Does Testosterone Cause Prostate Cancer and Heart Attacks?

Nelson Vergel from ExcelMale.com and DiscountedLabs.com interviews Dr. Mohit Khera, one of the world's top experts in urology and testosterone therapy with over 100 publications. He debunks myths about testosterone and prostate cancer, cardiovascular risks and DVT / blood clots. He discusses the use of hCG, clomiphene and other products. He also reviews data on natural ways to increase your own body's testosterone production. For more information visit: Testosterone Interviews on ExcelMale

Transcript:

Nelson Vergel:                  Hello everybody, Nelson Vergel here with excel male dot com and discounted labs dot com. I'm very honored today to introduce my urologist here in Houston. I'm very privileged to have doctor has published more than a hundred articles last time I Googled his name, and he's one of the experts in the field of men's health, urology, testosterone replacement, prostatic issues. I think you also treat, Doctor Khera, female sexual dysfunction, too. Very happy to have him, he's going to give today a lecture that I think everybody's going to find extremely interesting covering the controversies of testosterone therapy

Dr. Khera:                            Thank you for the introduction. I appreciate it. As you mentioned, there have been significant controversies with the use of testosterone therapy over the past five years. Cardiovascular risk, DVT, prostate cancer, BPH, and today I'd like to discuss some of those controversies and give you some further insight into the diagnosis and treatment of hypogonadism.

Dr. Khera:                            I always like to give you some of the statistics. I'm not sure if many of you know this, or are aware that in 2012 testosterone was one of the fastest growing medications in the United States. There wasn't a single medication that was selling faster than testosterone. The concern that while the testosterone sales were increasing, the testing in the United States during this time was also starting to decline. One interesting statistic was that roughly 27 percent of men who initiated testosterone did not have a blood test before taking the medication, and 21 percent of men who started testosterone didn't have a follow-up test. So clearly there was some abuse with testosterone and some concerns.

Dr. Khera:                            When I talk about controversies today I'd like to give you three different perspectives. I want to give you the perspective of what the FDA label has to say, as well as what the guidelines have to say. We were very fortunate in 2018; two guidelines came out. The AUA, the American Urological Association, came out with their testosterone guidelines the same time the endocrine guidelines also came out with their testosterone guidelines, as well. So I'd like to share with you these three different perspectives as we go forward.

Dr. Khera:                            The first is on the concept of venous thrombosis embolism or VTE, and so you should be aware that in the package insert of a testosterone products in 2005 in the adverse reactions section of the label, it was appended to note that one patient during the open-label extension trial did suffer from the DVT. Now in 2009, the label was changed again under the new medication guide that lists blood clots in the legs among the serious side effects. If you open the package insert for testosterone products, you will see, and this is just for Androgel, that they do put in the section warnings and precaution a concern for VTE. I'll read this. There have been postmarketing reports of VTE events including DVT, PE in patients using testosterone products, Androgel in this case. Evaluate patients who report symptoms of pain, edema, warmth, and erythema in the lower extremity for DVT and those who present with acute shortness of breath for PE. If a VTE is suspected, discontinue treatment with testosterone and initiate appropriate workup and management.

Dr. Khera:                            So this is in the package insert, and you should be aware that patients will read this and they will ask you about this. We should be very careful because the guidelines slightly differ, and if you look at the American Urologic Association guidelines, it states that patients should be informed that there is no definitive evidence linking testosterone therapy to a higher instance of VTE. The entering guidelines don't have a guidelines statement on this, but they do have some comments that they've made. They do state that case-control and pharmacoepidemiological studies have not shown a consistent increase in the risk of VTE with testosterone treatment. However, there is two huge testosterone associated VTE events in randomized controlled trials to draw meaningful imprints.

Dr. Khera:                            So you can see where there are three different perspectives here, and they all are slightly different in their beliefs in how testosterone affects VTE.

Dr. Khera:                            The second controversy is cardiovascular risk. Many of you may be aware of this. There was a significant amount of concern at one point that testosterone may cause a heart attack. So I'll put this in the context of a story. It was very interesting, Molly Shores in 2006 published a very nice study looking at men at the VA and what she found was that those men with lower testosterone levels were much more likely to suffer from earlier death. They died earlier or sooner than men with normal testosterone levels. If you look at the studies following the Molly Shore study, they were prospective studies, larger studies, all finding the same thing. Those men with lower testosterone levels tended to have increased mortality, and if you look at the right-hand column, the cause of death seemed to be cardiovascular death in many of these studies.

Dr. Khera:                            Before 2010 there were also many studies suggesting that giving testosterone may decrease the risk factors for cardiovascular events. Risk factors meaning obesity, metabolic syndrome, diabetes, cholesterol, and they may have some beneficial effect in decreasing the risk factors of cardiovascular disease.

Dr. Khera:                            We conducted our review and looked at every single article we could find from 1940 to 2014. We found over 200 articles addressing testosterone and cardiovascular disease. The majority of these studies being favorable against suggesting low testosterone is a risk factor of cardiovascular events, and we could only find four studies suggesting that testosterone may increase cardiovascular risk. Now, these are the four studies; I don't have the time to go into each one of these in detail. The majority of these studies are not randomized or placebo-controlled, and the Finkel study did not even have a control group. But suffice to say that these studies did bring up some concern that testosterone may have an increased risk for cardiovascular events.

Dr. Khera:                            Based on these studies, the FDA did put in the package insert, and you should be aware, that to date epidemiologic studies in randomized controlled trials have been inconclusive in determining the risk of major adverse cardiovascular events and patients should be informed of this possible risk when deciding whether to use or to continue the use of Androgel one percent. So this is in the package insert.

Dr. Khera:                            The EMA which is the equivalent of the FDA did look at this data and have not made any changes to their cardiovascular warnings of their products. The guidelines are a little different. I will tell you that in 2018 we also published another study looking at all the studies from the FDA warning in 2015 to the current date, and we found 23 studies also looking at testosterone and cardiovascular disease, and again we couldn't find any studies suggesting that testosterone increases the risk of cardiovascular events. We found studies suggesting that men who normalize their testosterone with testosterone therapy had a reduced risk of MI and death compared to those men whose testosterone failed to normalize.

