of high-grade prostate cancer.

02:17:14.520 Furthermore, we saw virtually no evidence that exogenous testosterone therapy was leading to

02:17:21.800 an increase in atherosclerotic cardiovascular disease.

02:17:24.620 Though there was one study that suggested in the short run, i.e. within one year, highly

02:17:30.840 susceptible men might see an increase in the risk of ASCVD, but that risk decreased at two

02:17:37.440 and three years post-treatment.

02:17:39.000 So with that being my current state of understanding, can you fill in the gaps?

02:17:43.940 This is a great topic.

02:17:44.780 So this thought that testosterone causes prostate cancer started in 1941, Huggins and Hodges, Nobel

02:17:51.200 Prize, based on one patient.

02:17:53.060 One patient in 1941, when they gave exogenous testosterone, the prostate cancer got worse.

02:17:58.540 If you look at the different paradigms, the American Urologic Association in 2018 came

02:18:04.040 out with the testosterone guidelines, guideline on that undersection, patients should be informed

02:18:08.560 there's no association between testosterone and prostate cancer, strong recommendation.

02:18:13.080 So finally, patients say, I Googled it, I heard I can get prostate cancer.

02:18:15.760 I said, no, the guidelines are very clear.

02:18:17.440 Based on the evidence, no data to support it.

02:18:19.380 So contrast that for a moment with the guidelines on estrogen therapy and breast cancer in women,

02:18:25.140 which we're not going to go down that rabbit hole because I get way too phosphorylated.

02:18:28.360 But talk about the difference between men and women and how differently they're treated

02:18:34.500 with respect to hormone therapy.

02:18:36.000 I think a lot of that started with the WHI.

02:18:37.540 The WHI, of course. 0.89

02:18:38.160 So you get this big news and everyone's off hormones.

02:18:41.840 And later on, you get a reevaluation of the WHI and say, hey, maybe we made some mistakes.

02:18:45.600 But all that noise.

02:18:46.500 But the damage was done.

02:18:47.260 So we're going to talk about the TRAVERSE trial.

02:18:49.020 So I've been involved in the TRAVERSE trial.

02:18:50.900 The TRAVERSE trial is coming out in June.

02:18:52.560 This year, it'll be coming out at the endo meeting about cardiovascular.

02:18:55.720 But that was very similar.

02:18:57.500 The impetus part of the TRAVERSE was, hey, we have no large trial in men.

02:19:01.100 You know, we have something in women. 1.00

02:19:01.960 We have nothing in men.

02:19:02.920 And the TRAVERSE, 6,000 patients, randomized placebo-controlled trial, largest of its kind

02:19:07.380 will be coming out pretty soon.

02:19:08.300 But I want to finish about prostate cancer.

02:19:10.220 So there's a paradigm shift.

02:19:12.060 And the paradigm shift is that maybe testosterone may not only be safe, but it may be protective

02:19:18.400 against the development of prostate cancer.

02:19:20.680 So I just want to give you an example.

02:19:22.020 In 2015, the Hopkins group published a very interesting study on a concept called bipolar

02:19:28.280 androgen therapy.

02:19:29.320 They called it BAT.

02:19:30.140 Who was the lead on that?

02:19:30.960 It's Schwartzer, and the senior was Denmead in 2015.

02:19:35.540 And they did something very unconventional.

02:19:37.720 You walk in with metastatic prostate cancer into Hopkins, and what they do is they give

02:19:42.120 you high doses of testosterone to treat your metastatic prostate cancer.

02:19:45.480 Which is mind-boggling because the standard care for that patient is the exact opposite.

02:19:49.980 Right.

02:19:50.260 It's to give you androgen deprivation. 0.97

02:19:52.340 It's to chemically castrate you. 0.97

02:19:53.820 Right.

