Dr. Mohit Khera spoke at the 24th annual Perspectives in Urology Point • Counterpoint meeting on Friday, November 13, 2015 on “Advances in the Treatment of Erectile Dysfunction.”
Keywords: erectile dysfunction
How to cite: Khera, Mohit. “Advances in the Treatment of Erectile Dysfunction” Grand Rounds in Urology. December 3, 2015. Accessed Nov 2020. http://dev.grandroundsinurology.com/advances-in-treatment-erectile-dysfunction.
Advances in the Treatment of Erectile Dysfunction
I want to thank Dr. Crawford and the program committee for giving me the opportunity to discuss advances in the treatment of erectile dysfunction. There’s really going to be six areas I like to go over today with you and give you the history of ED throughout the ages. I’d like to talk about current ED treatment options and go through some of the guidelines. As many of you know, the AUA is currently developing the updated guidelines that won’t be out until the end of 2016. So I’ll go through some European guidelines right now.
Talking about testosterone for the treatment of erectile dysfunction, looking at a new way to think about ED, changing the paradigm, and really focusing on the endothelium. Talking about treating the female partner for female sexual dysfunction and how does that play into treating men’s erectile dysfunction, and finally ending with some future potential ED therapies. So let’s get started. I always like to talk about history – where it came from – you know we’ve been living and treating ED for thousands of years. [su_spacer]If you look at even the 2600 BC, they talk about internal medicine as using 22 potions to cure impotence. Even the Egyptians talk about using crocodile hearts mixed with wood oil applied to the penis to treat ED. Even in the eighth century, they talked of consuming goat testes to treat erectile dysfunction. It wasn’t really until the 1860s where we talked and learned that this could be a neurogenic problem. Wasn’t until 1908 where we’d learn how to do a dorsal vein ligation procedure. [su_spacer]If you look at the modern era, Bentley Scott invented the peanut prosthesis in 1973, which really made a big impact on the way we treat erectile dysfunction. As you can see, as we go further at the advent of MUSE, and it was in 1998 with Viagra and PD5 inhibitors now we currently have 4 PD5 inhibitors all the way to Avanafil, which was in 2010. So we made a lot of progress here. So this is one of the older studies. I like to quote it because even on a plane or reading a magazine they always quote the Feldman study. [su_spacer]In this is the Massachusetts middle-aging study, which they show that roughly 52% of men between the ages of 40 and 70 have some degree of ED, it’s pretty profound. 52% of men between the ages of 40 and 70 have some degree of ED. And when patients walk into my office, they say “doc why is this happening to me? I don’t understand. Is this something unique to me?” And I tell them the statistics. I tell them, “you know ED is a natural part of aging. We have no choice. Every man will develop erectile dysfunction – it’s a matter of when.” The way to think of it is 40% at 40, 50% at 50, 60% at 60, 70% at 70. You live to a hundred, and 100 % of men will develop erectile dysfunction as a natural part of aging.
What is really occurring here is we’re predominantly getting a ptosis and atrophy of the cavernosa muscle. Many of us are also getting impairment of arterial inflow as well. But again it’s a natural part of aging. Many causes of ED, remember the mnemonic from medical school was “VENT.” That’s what I learned VENT – vascular endocrine neurologic and trauma. Vascular being the most common cause of ED and out of the most common cause of ED vascular, it’s venous leak right? So there are two options – arterial insufficiency and venous leak – venous leak being the most common cause of ED for these men. There are many drugs and they can induce ED on the boards for urology. They are always on there, it’s a beta blocker. If you see beta blocker, just check it right away because it’s notorious for causing erectile dysfunction. Ace inhibitors are actually okay but beta blockers are bad.