Dr. Khera:                            The AUA and endocrine guidelines do have statements on this, and the first statement by the AUA guidelines is very clear. Clinicians should inform testosterone deficient patients that low testosterone is a risk factor for cardiovascular disease. That's important. Low testosterone is a risk factor for cardiovascular disease. Now, they go on to say, "Before initiating testosterone treatment clinicians should counsel patients and this time it cannot be stated definitively whether testosterone therapy increases or decreases the risk of cardiovascular events." If a patient does have a cardiovascular event, the AUA guidelines suggest that we wait at least three to six months before starting therapy again. The endocrine guidelines are a little different. The editing guidelines recommend that we wait six months, not three to six months, but six months if a patient suffers from an MI we should wait at least six months. But the endocrine guidelines also agree there's no conclusive evidence to support that testosterone supplementation is associated with an increased cardiovascular risk in hypogonadal men.

Dr. Khera:                            Those mechanisms, just so you know, is several, there are four theories, but the most common theory is the belief that the elevated red blood cell count, also known as erythrocytosis, could then lead to thrombosis, atherogenesis, and increased cardiovascular risk. That is the most common theory. We spent quite a bit of time studying this; this is a study that we published looking at patients. Remember that the injectables have the highest rate of erythrocytosis. In our study it was 66 percent, in other studies, it's about 40 percent. So if a patient starts developing an elevated red blood cell count, one of the quickest things you can do is get them off the injectable, put them on a gel. A gel typically has an erythrocytosis rate anywhere from two; I've seen as high as 13, 14 percent. It's a lower rate. Because there's less of a spike that occurs with the gels. The injectables cause a spike which increases erythrocytosis rate.

Dr. Khera:                            Now that erythrocytosis typically doesn't occur until about three to six months, so there's no point in checking blood in two or three weeks. You have to give it some time. And the number you wanna remember is 54. The guidelines typically state that at 54 you want to either have the patient phlebotomize, which is donate blood, or you wanna decrease the dosage, but we don't want it to get above 54.

Nelson Vergel:                  Doctor Khera, one question here.

Nelson Vergel:                  Has anybody actually published data on hematocrit versus DVT risk?

Dr. Khera:                            So two points. One, there has never been a testosterone trial, a testosterone trial showing that the elevation in the cardiovascular risk on the testosterone trial was the cause of a DVT. There's been anecdotal data on patients taking testosterone and getting a DVT. But there's not been a trial showing that the testosterone which caused an elevation of hematocrit that led to a DVT. Majority of the data that comes from an elevation in causing a DVT is from Polycythemia Vera data. This is a malignancy of bone marrow. There have been several studies showing that an elevation in hematocrit in this population may lead to an increase in DVT. Some studies were inconclusive; some studies did suggest that yes, in this population an elevation of hematocrit did lead to a DVT. But we should be clear that this population is very different from the general population, right, and so it's using a transference. You're just insinuating that this population and this data can be used in the general population.

Dr. Khera:                            So again, I think you should be very careful. We need a trial.

Nelson Vergel:                  Okay.

Dr. Khera:                            One important point I do want to make is that if you look at the risk factors for low testosterone and you look at the risk factors for men who have cardiovascular disease, they're the same risk factors. It's obesity, hypertension, dyslipidemia, hyperglycemia, insulin resistance. These are the same risk factors. So it's not surprising that many hypogonadal men, whether they take testosterone or not, are at increased risk of having a cardiovascular event because they share the same risk factors for cardiovascular disease.

Dr. Khera:                            But we should also be clear. Yes, Nelson.

Nelson Vergel:                  No, no, go ahead.

Dr. Khera:                            We should also be clear on the indications for testosterone therapy. Who is it indicated for? You should be aware that the FDA and their androgen class labeling guidelines in 1981 had a statement. "Androgens are indicated for replacement therapy in conditions associated with a deficiency or absence in [inaudible 00:13:32]. This is the indication." Then they go on to list primary hypogonadism and secondary hypogonadism. They do have the word idiopathic. So if a patient, now I don't believe that these conditions are meant to be exhaustive. Other conditions could cause primary or secondary hypogonadism. But if you have a patient that does not have a medical condition that is associated with hypogonadism, in other words, in my opinion, they're considered idiopathic. They have low t, signs, and symptoms, but they don't have a condition listed on this list. The FDA, you should be aware, had a chance and they made a statement in 2015 that cautions that testosterone products are approved only for men who have low testosterone levels caused by certain medical conditions. And the benefit and safety of these medications have not been established with the treatment of low testosterone levels due to aging even if a man's symptoms seem related to low testosterone.

Dr. Khera:                            And so I think that's very important because if you look at the new FDA guidelines after 2015, this is very similar to the slide I showed you earlier when listing those conditions, the key difference is that the word idiopathic has been removed. That no longer exists. So the FDA is very clear that patients should have a medical condition listed on this slide here to be considered a hypogonadal. Again I don't think this list is exhaustive, but this is what we call indications for therapy.

Dr. Khera:                            Now realize this was a very nice study by Doctor [inaudible 00:15:08]. Looking at roughly four thousand men who came to his clinic. He found that roughly 20 percent of men had hypogonadism. But the majority of hypogonadism is secondary hypogonadism. So roughly 85 percent. Of that 85 percent of men that have secondary hypogonadism, only 11 percent of them have a true medical condition or a specific condition. Eighty-nine percent of them is due to an unknown cause. And if you look carefully at that unknown cause, roughly 70 percent of those men who are unknown have one of three conditions. It's either diabetes, obesity, or metabolic syndrome. Many of us believe that those are conditions, particularly obesity, should be considered a true medical condition associated with low testosterone. But again, it doesn't fit the list that currently lists those conditions such as a pituitary tumor.

Dr. Khera:                            Again, the majority of the patients don't have a medical condition listed on the list of conditions associated with hypogonadism. We believe that those men that don't have a medical condition but still have signs and symptoms of hypogonadism and low testosterone values also aren't benefiting from testosterone. In other words, men who have low testosterone due to a pituitary tumor, or men who have low testosterone just simply because their testosterone is low and they suffer from the condition should not be treated differently. They both will benefit from testosterone therapy. We call these patients adult onset hypogonadism. Remember a very important thing; men don't lose a significant amount of testosterone as they age, aging alone. They typically acquire medical conditions such as diabetes, obesity, metabolic syndrome that drop the testosterone below a threshold of 300. Aging alone, a majority of times, the majority should drop a man's testosterone level below 300. It is the acquisition of medical conditions as we get older that will drop the testosterone: obesity, diabetes, metabolic syndrome.