02:19:54.100 And the way they would do it, they would give you Lupron first to shut you down, and then

02:19:57.980 they would give you high doses, 400 milligrams every month, and it would go up and down,

02:20:02.140 and it would basically convert the castrate-resistant prostate cancer to castrate-sensitive.

02:20:07.460 And so essentially, the PSA went down by 50%, and what they saw was the radiographic disease,

02:20:12.980 metastatic disease, went down by 50%.

02:20:14.280 That is unheard of to give that metastatic prostate cancer patient testosterone.

02:20:18.600 The same group published numerous, really impressive studies, but my favorite was the one that came

02:20:25.100 out in 2021 called the TRANSFORMER trial.

02:20:28.460 This is mind-blowing.

02:20:30.100 So they took about 200 patients who had castrate-resistant metastatic prostate cancer, and they said,

02:20:35.980 okay, and if they became resistant to abiodarone, the treatment of care is enzalutamide,

02:20:40.680 which is an androgen receptor blocker.

02:20:42.720 They said, instead of giving everyone enzalutamide, we're going to give half the men high doses

02:20:47.240 of testosterone.

02:20:48.660 Okay, so let's see what happens.

02:20:50.500 So they gave them enzalutamide or high doses of testosterone.

02:20:53.040 They found that the overall survival between the two groups was the same, no different.

02:20:57.420 But the difference in quality of life?

02:20:58.880 Was significantly better on the patients.

02:21:00.240 Of course.

02:21:00.780 But it got even more interesting.

02:21:02.160 You were allowed to, if you took bipolar anogen therapy, you were allowed to switch

02:21:06.400 over to enzalutamide if you became resistant, and vice versa.

02:21:09.100 The patients who did bipolar anogen therapy and then did enzalutamide had significantly

02:21:15.300 greater survival, 37 months versus 28 months, than enzalutamide, which is the standard of

02:21:21.580 care.

02:21:22.300 The cost of enzalutamide is 8,000 a month.

02:21:25.040 The cost of 400 milligrams of testosterone is about 100 a month.

02:21:27.860 And they had significantly greater survival.

02:21:31.240 This was published in 21.

02:21:32.800 21.

02:21:33.460 So we're two years after that.

02:21:35.860 Yes.

02:21:36.260 How many men with metastatic prostate cancer are receiving that care now?

02:21:40.120 I think minuscule.

02:21:41.400 Why?

02:21:41.660 I don't know why attention was not given, more attention was given to this study.

02:21:46.180 It's called the Transformer trial.

02:21:47.660 It was really impressive as using a standard of care, which is enzalutamide versus bipolar

02:21:52.260 anogen therapy and then enzalutamide.

02:21:53.740 So I think you're going to see a lot more of therapeutic use of testosterone.

02:21:58.500 I also, you're going to see a lot of studies.

02:22:00.040 There have been some recent studies suggesting that giving testosterone to men after radical

02:22:03.080 prostatectomy may be potentially protective against biochemical recurrence.

02:22:07.040 That was Tom Ollerin's group.

02:22:08.720 Look, I'll tell you what.

02:22:09.440 So I have a lab.

02:22:10.540 In my lab, we do a lot of basic science work with testosterone and prostate cancer.

02:22:14.180 One of the studies we did is we took Petri dishes.

02:22:16.520 We put Lincap cells, prostate cancer cells in those Petri dishes.

02:22:19.960 And we gave each one of those Petri dishes different amounts of testosterone. 0.75

02:22:23.700 And it is true, when you initially give testosterone, you see prostate cancer cell growth.

02:22:28.480 No question.

02:22:29.460 But when you give higher and higher doses of testosterone, you see greater and greater

02:22:33.140 suppression of prostate cancer cell growth.

02:22:35.740 We call that the inverted U, where maybe castrate may be protective, eugonadal protective, but

02:22:42.180 hypogonadal is dangerous.

02:22:44.400 So then we said, okay, let's do it in animals.

02:22:46.560 200 mice.