Remember this concept, the psychogenic ED, because we know that is a good percentage of patients even in the 30s. Up to 27% of patients in their 30s can have ED. Predominately patients have psychogenic ED and not organic ED. So we know that numerous men have ED but not many men are treated. You know there are studies looking at millions of men not realizing that roughly 75% of men who have erectile dysfunction are not being treated for this condition at all. Other studies found that roughly 77% of men with ED were not being treated for this condition. And there’s many reasons for this. There’s feelings of shame, concern that physician won’t take the sexual problem seriously. You know my wife is a family practitioner and she tells me that when these patients come in pretty sick, and you have about 12 to 15 minutes per patient, they got diabetes, hypertension, hyperlipidemia, and usually ED is at the bottom of the list. And so they really don’t question patients on erectile dysfunction. So this is the European guidelines and again remember I mentioned the AUA’s coming out with updated guidelines the end of 2016. So I’ll just show you the European guidelines that I think are excellent.
A patient comes in with self-reported ED and typically in our practice we use the IIEF. We actually use an abridged version that is a lot easier. Do they have Peyronie’s disease? Premature ejaculation? Is there any other concomitant conditions? Identify common causes of ED. Are they diabetic? Did they have a radical prostatectomy? And then are there any irreversible factors as I mentioned earlier. If they’re on a beta blocker, get him off a beta blocker. If they’re on an SSRI, can I get them off the SSRI? If they’re smoking, can I get them to stop smoking? These are things I can reverse and improve the erectile function. And then we look at psychogenic causes as well.
So it’s a focused exam. We look for penile plaques and deformities particularly Peyronie’s disease, prosthetic exam, signs of hypogonadism meaning small testicles or atrophic testicles or soft consistency. Then we do a cardiovascular neurologic exam, which I think is extremely important and I’ll get to that in just a minute. And then on the board, remember the boards require three tests for a man who walks in with ED. These are the three tests. You need to get a testosterone, you need to get a hemoglobin A1C, and you need to get a lipid panel. Those are on the boards every year as well testosterone, hemoglobin, A1C and lipid panel. Those are the standard lab tests for a man who presents with ED.
So these are the treatment algorithms. So the patient comes in and you defined that he has erectile dysfunction. I would provide information reversing some of the causes to lifestyle modification, diet and exercise. We educate the patient and it’s important to educate the partner. And again I’ll be talking about this briefly as well. Typically, first line therapies are PD5 inhibitors. So we’ll start at PD5 inhibitor. If a patient can’t take a PD5 inhibitor, you can use intracavernosol injection therapy or vacuums from Muse, which we’ll talk about. And then you assess the response to therapy.
Now the focus on one thing, it’s really about this retrial because many patients will take a P5 inhibit if they’re first time. And what happens when they take that PD5 inhibitor and they engage in sexual activity is that they’re nervous and they have a huge adrenergic response and they clamp down those arterial arteries. And so we tell patients that you have to have at least three tries. Andy McCullough would tell you six tries of a PD5 inhibitor before you know that it truly fails. So it’s important to counsel them to take it on an empty stomach. When do these patients want to have sex? They go out and have a wonderful meal and a couple of drinks – that’s when they want to take Viagra. Viagra does not work like that. You have to take before you go out to dinner on an empty stomach, then you can have the meal, then you can have the drinks, and it’s much more effective. So again we really want to take it on an empty stomach.
So this is an algorithm that I like a lot because it really breaks down the first line – second line therapy. You can look at the first line therapy is really the PD5 inhibitors at 75% to what’s being prescribed. We know that urethral suppositories, injectables, vacuum pumps make about 25% of the therapy prescribed by both PCPs and urologists. Really implants are about 5% of patients; only 5% of patients ever make it to a penile implant, less than 1% with corrective vascular surgery. So I’m just going to through some of the in the background of these meds. You’re already familiar with most of this but sildenafil remember that it really should be taken on an empty stomach an hour before engaging in sexual activity. Half-life is only 4 hours, Tadalafil at 17.5 hours, and so if you have a patient that typically engages in sexual activity they usually take 20 mg on Friday at 5 o’clock. Then they’re usually covered Friday night, Saturday morning, Saturday night and Sunday morning. Don’t have to think about it so most patients will take the Tadalafil on the weekends.