Dr. Khera:                            Again, this is illustrating a point. These are two studies by Travison and Handelsman. That red bar is the cutoff of low testosterone and if you look even at the first study by Travison, even up to 85 years of age the majority of men, healthy men, do not have a decline in their testosterone below 300 due to aging alone. If you look at the study by Handelsman, as well, if you look at the fiftieth percentile, even up to 100 years of age, that's whey they start seeing a slight decline. Again, aging alone should not cause a significant decline in testosterone; it's the acquisition of comorbid conditions.

Nelson Vergel:                  Doctor Khera, a question here on the previous slide. I get this question a lot. We talk a lot about total testosterone but do not know how to address free testosterone. There are very few studies that have looked at free testosterone but does the free testosterone decrease with age somehow as sex hormone-binding globulin increases as we age.

Dr. Khera:                            That's a great point. Such a great point. And that is true. We do know that the total testosterone does not decline significantly as we age, but we do know that SHBG does go up as men age. That is true. That rise in SHGB is greater than the decline we see in total testosterone. Your point is very valid. The net effect is that we do see a significant decline in free testosterone more so than we see in total. And remember that the body is much more sensitive to free testosterone levels than the total testosterone levels, and so many of these patients who have normal, as they get older particularly, as they get older, who have normal testosterone levels, let's say in the 350 or 380. If you check the free testosterone, SHGB, you'll find that it's low. And that's because, remember, as we get older the SHGB goes up much more rapidly. So you're correct. The free testosterone does go down more as we age.

Nelson Vergel:                  Yeah. Some guys ask me why don't we have guidelines are based on free testosterone instead.

Dr. Khera:                            Well there is data looking at free testosterone ranges, but if you look at them, even these slides I'm showing you here and you look at the total testosterone in men between 50 and even 70 in the Travison study, or even between 60 and 70 in the Handelsman study, we don't see a significant decline in total. We were taught in the old days total testosterone goes down; the andropause concept is not necessarily true. Healthy men should not have a significant decline in their total testosterone levels. When these healthy men develop obesity which will plummet the t. Diabetes, metabolic syndrome. Opioid use. Prednisone use. HIV will drop it. These are certain conditions you acquire that will drop it down. So yes you acquire them as you get older, but it's not the aging; it's the acquisition of those conditions. But your point on free testosterone is very valid.

Dr. Khera:                            So, what do the guidelines say? The guidelines say a little bit different. The guideline says that you must have a low testosterone level, and they want you to have two-morning testosterone values, and signs and symptoms. Both the endocrine guidelines and the AUA guidelines both say signs and symptoms and low testosterone on two accounts. They are not saying that you have to have a medical condition listed to be a candidate for testosterone therapy. So it's slightly different.

Dr. Khera:                            Remember, as I mentioned earlier, it's low total testosterone, the number that most of the country uses is 300 nanogram per deciliter, and also they use signs and symptoms. The laboratory value, the problem with this is that some guidelines say that you should use the lab's reference range. In other words, you should use, if the lab's reference range is 280 to 900, the number's 280. If the lab's reference range is 190 to 800, the number's 190. There's a problem with this, and this is nicely illustrated in the study I'm showing you here, where Doctor Morgentaler’s group called up 25 labs and said, "Could you please give me your lower reference range?" And what they found was that the lower reference range was anywhere from 130 to 450 nanogram per deciliter.

Dr. Khera:                            So let me give you an example. If a patient walks in and their testosterone level is 190, according to that lab, if the range is 130 to 800, he's considered normal by those guidelines. It's a little concerning because we all know that 190 is low. Some insurance companies have also adopted these labs reference ranges as the lower limit as the cutoff. So I've had a patient before that came in and the lab reference range for his lab I believe was 190 to 800, and I think he came in with a lab of 210, which I know is low and symptomatic. I prescribed a testosterone product, and the insurance company said, "I'm sorry, but according to this he's considered normal." And because the range is 190 to 800 and he's 210. And so again, there are concerns with using the lab's lower reference range because many patients who are truly hypogonadal, can I even get therapy covered because of these regulations?

Nelson Vergel:                  Yeah, I want to add something to this, too. I see it in the 300 range. Some guys are emailing me about they have 300, 280, 290 and obviously all the symptoms, and they get declined for coverage on insurance. I remind people we have other ways to get testosterone with a prescription and that's through compounding pharmacies.

Dr. Khera:                            Sure.

Nelson Vergel:                 Compounding pharmacies make testosterone products at a lower price that even out of pocket, cash price, is even as low as a co-pay. Believe it or not, because you're a great doctor and you obviously are an expert in the field, but maybe doctors don't tell the patient that gets declined by insurance that there is that option, and the patient just walks away without treatment.

Dr. Khera:                            Yeah, it's really important that we let them know that there are other options. You're correct. If a patient cannot get medication from insurance, you can get it from a compounding pharmacy, which is much more affordable for them, and that's one of the huge benefits of having compounding pharmacies is that patients can afford the medications, which makes a big, big difference. You're correct.

Dr. Khera:                            So this is just illustrating the point again that if 300 nanogram per deciliter is the cutoff, I just wanna make my comment here. I don't believe that we have to have one number for everybody. It doesn't make sense. What you're saying is that at 290 everybody must feel bad and at 310 everybody must feel good. That doesn't really make a lot of sense. We also showed, at Baylor, we took the blood from many patients who came in as patients, and we looked at their DNA. We looked at something called the CAG repeat which is the sensitivity of the androgen receptor. We showed that many patients who have very insensitive androgen receptors need more testosterone to feel better. We showed that many patients who are very sensitive to receptors don't need as much testosterone. Because we've all seen this, we've seen patients come in at 250 and feel fantastic, and we've seen some patients come in at 450 and feel lousy. Everybody has their own threshold, and it's hard to use one threshold for everybody. There has to be some leeway here.

Nelson Vergel:                  Another factor is thyroid, too. Some doctors have even checked thyroid function.