02:22:47.520 Wow.

02:22:47.920 Castrated 50 mice.

02:22:49.260 We gave castration.

02:22:50.680 We gave 50 controls.

02:22:51.760 We castrate and give low doses of testosterone.

02:22:54.320 And then we give castrate and high doses of testosterone.

02:22:56.240 These are pellets in the mice.

02:22:57.820 We published both these articles.

02:22:58.940 What we found was that if you castrate the mouse, you get a decrease in prostate cancer

02:23:04.100 growth.

02:23:04.900 No question.

02:23:05.740 It helps.

02:23:06.740 Low doses of testosterone, you start getting increased in prostate cancer growth.

02:23:10.300 High dose, you get a statistically significant decrease in inverted U.

02:23:14.240 So if I have prostate cancer-

02:23:15.420 And the high dose compares how much to the castration?

02:23:18.760 Essentially, it's a eugonadal range.

02:23:20.420 Essentially, castrate-

02:23:21.080 So castration behaves almost the same as-

02:23:23.800 Slightly better, but in certain cases, in the animal case, in the Petri dish, it was better.

02:23:28.220 It just varies.

02:23:29.360 But the key is this.

02:23:30.440 If I have prostate cancer, either castrate me or put me in the normal range, but do not,

02:23:35.800 I think, personally, put me in the hypogonadal range.

02:23:38.280 I think it's the danger zone.

02:23:39.800 Yeah, except I would say having watched men get castrated chemically, it's awful.

02:23:45.740 I mean, I generally advise men to undergo surgery whenever possible.

02:23:49.380 If surgery is an option, if you're that Gleason 3 plus 3 or 3 plus 4 or whatever, and it's

02:23:54.880 just a question of having the best surgeon operate on you, yes, there is a lot of downside

02:23:59.680 of surgery, but I think it pales in comparison to the downside in what I see from men that 0.92

02:24:05.920 undergo chemical castration.

02:24:07.420 The metabolic syndrome-

02:24:08.440 Yes.

02:24:08.620 And the metabolic derangement that follows from being hypogonadal, beyond hypogonadal,

02:24:13.160 they're basically eugonadal, not to mention the complications of bleeding that follow with

02:24:17.840 the radiation.

02:24:18.500 So again, I'm sure there's lots of medical oncologists and radio oncologists that are

02:24:21.980 listening to me now wanting to put arrows into the back of my head, but I don't think

02:24:26.140 I'm speaking with just a surgeon's bias.

02:24:27.840 I think I'm speaking from watching men in the years that follow undergo complete metabolic

02:24:33.700 destruction.

02:24:34.760 And even if they're still alive, their quality of life is so poor.

02:24:39.580 So that's why I would say like, gosh, if there's a medical way to do this with high-dose

02:24:43.620 testosterone-

02:24:44.740 You're right.

02:24:45.120 And certain patients do benefit better with radiation just based on Gleason score.

02:24:48.720 But at the end of the day, yes, if it's moderate, we give them six months.

02:24:51.960 If it's severe, we give them two years of androgen deprivation therapy.

02:24:55.040 But we do, in my practice, treat men after radiation with testosterone.

02:24:59.160 It's controversial.

02:24:59.820 We'll get into this.

02:25:00.460 And what dose are you using?

02:25:01.380 100 a week?

02:25:02.080 So typically, I will use gel first.

02:25:03.980 I want a short acting so I can stop it if the PSA.

02:25:05.940 Then we'll move on to an injectable.

02:25:07.420 But I treat them just like I normally would treat any other patient.

02:25:10.000 You treat them to a level of total T or free T at the top quartile?

02:25:14.360 Just like I would at someone in the normal therapeutic range.

02:25:16.740 But there's no data to support that it causes cancer.

02:25:18.820 And what kind of consent form do these men sign to undergo something that is so radical?

02:25:22.680 And do you need an IRB for this?