So if you have a patient who has a history of an MI or your concern that they have a history of an MI, you don’t want to give them Tadalafil. Because if you give them Tadalafil today and they have an MI tomorrow, they could still not get nitroglycerin in the ER right? So you can, you should, only give that patient Viagra or Levitra or the Avanafil. If someone has an arrhythmia, you don’t give them Vardenafil because it prolongs the QT interval right. So if they have an arrhythmia you don’t give them Vardenafil. Avanafil’s new, it came out in 2000, end 2013. It has a five hour half-life. What’s different about Avanafil is that it’s FDA approved for 15 minute onset as early as 15 minutes to be taken with food and alcohol. And it’s highly specific for phosphodiesterase five, which is in the penis. So we don’t see a lot of side effects you may see with other medications.
I’m putting this in here because it’s in the package insert of every single one of the PD5 inhibitors. I thought it’s very interesting. I’m going to just skip to the section which I think is very important in the center. I think for legal purposes, medical legal purposes you should know what it says. And it says patients with the following characteristics – recent serious cardiovascular events, resting hypotension, uncontrolled hypertension, unstable angina, angina with sexual intercourse, New York Heart Association class II or greater with CHR, hereditary degenerative retinal disorders including retinitis pigmentosa – were not included in the clinical safety and efficacy trials. PD5 inhibitors are therefore not recommended for these patients.
I think that’s very important because if you give a patient with anyone of these conditions a PD5 inhibitor and they do have an adverse event, again it will be hard to defend because it’s in the package insert these patients are not recommended to get PD5 inhibitors. Remember historically they can’t take a PD5 inhibit if you’re on a nitrate. It’s all we really remember, but there are other conditions that you should be or aware of. The markets interesting if you look at what’s happening. You know all these PD5 inhibitors are actually not, are actually decreasing in sales except one. And it’s Cialis but it’s really Cialis 5 mgs. 5 mg Cialis seems to be the only one that’s really taking off and growing in a market were the rest are actually declining. And there’s a reason for this now, I’ll show you why. But I think that the daily PD5 inhibitors have a huge impact on not only improving erectile function by preserving erectile function and actually reversing the ED process. Daily PD5 inhibitors are myotrophic. They actually increase smooth muscle content within the cavernosum muscle, the only type that does.
Just a comment on testosterone treatment to treat ED. We know that testosterone actually has a profound impact on the cavernosum smooth muscle. So every time we do a penile implant we actually harvest the cavernosum muscle. We send it to my lab. Some of the high-density testosterone receptors, they’re actually in the cavernosum muscle. And we know that if you take away testosterone, you can impair nitric oxide synthase, which is within the cavernosum muscle. You can alter PD5 expression – it impairs cavernosum nerve function – and also contributes to veno occlusive disease. We know that patients who are hypo gonadal tend to have increased fat deposition within the cavernosum. And many of you know fat is very hard to compress the walls and they develop venous leak.
There have been some studies looking at testosterone to improve erectile function. Some of the studies have looked at patients who are PD5 inhibitor failures. You put them on testosterone supplementation, up to 50% of patients will respond to PD5 inhibitors. I will tell you that testosterone as a monotherapy is not great. I’ll tell you if a patient walks in with ED – you know moderate ED – just up in one testosterone alone is not going to cure their ED. But maybe 10 to 15% mild ED may see a difference. Where testosterone is very effective is in combination with other medications. The user with a PD5 inhibitor and urethral suppositories tends to increase the efficacy of those medications. Inter cavernosum injection therapy – many are familiar with Edex’s commercial -most of us are using Trimix because it’s generic and a lot cheaper. One of the biggest complaints I get with Trimix is, “doc you know we’re on going on vacation this weekend and I got to take a bag and an ice pack in a cooler.” And I can guess you can go with the Edex, but the difference in price is $60 versus three dollars an injection. So it’s a big difference.