Dr. Khera:                            Thyroid's very important, and then there are other factors, too, that are not hormonal which we'll get into. But the reality is looking at the symptoms. Maybe they're depressed because of ED or low libido. Increased weight gain, decreased muscle mass, depression. So depression, hypothyroid. Even simple things like weight, diet, exercise, sleep, and stress. Poor diet, poor exercise, not sleeping at night and increasing your stress can be very similar to the signs and symptoms of hypogonadism. So we always question, I call that the four pillars: Diet, exercise, sleep, and stress. We wanna make sure that if we start therapy that you also meet me halfway and you be accountable for the diet, exercise, sleep, and stress.

Dr. Khera:                            Two things that always come up, Nelson, are prostate cancer and BPH patients that say, "I Googled it, and I heard I can get prostate cancer." And so you really wanna know where does that data come from. If you look at the first point on the warnings and precaution under BPH, it says, "Patients with BPH treated with androgens are at an increased risk for worsening the signs and symptoms of BPH. Monitor patients with BPH for worsening signs and symptoms." So I wanna be clear. There's not a single study that shows that men taking androgens have a worsening of their BPH symptoms. In fact, the majority of the studies show that there's no effect or there's an improvement in overall urinary symptoms over long term therapy. It also says that you shouldn't treat men with an incident of breast cancer or prostate cancer, as well. So I just wanna show you some of that data.

Dr. Khera:                            The guidelines are very clear, and I'm so glad that the AUA finally put out this statement because until then we didn't have a statement like this. But the first statement says, "Clinicians should inform patients of the absence of evidence linking testosterone therapy to the development of prostate cancer." Period. Strong recommendation, grade b. So finally there is a statement by the American Urological Association making it very clear that those men should be informed that testosterone does not increase their risk of developing prostate cancer.

Dr. Khera:                            Now the AUA also goes on to say that if a man has a history of prostate cancer, radical prostatectomy, radiation, we should inform them that we still don't have enough evidence to support the risk and benefit ratio of testosterone therapy in that population. But again, these are important statements.

Dr. Khera:                            We know that testosterone is very important in stimulating nitric oxide and nitric oxide synthase within the bladder and the prostate. Why is that important? Because nitric oxide and nitric oxide synthase are very important in keeping the bladder healthy, helping contractibility, also within the urethra as well.

Dr. Khera:                            Go back, when you lose testosterone, and you decrease nitric oxide and nitric oxide synthase, it's the belief that that can make urinary symptoms worse. That's one of the main theories between BPH testosterone, and that's the link. If you look at one of the earlier studies by Shagera in 2011, they showed 52 men with BPH lower urinary tract symptoms; they were receiving testosterone every week for four weeks, excuse me. Every four weeks compare to a control group. Those men that received testosterone had an improvement in urinary symptoms, mean flow rate and boarded volumes at the end of 12 months, not a worsening. In a very nice study by Hader's group in 2009 also showed the same thing, that those men receiving testosterone over a long term have an improvement in urinary symptom scores. And the c reactive protein also went down, suggesting that this is an anti-inflammatory effect, testosterone on the prostate.

Dr. Khera:                            By far this is the best review article that I've seen on testosterone and BPH. It's by Delay and Kohler, and they went through every article they could find on testosterone and causing worsening of the lower urinary tract symptoms. What they found was that either there was no worsening of lower urinary tract symptoms at all or an improvement in lower urinary tract symptoms over long term therapy. So again, it's important that we know the data.

Dr. Khera:                            If you ask men throughout the world, "What's your number one reason why you don't take testosterone?" If you ask clinicians, "What's the number one reason why you don't prescribe testosterone?" If you look at every country, it's predominantly, "I'm scared of giving this patient prostate cancer." That is the concern. It started in 1941 by Huggins and Hodges, where they showed an [inaudible 00:29:48] paper that reducing testosterone to castrate levels caused prostate cancer to regress. In that same paper, they showed that the administration of exogenous testosterone caused prostate cancer to grow. If you pull that article, you'll find something very interesting. It's based on one single patient. 1941. One single patient. That's where we got this concern.

Dr. Khera:                            One of the most amazing studies I've seen is by Lenny Marks, and this illustrates the prostate saturation model. He did a very interesting study. It was a randomized, double-blind placebo controlled trial, 44 men. You had to have low testosterone and symptoms to enter the trial, and they received testosterone injections every two weeks. They did something very interesting. They biopsied these patients prostates before and six months after starting therapy. And what did they find? If you look at the blood, those men who received testosterone had an increase in their sham testosterone and their DHT levels. That's what you'd expect. You didn't see any change whatsoever in the placebo arm.

Dr. Khera:                            How about in the prostate? This is very important. Absolutely no change at all in serum testosterone or DHT. Excuse me, prostate testosterone DHT. Suggesting that the prostate acts like a sponge. It takes up all the testosterone that it wants and then it doesn't care how high you raise the testosterone, it's finished. So I'll show you some examples.

Dr. Khera:                            This is the prostate saturation model. Let's say, for example, that a man walks in with a testosterone of 250. If you raise the testosterone, and that's the x axis, you don't see any change in PSA or prostate growth based on this model. If you give this man Lucron, a medication that shuts down the testosterone, you will see the PSA go all the way down. This is called the prostate saturation model. Many of us, including myself, believe that the saturation is roughly around 250. Roughly around 250. This is an excellent example. This is Doctor Shelly Bhasin's study where you gave testosterone at 600 milligrams of testosterone or placebo for 10 weeks. What did he find? Even when you raised testosterone levels almost up to 2500, if you look at the orange line there's no change in PSA whatsoever.

Dr. Khera:                            This is called the testosterone flare. We were taught in residency, if you give Lucron, which is LHRH, in agonist, you will see a significant increase in serum testosterone, and that's the white bar. But you can see there's no change in PSA, the yellow bar. But as the testosterone starts to come down, you see a decrease in serum PSA. A very nice example of the prostate saturation model.

Dr. Khera:                            This is a study that I conducted in 2011. I had 451 patients, and I divided them into two groups. Those with low testosterone, less than 250, where we believed the saturation model, those above 250. What did we find? Exactly what I expect. Those patients less than 250 when you put them on testosterone, their PSA increases when you give them testosterone. You see a correlation. Those patients above 250 we did not see a correlation between giving them testosterone and giving them PSA. And that change in PSA is roughly about point three nanograms per deciliter. About point three nanograms per deciliter.