02:25:23.860 If you look, most clinicians or urologists, there was a recent survey looking at urologists,

02:25:28.240 96% of urologists will treat men after radical prostatectomy with testosterone.

02:25:33.120 86% of urologists-

02:25:33.960 Yes, after radical.

02:25:34.880 After radical, 86% after radiation therapy.

02:25:37.220 Look, there has to be some consent here.

02:25:39.360 There has to be some informed decision making.

02:25:41.260 The American Urologic Association made it very clear.

02:25:43.640 The risk-benefit ratio after prostate cancer surgery or radiation is unknown, right?

02:25:47.500 We don't have the randomized placebo-controlled trial.

02:25:49.760 So I tell them, look, we don't have a randomized placebo-controlled trial.

02:25:52.080 These are the risks, these are the benefits, and we have a shared decision-making model.

02:25:55.740 But there's something important.

02:25:57.020 You have to understand something called the prostate saturation model.

02:26:00.140 It's really important.

02:26:01.740 We were taught in medical school that the higher the testosterone, the greater the PSA.

02:26:05.620 We were taught it was linear.

02:26:06.920 And the higher the testosterone, the greater the growth.

02:26:08.600 That is not true.

02:26:10.020 At some point, it saturates.

02:26:12.480 We did a study in 2011.

02:26:13.860 We said the saturation was around 250 nanograms per deciliter.

02:26:17.480 So if you take a guy who is-

02:26:18.940 That's pretty low.

02:26:19.620 Pretty low, but that's where the inflection point was.

02:26:21.820 And others have shown the same thing, roughly around 250, but we're all different.

02:26:25.000 But why is that important?

02:26:26.180 Because if you have a man who starts out with a testosterone level of 190, and you put him

02:26:30.400 on testosterone-

02:26:31.440 His PSA should go up.

02:26:32.380 It should go up.

02:26:33.300 If he's at 290, and you put him on testosterone, it should not go up.

02:26:36.620 And if you take the guy from 290, and take him to 3,000, it should not go up.

02:26:40.620 Because it's saturated.

02:26:42.100 It plateaus.

02:26:43.320 So that's why if I give someone Lupron, that testosterone goes down, but the PSA goes down.

02:26:48.240 But if you raise the testosterone, it's not the more I raise it, the more the PSA goes

02:26:52.720 up.

02:26:53.600 So the tricky part for me is when patients come to me after radiation therapy, because

02:26:57.340 they've been given androgen deprivation therapy.

02:26:59.040 The testosterone is 50.

02:27:00.380 Their oncologist spent all this time taking away the testosterone.

02:27:02.400 That's right.

02:27:02.800 And when you get it from 50 past 250, you're going to see that rise until you hit saturation.

02:27:06.720 And so the oncologist says, what are you doing?

02:27:08.660 Patient says, what's going on?

02:27:09.520 I have to set the expectation.

02:27:10.720 It's going to rise.

02:27:11.820 It's going to plateau.

02:27:13.160 I just have to have the understanding with you based on the saturation model.

02:27:15.980 You just have to have this understanding.

02:27:18.080 What about testosterone and breast cancer?

02:27:20.600 This is a topic I have become very fascinated with.

02:27:24.020 I want to do a dedicated podcast on breast cancer and all things that have to do with it,

02:27:27.920 because it's obviously such a comprehensive and such an important topic, given its obvious

02:27:33.120 impact on women.

02:27:34.500 But while I have you here, does anything you do focus on from a research perspective?

02:27:38.740 The effects of testosterone as an adjunct to therapy, especially in the estrogen-sensitive

02:27:45.480 breast cancers?

02:27:46.840 Yeah.

02:27:46.980 So I do treat women who have a history of breast cancer.

02:27:50.020 We may treat them with testosterone.

02:27:52.080 It's working with the oncologist.