Something pretty popular in our practices is using a lyophilized compound, Trimix, which actually comes in a kit like this and comes with 10 vials already to go. And what the patient will do is he’ll take the syringe and inject 0.5 cc’s into one of these vials and they can use it as needed. So they don’t have to worry about refrigeration or having to keep it on ice. It’s ready to go and patients can actually use it for a longer period of time.
So urethral suppositories have been around for a while we’re all familiar with this as well the medications at the tip the place into the penis. I would tell you that as monotherapy I don’t find these to be extremely effective. I think it’s very good combination therapy. Patient walks in and says, “doc I’m getting 70% rigid on Viagra and I don’t want to stick a needle in my penis what can you do?” I say, “well you can use MUSE in combination therapy.” There also is a compound Trimix gel as well, which is about $7, where alprostadil – these suppositories – typically come in at $60, so it’s a big difference in price.
Vacuum erection devices, many of you are familiar with as well. I will tell you that one of the benefits of this is obviously the cost. Once you pay for it, you can use it as many times as you want at no cost. The second benefit is for penile rehabilitation. So remember that most men will lose some penile length after radical prostatectomy. The vacuum has been the only thing shown not only to preserve penile length, but in some studies it’s been shown to actually increase penile length on radical prostatectomy.
And then finally the penile implant, as many of you arevaware invented by Dr. Brantly Scott in 1973. Typically a three piece is the most commonly used. There has been one change in the way we place our reservoir. Majority of us are now placing an ectopic reservoir because many of you know that the reservoirs are now flat so we don’t place them into the space erectus. We really just place them underneath the fascia and there’s less chance for injury to the bowel or bladder.
So I just want to change, spend a few minutes about changing the way you think about ED. So I want you to think about ED like a disease. It’s a progressive disease like cardiovascular disease, and as we get older everyone develops this disease. Now if you broke your leg today, I would have two choices. I could give you Vicodin for the rest of your life and you can continue to try to walk, or I can fix your leg. Those are the two options. The problem with all the medications I showed you up there is like giving you a Vicodin right. Give someone Viagra when you want to have sex but the disease continues to get worse and Vicodin is just masking the problem. So what can we do to reverse the disease process?
Well, we’ll tell you that many have shown that there’s a correlation between eating and cardiovascular disease, and I think that’s important. Ian Thompson was the first in 2005. He looked at the placebo arm of the prostate cancer prevention trial. Roughly 4,000 men, none of them had ED, but 57% of those men developed ED at five years. But he found something interesting. If a man developed ED today, 15% of them had a heart attack or stroke within seven years. That was interesting and so we say how do we explain that. And Dr. Montorsi was able to explain it. He was able to also describe something called the arterio-diameter theory. He noticed that many of these men were developing ED about three years before they had their heart attack or stroke.
And so he described his theory, and it makes a lot of sense. The arterio-diameter theory states this: the smallest arteries are the penile arteries 1 to 2 mm, the coronaries 3 to 4 mm, carotid 5 to 7 mm, femoral 6 to 8 mm. If you remember from physiology, 50% occlusion of an artery equals end organ damage. So you’re much more likely to occlude the penile arteries before the coronary, the coronary before the carotid, and the carotid before the peripheral. And if you look at the statistics, a man always will get ED before he gets a heart attack, a heart attack before he gets a stroke, and a stroke before he gets peripheral vascular disease. So it’s not surprising that ED could be the first marker of a man’s cardiovascular status. So we screen these patients if a man walks in and has ED and two cardiovascular risk factors, those patients get a stress test.