Dr. Khera:                            There are many studies looking at testosterone and prostate cancer risk. We were taught that high testosterone increases your risk for prostate cancer. That's what we were taught in medical school. But the literature actually shows the opposite. The literature shows that low testosterone may increase your risk of prostate cancer. It said higher prostate cancer incidents, higher tumor burden, higher pathologic stage, higher Gleason higher risk of [inaudible 00:33:31] invasion, and higher positive surgical margins. The literature would suggest the opposite.

Dr. Khera:                            There have been several studies looking at giving testosterone after radical prostatectomy. Two of these studies are mine. Initial studies suggested there was no increased risk in giving men testosterone after radical prostatectomy. Let's be careful. These are not randomized; these are not placebo-controlled studies. These are observational, retrospective studies. But there's some hint that there may not be an increased risk. Our last study that we conducted in 2013, we had 103 patients, and we did see an increase in PSA in four patients, and I wanna show you this. This is a study; we had 103 hypogonadal men. We treated them with testosterone after radical prostatectomy. We had 49 [inaudible 00:34:17] controls. We did something a little unconventional. We did treat some of these men who were high risk, meaning at least a score eight or higher — positive surgical margins. Positive nodes. We also had a control group. In that control group, 15 men were high risk, 34 were non high risk. In the testosterone group, 77 men were not high risk, 26 were high risk.

Dr. Khera:                            What did we find? Only patients that had a biochemical recurrence or recurrence of their prostate cancer were men who were in the high-risk group. And typically we saw this recurrence at 36 months. If you were being treated with testosterone, the recurrence rate was 15 percent, which I would argue is quite low after 36 months. In the control group, it was 53 percent, so significantly higher.

Dr. Khera:                            If you look at all the patients that have been treated with testosterone after prostate cancer, whether it be radiation, reiki therapy, the literature will support that their recurrence rate seems to be lower. Now some would argue that this is a selection bias, that maybe you're selecting patients that are less at risk. Although in the study I just showed you we did treat high-risk patients. But again it seems that the patients treated after radical prostatectomy with testosterone may, and again, I don't have a randomized placebo-controlled trial but may have a lower recurrence rate. And some would say, "Are you suggesting that may be protective?" Well, there is some basic science data to suggest that testosterone itself may cause prostate cancer cells to regress or not grow. And there may be some protective benefit. There's a very interesting study going on at Johns Hopkins right now by Doctor Denmeade, who has done some amazing work with testosterone and prostate cancer. This is one of his first studies looking at 14 men with castrate-resistant prostate cancer. He gives them high doses of testosterone, 400 milligrams every three months. At the same time, he gives them Lucron. We call this bat from bipolar androgen therapy. High dose of testosterone then it comes down.

Dr. Khera:                            What did he find? And again, these are men with metastatic prostate cancer. He found a 50 percent reduction in PSA with giving them testosterone as therapy, and 50 percent of these patients had a radiographic response improvement on metastatic disease. This study would have been unheard of 10 years ago, but to treat men with metastatic prostate cancer with testosterone is a completely different paradigm shift in the way we think about testosterone and prostate cancer.

Dr. Khera:                            This was his second study. 29 asymptomatic men who had a low metastatic burden, so they had metastatic prostate cancer or they had a biochemical recurrence. Prostate cancer had returned based on the PSA. Again he used bipolar androgen therapy in his patients for three months. Almost 60 percent of these patients had a very low PSA less than four after the end of 18 months, which is his endpoint. What do you expect, many of these men reported an improvement in their quality of life, they recorded an improvement in their erections. This study would have been unheard of 10 years ago. But again, to think that some men are using testosterone to treat metastatic prostate cancer is very, very novel and interesting.

Dr. Khera:                            This is coming from my lab. So in my lab, we do a lot of basic science work looking at testosterone. We took Petri dishes. Each Petri dish was filled with prostate cancer cells, and we put different degrees or different amounts of testosterone in each one of these Petri dishes. So at low levels of testosterone, you can look at the very dark gray bar, you can see that there may be not much growth. As you add testosterone to these Petri dishes, yes, there is more growth of these prostate cancer cells. As you get higher and higher doses of testosterone, you see greater and greater degrees of suppression of prostate cancer cell growth. I call this the inverted u, with castrate may be beneficial, eugonadal may be beneficial, but the hypogonadal range may be the danger zone. This is what we saw in our lab. These are again prostate cancer cells, letter a on top is with no testosterone. Letter b is when we start adding testosterone, letter c is with high doses or higher doses of testosterone where you see the suppression — again illustrating the inverted u.

Dr. Khera:                            We did in the past start a randomized placebo-controlled trial with giving testosterone in men after radical prostatectomy. We worked with the FDA on this and what we were able to do is treat men as early as three months with testosterone, but they had to have two undetectable PSA's, and we couldn't treat anyone higher than a Gleason three plus four was the highest that we could treat. Just a word that many men will receive testosterone will have a biochemical recurrence, and they should be counseled appropriately, and I do tell them and speak to them about the guidelines, letting them know with the history of radical prostatectomy the risk-benefit ratio has not been defined because we don't have, in all fairness, we don't have a randomized placebo-controlled trial as of yet looking at men after radical prostatectomy receiving testosterone.

Dr. Khera:                            I just wanna make a comment about a cult prostate cancer because there's a movement in the United States on this concept of active surveillance. Active surveillance means that many men will be diagnosed with prostate cancer and we will follow them. We'll cautiously follow them over time. Well, some of these men will say, look, I have low testosterone, I'm on active surveillance, I want my testosterone back. And how do you respond and what does the literature show? One of the first studies was ours in 2011 where we took 13 men who were on active surveillance which had been on testosterone, that received testosterone therapy for a minimum of six months. A majority were Gleason three plus three; we had one patient who was a Gleason three plus four. And the mean duration of testosterone therapy after the diagnosis of prostate cancer was roughly two years.

Dr. Khera:                            So what did we find? We found no change in the PSA; we found no change in prostate volume. There were no [inaudible 00:40:26] or progressions in any of these individuals, and we re-biopsied these patients 54 percent of them did not have cancer on the biopsy. So again, there are patients that will receive testosterone and active surveillance. Again we do not have a randomized placebo-controlled trial as of yet, but there is some data out there. There are several other studies out there besides this one also looking at testosterone in active surveillance population.

Nelson Vergel:                  I'm sorry before we proceed. I'm sorry. These patients, are they treated with higher doses or just a regular TRT dose?