02:27:53.860 Many times, though, I will typically use drugs that are not hormone-based, like Adi particularly,

02:28:00.260 because that will give me the same benefit of libido, but with using dopamine.

02:28:04.580 Oh, but you're using it for sexual function. 0.99

02:28:07.300 Sexual function. 0.98

02:28:07.660 I got it.

02:28:08.140 No, I meant for...

02:28:09.800 I've been reading a lot of case reports that have suggested that testosterone replacement

02:28:14.500 therapy with aromatase blockade in women with breast cancer is a therapeutic option.

02:28:21.240 In other words, testosterone is protective against breast cancer.

02:28:26.900 And I don't know if the aromatase inhibitor is necessary.

02:28:29.000 That's an even more controversial topic, but at least the thinking there would be you want

02:28:32.640 to prevent testosterone from becoming estradiol.

02:28:35.480 Sure.

02:28:35.660 So the studies I've seen are giving testosterone without the aromatase inhibitor.

02:28:39.320 And letting both go up.

02:28:40.280 And showing that it's still protective.

02:28:41.960 But I don't have a lot of experience in treating women with breast cancer.

02:28:44.420 Yeah.

02:28:44.440 I'm going to hopefully find somebody that can.

02:28:46.940 Well, we've covered a lot here today.

02:28:48.140 This is a really interesting topic.

02:28:51.240 And even though I came into it knowing very little, I feel like I've learned a lot, both

02:28:56.060 in terms of pathology and the treatment.

02:28:58.740 So Mo, I want to thank you very much for this.

02:29:00.460 My pleasure.

02:29:00.940 My hope, of course, is that everybody listening to this, who's impacted by anything on the

02:29:04.640 spectrum that we've talked about, is at least a little more empowered to kind of realize

02:29:07.860 that there are people like you out there.

02:29:10.060 And presumably, do you have a sense of how many doctors in the country would have your degree

02:29:14.900 of certification?

02:29:15.740 So the urologists who have been subspecialized.

02:29:17.780 Sure.

02:29:18.260 So I'm part of an organization called the Sexual Medicine Society of North America.

02:29:21.800 And this is exactly what we do.

02:29:23.240 It's a great organization.

02:29:24.140 We're 1,200 strong.

02:29:25.520 And urge you to go to the website, look at it.

02:29:27.280 Which is very interesting.

02:29:28.000 That's almost, if I remember correctly, that's about the same number Sharon said, that there's

02:29:31.800 about 1,200 or so doctors that are kind of doing what she's doing as well.

02:29:35.660 In that group, there's a lot of APPs, nurse practitioners.

02:29:38.940 So that 1,200 encompasses all of us.

02:29:41.140 But all of us have the same passion and desire in this space.

02:29:44.980 So sometimes someone's looking for a provider in their area.

02:29:47.880 You can go to the website and find a provider in that area.

02:29:51.100 Sometimes you work via telemedicine.

02:29:53.300 In the state of Texas, it only can be in Texas.

02:29:55.660 So I can only do telemedicine in Texas through Baylor.

02:29:58.780 Yep.

02:29:58.940 What percentage of those 1,200 are at major academic institutions like you are versus

02:30:04.020 in private practice?

02:30:04.860 Yeah.

02:30:05.100 So I'd say the majority are in academic institutions.

02:30:07.320 I'd say about the 1,200 or 400 or 450 are urologists.

02:30:11.040 Majority are in academic institutions.

02:30:13.200 Well, Mo, thank you very much.

02:30:14.580 I hope you enjoy the rest of your weekend here in Austin playing tennis.

02:30:17.260 The weather looks to be a little warm.

02:30:18.800 Thank you so much for the invitation.

02:30:20.060 Thank you, Peter.

02:30:20.860 All right.

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02:32:57.180 I don't know.

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02:33:04.640 I don't know.

02:33:06.160 I know.

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02:33:10.020 I know.

The Peter Attia Drive - June 26, 2023

#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.

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