So what’s the link? The endothelium is the common link. You can have hypertension, diabetes, hypogonadism, lipidemia, oxidative stress leads to endothelial cell injury, vasoconstriction, autonomic activity, thrombosis, atherosclerosis – the end result is ED and cardiovascular disease. So the trick is how do we protect the endothelium or how to do we actually reverse the endothelium? And so there are many ways to do it. You can look at serum markers in the blood. You can look at cellular markers, you can look at imaging, and you can actually look at physiological measurements. So we use peripheral arterial tonometry. And in many old studies, we’ll flow media dilation of the brachial artery and really what that is, I’ll show you a device that we use. This as a device called the EndoPAT. So the patient walks into my office and I put a tourniquet around the bicep. I will then elevate those pressures superficially. There’ll be a probe on the one finger and there’ll be a probe on the contralateral finger. And if a patient has a very healthy pressure, then we’ll release the tourniquet. If a patient has very healthy arteries, the artery will be able to vasodilate when it sees the blood and it dilates very well. So we use a ratio called RHI, which is the dilation of the control finger over the normal finger, which gives me a number.
Now why is that important? Because in 2004 at the Mayo Clinic, they did a very clever study. They took all these patients and they did the EndoPAT study. And right after the EndoPAT study, they put them back into the cardiac cath lab and did a cardiac cath. And they showed that if a patient had RHI less than 1.47, they had a high risk of having occult cardiovascular disease. So the finger was a surrogate marker for the heart. So several years later, we say we’re going to repeat the same study. We took all these patients we did an EndoPAT study and we’ll put them in penile duplex. Same thing was cutoff was 1.8. If a patient had RHI less than 1.8, they had a very high risk of having an occult blockage arterial insufficiency on penile duplex.
So again the finger could be a nice marker for the rest of the body and the endothelium as well. As I mentioned earlier, the common link is the endothelium. So I want to show you something. Some of the smartest doctors I know out there are actually cardiologists. They are brilliant. I’ll tell you why. Because several years ago, they figured out how to reverse cardiovascular disease, how to reverse it. And so they said, if we can improve the endothelium we can actually improve cardiac blood flow and we can actually treat coronary artery disease. Very interesting. So if you believe that the endothelium is the common link, how do they do it? They did several things. They did diet and exercise. If statins, improve insulin resistance, they get aspirin, smoking cessation, summaries using PD5 inhibitors, and believe it or not some are using testosterone placement therapy to improve the endothelium to reverse cardiovascular disease.
So it’s not rocket science if you believe that the endothelium is the common link between eating and cardiovascular disease. All we have to do is copy the cardiologists. Just take their model right and now we can use the endothelium to treat ED. Cardiovascular disease and ED are related. So if we improve the endothelium, we can improve penile blood flow and treat ED. So you may say this doesn’t make a lot of sense. I’ve never seen these therapies treat or reverse erectile dysfunction but you would be surprised. So the first was Esposito in 2004, a remarkable study. And what she did was she took 110 men, 55 men were asked to do a diet and exercise program, 55 were not. They all have ED and they were obese. And the control group just had counseling, I mean no counseling whatsoever. So if after two years, those that did some diet and exercise lost weight. And make sense right, but they also had a significant improvement in endothelial function markers. In fact statistically significant improvement in erectile function scores with just diet and exercise alone. And a multivariate analysis changes in body mass, physical activities and C-reactive protein were all independently associated with IIS scores.
So diet and exercise do matter. Statins believe it or not are very helpful as well, and this is just a small study looking at 18 men with hyperlipidemia as the only risk factor for ED. Organic ED was verified by abnormal nocturnal penile tumescence in a SHIM score. And they were given Lipitor to decrease their cholesterol. After just four months, 88% had improvements in erectile function, SHIM score significantly increased and also RigiScan scores, which are objective, also increased as well.
This is a smaller study to randomize, but double blind placebo control study looking at men who had ED who failed Viagra. So these patients were given Viagra, it failed and what they decided to do was give these patients Lipitor. And at the end of four months, what they found was those patients that took the Lipitor had not only improvements in LDL, but many of them became responders to PD5 inhibitors. So again you may be able to salvage some of those nonresponders to PD5 inhibitors. This is a meta-analysis of looking at 11 randomized trials assessing the effects of statins on erectile function. Highest score significantly improved with statins compared to controls. And what’s interesting is that increases in IIEF with statins were approximately 1/3 to 1/2 of the PD5 inhibitors. This is pretty impressive.