Dr. Khera:                            This is a different population than the population of men that we showed you with Doctor Denmeade's study. Doctor Denmeade's study was men with castrate-resistant prostate cancer which is metastatic disease or a biochemical recurrence. These patients are on active surveillance, and they are low testosterone and just being put back into the normal range.

Dr. Khera:                            Now let's think about something for a second. We know that one in six men, one in six men have occult prostate cancer. There's no question. They're walking around with it; they just don't know. When you treat 60 men in your practice, I promise you you're giving 10 men with active prostate cancer testosterone. You just don't know it. You just don't know it. But they have occult prostate cancer. And there's not been a single study to show that those men being treated with testosterone have a higher rate of developing prostate cancer than those men not being treated with testosterone. And so again, I know when I'm treating many of these men with testosterone that potentially have occult prostate cancer, but they're not lighting up. It's very similar to what you're seeing in this study that I showed you prior to men who are receiving testosterone on active surveillance.

Dr. Khera:                            I wanna urge some caution here. There's been no randomized; no placebo-controlled trials. I'm just showing you some preliminary data, and it's hard to say on these small studies, to comment on safety. We do need a randomized placebo-controlled trial to really help us illustrate the safety of this medication, this population.

Dr. Khera:                            I also do believe that hypogonadal men are at a significant disadvantage in recovering their erectile dysfunction following radical prostatectomy. I do think that the window is the first six months and I tell patients if they have low testosterone, two undetectable PSA's I do think it's very important to consider testosterone therapy early on to help recover their overall erectile dysfunction.

Nelson Vergel:                  And what is that period of time? You said six months is probably the tops, and...

Dr. Khera:                            The first six months is very important. We know that the majority of recovery of erectile dysfunction is within the first year. Majority of... to me the first six months is extremely important, and that's what we spent a lot of time working on a concept called penile rehabilitation and using medications and help increase the blood flow and the oxygen to the penile tissue. Helping these men once again obtain their erections because you have to do it early on because if you wait, we know that men develop [inaudible 00:43:34] and more likely to develop increased collagen fibrosis within the penile tissue if you just stay dormant and watch. It's a proactive approach and part of that proactive approach is also using testosterone therapy to help with the recovery of overall erectile dysfunction.

Dr. Khera:                            I wanna comment on testosterone fertility because it's important. Many clinicians do not know that testosterone is a natural contraceptive and it significantly decreases a man's sperm count. So many young men are not aware. I'll see many men in my practice every month who come in; they've started testosterone, they did not know or were not told that testosterone could significantly decrease their sperm count. How many men are we talking about in the reproductive years? We know that men in the reproductive years who are hypogonadal, roughly three to eight percent are the men between the ages of 20 and 45 have a true incidence of hypogonadism. This translates into roughly two point five million men. A significant amount of men. And some of these men will come to you, they have low testosterone, and they'll say, "Look, I want to start testosterone, but I also want to have kids in the future." What do you do?

Dr. Khera:                            Historically you can use off label medications, and this is off label, but clomiphene citrate has been used to help raise and dodge testosterone. It doesn't lead to infertility. In other words, it doesn't shut a man's natural sperm count or testosterone down. You can use HCG if he truly is hypogonadal, HCG. Human chorionic gonadotropin injections. ACG [inaudible 00:45:02] LH analog, and that can be used to help improve a man's own natural testosterone production, as well. We did conduct some novel studies in the past. This is actually a study by the WHO, which showed that if you give men 200 milligrams of testosterone a week, which many men are on 200 milligrams weekly, 65 percent of them are azoospermic at six months. It means that sperm count is zero at six months. If you stop the testosterone, many of these men will recover, but they don't necessarily recover back to baseline. So when you look at the recovery, how many recover greater than 20 million? An average man makes 80 million sperm per ml. So most of the studies will tell you how many recover, but they won't tell you how many recover back to baseline. This study showed that only 46 percent of men came back to baseline in roughly seven months. So again, men should be very cautious when they're using testosterone if they wanna conceive shortly.

Dr. Khera:                            so can we preserve fertility? Some men wanna take exogenous testosterone and still preserve their fertility. There are some very interesting studies, and one of the most fascinating studies was the Coviello study where he had 29 normal, healthy males and he gave them testosterone, 200 milligrams per week, and we just talked about the fact that if you give them 200 milligrams a week they become azoospermic in six months, but he also gave them HCG at zero, 125, 250 and 500 units every other day. Very interesting. Again, he's hoping that he can give the HCG to preserve the internal access while still giving exogenous testosterone. And he measured intratesticular testosterone at zero and 21. So let's see what he found.

Dr. Khera:                            If you look, this is where testosterone was given at baseline, and you can see the orange bar is the baseline intratesticular testosterone and day 21 the intratesticular testosterone. Exactly what you'd expect, when you give someone high doses of testosterone, you shut down their own natural production of testosterone production. That's what you see. But when you start giving low doses of HCG, what you see is you start preserving intratesticular testosterone at the same time that you're giving exogenous testosterone. Very interesting. So you're not shutting down. This is the reason why many clinicians use HCG to preserve testicular atrophy because what it does is it continues to reproduce your own natural testosterone to some degree without shutting down those cells, and that does help with atrophy, and it does help with producing your own natural testosterone.

Dr. Khera:                            At Baylor, we looked at extrapolating that data and saying, "Okay, if it's true, can you also preserve someone's fertility by giving them HCG?" This is a study looking at 26 men treated with daily testosterone gel or weekly testosterone injections. They received HCG 500 every other day, and the follow up was six months. What they find is, again, six months you see a very slight decline in spermatic genesis, from 35 million to 30 million after six months of giving them HCG plus testosterone. This is an older study; it was in 2013. I have continued to do this. I just wanna give a word of caution that there are some men even if you give them HCG 500 every other day, they will see a significant decline in sperm production. So not all men will have just a slight decline. Some will have a much more significant decline. [inaudible 00:48:27] preserving testicular volume and possibly preserving fertility in some of these men.

Nelson Vergel:                  A question here. I've reviewed the data that you and Doctor [inaudible 00:48:39] group created on this. Seems like the older you are, the longer you have been on testosterone, the lower the response.