Chronic PD5 inhibitors – this is what I really believe in, and most of my patients are on chronic PD5 inhibitors, with a full dose of the PD5 inhibitor is what we call a kicker. So we’re all on the baseline of PD5 statin daily with a kicker on top. There’s several reasons for this. So this is a randomized controlled trial of 20 men with ED treated with Tadalafil 20 mg on alternate days or on demand. So this is chronic versus on demand. Endpoints were peak systolic velocity as I mentioned earlier, flow media dilation the cavernous arteries. They look erectile function scores and markers endothelial function as well. And so peak systolic flow media dilation was actually improved and higher on those patients taken chronically versus on demand. And chronic treatment patients had great improvements in morning erections but what was most important was this one right here. So there were significant improvements in markers for endothelial function if you took the PD5 inhibitor regularly, and even if you stop the PD5 inhibitor and measured the blood three months later. Those men that had taken it still had significant improvement in markers of endothelial function showing persistence affect even three months out.
Just one comment on testosterone, because there is some controversy here but there is data support that testosterone may improve the endothelium as well. This is a study by Aversa where he took 50 men and what he really did was, these are hypogonadism men, and he gave them testosterone and measured the plaque in the carotid. It was supposed to be a two-year study, and he stopped at the end of one year, because what he found at the end of one year was that those men that were being treated with testosterone had a significant reduction. A reduction in carotid plaque compared to those that weren’t – again suggesting that there may be some improvement in endothelial function and arterial blood flow.
So this is typical what we do in our practice. We’ll give patients questionnaires but we do look at markers and affiliate function, C-reactive protein, look at Apo B, micro albumin? Some patients with specialized testing, but we do lean heavily on lifestyle modification? These patients are on daily PD5 inhibitors. Most of them I will start them on statin. I’ll let their primary care physician know if I do. But I will start them on statin and, as I mentioned earlier, if they have greater than two cardiac risk factors I’ll send them for cardiac evaluation. And again we do replace testosterone in those patients who are hypogonadal.
One comment on female sexual dysfunction because there is no point in improving a man’s erections if they have no one to have sex with I will tell you that right now. We used to treat a lot of men who get these great libidos, great rectal function. They would go home and many of their wives were postmenopausal and the wives would call and threatened to sue me, and say look we were doing great until he met you. He never wanted to have sex and now he chases me around the house; he wants to have sex all the time. And it’s my fault. And it’s true, so the reality is either you raise both libidos and sex drive and function, or you keep them both low. But the problem is when one is high and one is low. It is set up for disaster you know so we treat the couple. And really, we look at this as a couples disease.
And so I’ll just mention that we know that many men out there, when we asked about the wives, 43% of women, this is statistics, 43% of women suffer from some degree of female sexual dysfunction. Most of them are just using lubrication as the only form of therapy; some are using hormones as well. Only 9% are being treated. If you look at those women who have female sexual dysfunction, thy report that about a third of the men at home have ED. Again this is a couple’s disease. If you’re treating one partner, you should really think about the other as well.
I think the best was Irwin Goldstein’s study. Irwin Goldstein did a very clever study. He said I’m going to give all these guys Levitra or placebo, and I may give their wives a female sexual function index, which is the most validated questionnaire for penal sexual function. And all I want to do is see what happens with these indices as these men are treated. And so the men who got Levitra had a great improvement in ED, which you’d expect, but the women, if the partner was being treated with Levitra, women saw significant improvement in sexual desire arousal, lubrication, orgasm, overall satisfaction without any form of therapy. The only therapy was treating her partner with Levitra right. And greater improvements in ED scores were correlated with greater improvements in FST scores. So I will tell you that we treat a lot of women and that we treat a lot of men. So part of the treatment for ED, I will tell you, if you treat men for ED is that you really want to focus on the female partner. If you improve her libido, you’ll significantly improve his erectile function as well, and realize men women are very different.