Dr. Khera:                            Absolutely correct and that is true. It depends on age, ethnicity. We also know that if you, how long you've been on the medication, and the dose, right? That all impacts this recovery. Remember that one of the most important things is some of these patients have been on very high doses for many years, and at that time it's very difficult to recover their access. Now [inaudible 00:49:21] protocol. The protocol is we stop the testosterone, and we put them on high doses of HCG. Three thousand three times a week. Many patients can see recovery [inaudible 00:49:31] Genesis, but it can take about seven months. So I tell many of these patients when you're thinking about conceiving, I need a runway of about seven months before, let me know so I can make the switch.

Nelson Vergel:                  Have you ever used Clomid, Clomiphene with HCG, or is that a no-no?

Dr. Khera:                            I do. Actually I do it quite a bit if they're trying to recover their fertility. Because Clomiphene Citrate will help increase the FSH, while HCG will increase the LH. I would prefer to use [inaudible 00:50:00], which is recombinant FSH. But it's very expensive. So what I use is I use Clomid instead of [inaudible 00:50:07] as a substitute because it's much cheaper. But if-

Nelson Vergel:                  You can also use compound FSH. Let's go to the previous slide if you don't mind. Yeah, that one. I've also reviewed this data; I wrote an article. I have a few videos on HCG myself. [inaudible 00:50:23] What most doctors and patients do not understand is that this thing, the intratesticular testosterone, the testosterone inside the testicles, is not equal to the testosterone in the blood. And also they don't understand that once you shut down LH and FSH, IDT goes down even if your testosterone in your blood is 700. So can you tell us a little bit about that? [crosstalk 00:50:53] on that explanation.

Dr. Khera:                            So the key recall is the access. Remember that [inaudible 00:51:00] fuel to the testicle. The fuel to the testicle is the pituitary. The LH. If you shut off the LH you will decrease the testicular production of testosterone. No question. What does exogenous testosterone do? Exogenous testosterone goes back to the brain and shuts down LH secretion. That shut down LH secretion will decrease intratesticular testosterone production but even though your T levels are 700 because you're taking exogenous testosterone. So your exogenous testosterone will look great, LH and FSH are suppressed, and intratesticular testosterone goes down. That's the mechanism.

Dr. Khera:                            I wanna make one comment, and this is very important. If you look at diseases in the United States, obesity, diabetes, hypertension, hyperglycemia, you go to your primary care physician. They don't start treating you with a pill. In America, we try to do disease modification before we give you the pill. And the question is, are testosterone and hypogonadism any different? Are there things that we can do to improve the testosterone level without using testosterone therapy or using medications to raise endogenous testosterone? Should we consider them first or not? I wanna show you some things that you can do. I definitely have patients in my practice that say, "Doctor, I do not wanna take any medication. I just want you to show me natural ways that I can raise my serum testosterone level." And I do tell them that, the four things you wanna remember. We talked about this earlier. Diet, exercise, sleep, and stress reduction can all raise your natural testosterone value, as well.

Dr. Khera:                            So let me show you some interesting slides. There are natural ways. Diet and exercise, improving insulin resistance, weight loss, stress reduction, sleep, varicocele repair has also been shown to raise natural testosterone levels. This is one of the earliest studies looking at lifestyle modification. These are 44 of these men that were put on a 12-week exercise and diet program. They had significant improvements systolic blood pressure, and they also had a significant improvement in their serum testosterone values. But this improvement was very mild — 25 nanogram per deciliter. Although statistically significant, in many opinions is not clinically significant of an increase.

Dr. Khera:                            There's another study by Hugh Felder, 52-week randomized trial. These are 32 men with diabetes metabolic syndrome. 16 were able to do diet and exercise, 16 had diet, exercise plus testosterone. Diet and exercise alone significantly improved serum testosterone values. That is true. But the key thing here is that when you add testosterone to diet and exercise, it is even that much greater in terms of weight loss, as well.

Dr. Khera:                            This is my favorite study on obesity and testosterone. It's the Camacho study, and it really comes from the European [inaudible 00:53:57] study where they had almost 27 hundred patients that were falling longitudinally. If you look, just a 10 percent decrease in weight can increase your serum testosterone by 85 nanograms per deciliter. But remember the opposite is also true. A 10 percent increase in weight decreases your testosterone by 85 nanograms per deciliter. There's a bimodal direction we call it. But look at the line. It's not straight. It's curvy linear. So if you lose 15 percent of your body weight, you can almost see 180 nanograms per deciliter increase in your serum testosterone. Vice versa increases as well.

Dr. Khera:                            Again, I tell patients if you can lose weight and keep it off, you actually will see a significant improvement. Let me show you a great example. It comes from the Bariatric literature where we do weight loss surgery. In this study it's a meta-analysis of 22 studies and a mean percent weight loss was 10 percent on a low-calorie diet, but you lose 32 percent of your weight by bariatric surgery. What happens on a low-calorie diet? 83 nanogram per deciliter increase in testosterone. That's great. 83 percent nanogram per deciliter. But in patients that had bariatric surgery, 250 nanograms per deciliter increase in testosterone. That is not only statistically significant, but it's clinically significant. If a guy comes in at 250 and you put him basically at 500, that means something, just by losing weight.

Dr. Khera:                            So sleep is also very important. We don't realize this, but we make testosterone when we sleep. That's why our highest level of testosterone in the morning because we make it while we sleep. If you're not sleeping, it can be an issue. This is looking at men with sleep apnea. They have a higher prevalence of hypogonadism because remember, when you sleep apnea, you are hypoxic, you don't have oxygen in the brain. When your oxygen goes down, it decreases the LH and FSH secretion in the pituitary. But this is looking at studies during; we'll call it UPP surgery, which is fixing the sleep apnea. Within three months you'll see almost a hundred nanogram per deciliter increase in serum testosterone just by imploring sleep apnea.

Dr. Khera:                            Sleep deprivation si very interesting. If you restrict the sleep for eight nights, if you restrict your sleep for eight nights on only five hours every night, you will see almost a 15 percent reduction in your serum testosterone. That's a lot — 15 percent reduction just by restricting your sleep. The important part of sleep is actually not 12 to four am, but it's four a.m. to eight a.m. because when sleep is restricted during the first half of the night, and you're allowed to sleep from four a.m. to eight a.m., no change in serum testosterone. So the second half of the night is more important than the first half of the night when it comes to serum testosterone values.

Dr. Khera:                            Stress is a killer. Remember that stress increase cortisol. You see true physiologic changes in the body. Shallow breathing, increased rapid heart rate, high blood pressure, insulin resistance, decreased immunity. Many changes occur. This is just an example of looking at medical students and residents. I don't know if this really illustrates the point well, but the point is that when you look at internal medicine residents, and you look at their testosterone values compared to other hospital personnel, the residents tend to have very low serum testosterone. It may be due to stress; it may also be due to lack of sleep. It's about 250 nanograms per deciliter. These are typically younger patients, which should theoretically give slightly higher testosterone values.

Dr. Khera:                            Andy [inaudible 00:57:34] a wonderful study looking at what are the significant factors associated with hypogonadism, and there were four. Hypertension, tobacco use, sleep apnea, and work stress. Work stress was an independent predictor of those patients who were gonna have lower testosterone values.

Dr. Khera:                            Finally varicocele repair. As many of you know, a varicocele is a dilation of the blood vessels around the testicle. That dilation contains heat and pressure on the testicle, puts the testicle under stress. Many have looked at the use of repairing varicoceles to improve testosterone. This is one study; it's a retrospective view of 53 patients. It was one of the earlier studies; it was done back in 1995 showing that those patients who had a varicocele repair in this study had almost 90 nanogram per deciliter improvement in serum testosterone values. After the study there were many other studies; it was a prospective study and a net analysis. What did they find? If you fix the varicocele, you can see anywhere from an 80 to 100 nanogram per deciliter improvement in serum testosterone values just by fix the varicocele.

Dr. Khera:                            Before I go any further, and these are my last two slides, I just wanna illustrate the point that there could be some benefit in lifestyle modification. For example, if you lose a significant amount of weight, if you fix the varicocele, if you fix the sleep apnea, if you take it additively, hundred here, 200 here, 100 here, it could be significant. Lifestyle modification could significantly raise those serum testosterone values where you may not need serum testosterone.

Dr. Khera:                            In the future, there are some technologies. We worked on some technology which we patented in the past called nanotechnology. It's like a chip, and basically this chip is implanted underneath the side of the hip. This chip will then release testosterone like an hourglass. It's consistent. So if you look at the bottom right-hand corner, the red line is what you see with testosterone pallettes. Injectables you get a surge, and then at four months, it comes down. But theoretically, with nanotechnology, it's a slow, even release over the four-month period that you can see with the green line.

Dr. Khera:                            And then also this concept of stem cells. So [inaudible 00:59:50], he was a fellow here at Baylor, did some amazing work looking at lactic stem cells. Basically taking stem cells, remember the stem cells can turn into any cell in the body, he's taking stem cells that will then be injected into the testicle, and those stem cells now start producing a man's own testosterone again. So instead of giving him testosterone, he's now producing his own testosterone which is fascinating work.

Dr. Khera:                            So in conclusion, the diagnosis of hypogonadism can be challenging, with many men being treated off label. Clinicians prescribing testosterone therapy should be aware of the 2018 AUA and endocrine guidelines, and also the recent FDA label changes. Testosterone therapy's been shown to improve BPH and lower urinary tract symptoms. Serum testosterone has been associated with an increased risk of MI and cardiovascular risk factors. To date, there are no convincing data to support that testosterone therapy causes prostate cancer. Now I do believe that patients should be appropriately counseled on the risk of VTE, CVE, BPH and prostate cancer when prescribing testosterone therapy.

Dr. Khera:                            Thank you very much for joining me today.

Nelson Vergel:                  Thanks a lot, Doctor Khera. This is one of the best lectures I've seen. I just love that not only you're a clinician that treats patients but also spends a lot of time on research. I have only two questions. Actually not really related to the content you presented, but more side effect management because I get this question a lot. When it comes to edema, and it's about managing edema, two separate subjects, what do you do when a patient presents with either edema, water retention in the extremities, or even general water weight gain?

Dr. Khera:                            So two things. First of all, I look at the source of testosterone that you're using. We know that cypionate is a little bit more antibiotic and is a little bit more sodium retention. So if he's on cypionate, I will convert him from cypionate to an update. That's important. Sometimes it's a dose effect. If it's a [inaudible 01:01:48]too high and they get too much edema as well, so you may wanna lower the dose as well. I do look at estradiol, but estradiol's more important to me for two things. One, it's too high, I'm worried about gynecomastia. But it's interesting, in the old days we used to give men a lot of [inaudible 01:02:05] because we said estradiol is bad. We must decrease estradiol because of more the more estradiol, the worse. And we'd shut them down. But that is not true. Actually Finkelstein had a phenomenal article showing that many of the beneficial effects, even sexual effects, of testosterone are actually an estradiol effect. You don't wanna shut the estrogen down. You want to keep it at a good level, and you want to, you obviously don't want it too high, but I don't want it zero either. My sweet spot has historically been between 30 and 60. I don't want it below 30, but I don't want it too much higher than 60. So I will use aroma taste inhibitors to keep it between that range.

Nelson Vergel:                  But you don't use it in any patients? What proportion of patients that you use it?

Dr. Khera:                            Only who needs it. I don't throw it on liberally with everyone without checking their estrogen. Remember, what's their conversion rate to estradiol? It's point three percent. So of the testosterone that we give, point three percent is converted to estrogen. Based on his estrogen level, you can decide how much aromatase inhibitor to give. It's about managing it. So you look at the level, you start at one milligram a week. If you recheck it, it's still too high; you can give two milligrams a week. But manage it. In the old days, we used just to give them one milligram a day and just not look at it. But that wasn't right because that had an adverse effect on libido.

Nelson Vergel:                  And bone.

Dr. Khera:                            And bone. That's right. Long term. That's correct.

Nelson Vergel:                  Well thank you very much. I'm sure you're gonna get a lot of questions from this video. We're posting it on YouTube, excel male dot com and other networks like Facebook. So hopefully we'll have you back in a few months to answer some of those questions. Thanks a lot.

Nelson Vergel:                  How can people get a hold of you or get to see you as a doctor? Do you see patients in Houston?

Dr. Khera:                            Absolutely. One of the easiest ways is to go to the Baylor website. Www dot B-C-M or Baylor College of Medicine dot E-D-U. Under the urology website, there are ways to see some of the work, some of the videos, and it's a great way to get in touch with the program.

Nelson Vergel:                  Alright. Thanks a lot, Doctor Khera.

Dr. Khera:                            Thanks so much. I appreciate it, Nelson. Thank you.

Nelson Vergel:                  Bye-bye.