When I treat men it’s simple – a little Viagra and testosterone. With women, we really need to focus on a multi-modal approach. What we typically will do is have lifestyle modification for them – weight loss, therapy, biofeedback. You know sometimes we need vasodilators, relaxation and many of them are SSRIs, so you want to stop the SSRI and typically put them on Wellbutrin. So these are the theories. We use hormonal therapy for women; we also use non-hormonal therapy as well, a lot of that testosterone been very effective. One thing that is very effective is this new drug here. This was released on October 17, 2015 called Addyi. You may have seen it in the media; they call it the female Viagra. It’s not really female Viagra. All it is is a daily pill that you take every day that increases dopamine, decreases serotonin, and increases a woman’s desire for sex. So until October 17, there were 26 drugs to treat men for ED; there were zero drugs to treat women for sexual dysfunction. Now there’s the first drug ever to treat women for female sexual dysfunction.
I am going to end with three things I want you to be aware of that could be coming in the future. This is nitric oxide polymers. This is a study we did in our lab and basically our goal, if many of you know what TESTOPEL is, is for patients to come in they would get an injection in the penis and they would be able to have erections, great erections for four months or six months. And come back and get another injection every four to six months. Across the street is Rice University, and they invented these small polymers. They’re called nitric oxide polymers that are currently used in cardiac stents to prevent stenosis after patients get cardiac stents. And so these polymers are tiny, there hundred microns, and we would first label them in the rat to make sure that they don’t migrate. And so we did some in vivo studies where we actually made these rats diabetic. We would check the blood sugar to make sure they were diabetic and we put them into forearms, diabetic, diabetic plus Viagra, diabetic plus nitric oxide spheres, and nitric oxide spheres plus sildenafil. So again the goal is these are small spheres injected into the penile tissue that don’t migrate. And there just chronically releasing nitric oxide, which is what you do when you take Viagra.
And so these are some of the studies. We’ll then cumulate in the carotid to get the mean arterial pressure. We will stimulate the cavernosum nerves as well – this is the cavernosum nerve being stimulated – the rat penis we’re measuring the pressures inside the rat penis as well. And these were what the curves look like and what I want you to focus on really is you can look at this one right here. These are controls right here, these are diabetics; you can see a significant reduction in each of cavernosum pressure. If you give the diabetic rat’s sildenafil they improve. Diabetic rats with nitric oxide spheres, it’s always back to controls, and you give them nitric oxide spheres plus sildenafil, that’s actually better. So we’re trying to now take this to human trials and we have a few more animal studies to do, but to take this to humans where they’d come in and we would inject the penis with nitric oxide spheres.
Two other things to keep aware of in the future, it’s stem cells. Stem cells really are I think the way of the future for the treatment of erectile dysfunction. And the first, about a decade ago in 2004 when it really first got published, over the past 10 years there’s been a tremendous amount of interest. Most of the studies are animal studies but the real mechanism, the way this works, is it increases angiogenesis and actually increases cavernosum smooth muscle to potentially reverse venous leak. We have two trials going on now. We have a human clinical trial that we’re doing right now. And we also have an animal trial as well.
And finally one comment on shockwave lithotripsy. This has actually taken off quite a bit as well and this is, we call it low intensity shockwave lithotripsy or shockwave therapy, which is LIST. Now there are different protocols. The one I see most common is 1,500 shocks twice a week for a total of three weeks. Some go all the way to six weeks and the thought is that it increases angiogenesis neo vascularity. Some of the studies in the literature have shown that it improves endothelial function. And it can improve some patient non-responders to PD5 inhibitors to be responders. After two years, about half of the patients maintain their improved erectile function. So this is something just to keep an eye on.
So in conclusion, testosterone therapy should be considered as a treatment option in hypo gonadal men with ED. The endothelium offers a new and exciting target for the treatment of erectile dysfunction. The treatment ED should take into account the status of potential treatment of the female partner’s sexual function. And finally nitric oxide microspheres, stem cells and LIST may offer new future treatment options for ED. Thank you for your attention.