Practical Aspects of Managing Obesity and Hypogonadism in Men

Thank you very much for this opportunity to share some of my thoughts. I really always appreciate physicians who are willing to invest time and effort in not only understanding the basis for illness, but understanding that wellness is not the absence of illness. And, you know, as I explain to my medical students and some of the doctors who are willing to listen at our center, that, you know, a good doctor will generally select the right medication for a patient. But the great doctor often manages to take the medicine away because, as you know, every medicine, every disease that I treat is fraught with problems in the sense that there's always collateral damage from the drugs that I use in the treatment of disease. So if we can reduce the severity of the disease, prevent the disease, I'm certainly going to be doing a much better job. And I think that's what most of the doctors in this room are actually studying and trying to apply to their patients. So just as a little advertisement, you know, the Center for Men's Health is really at 555 Madison Avenue, the most amazing location you could possibly imagine. And this was the result of a generous contribution of more than $15 million by the Tisch family. And it's a multidisciplinary center in the heart of Manhattan in which physicians really communicate and crosstalk with each other in a very, very unique way and provide an opportunity for patients to actually, you know, have multidisciplinary care in an efficient way. You know, when you deal with men, you have to, you know, remove all obstacles to care. You can't even ask them to go across the street to give you a sample of urine, because if you ask them, they will pee in their pants instead. So you understand you've got to remove the barriers. Make it simple. Another very important point about men, don't criticize them. All right? They they won't respond. You know, you can make them change, but it doesn't work. So if you're a great doctor, if you think you're a good doctor and you tell a patient not to smoke and not to drink and start exercising and they don't listen to you, five or ten years later, they've had an MI or they've had an abdominal angina or something serious. And it's not because you didn't tell them the right thing. You didn't deliver the message in an effective way and then everything is lost. So I think the important thing is to connect with the patient before you can connect with the disease. And I think that practices such as yours really provide you with the time to do that. You can spend time understanding the uniqueness of every patient and then tailoring your approach to that patient as opposed to the generic approach of giving a statin and or giving a blood pressure medicine to every single person who's got a cholesterol elevation or blood pressure elevation. So I applaud you for all of those aspects. Just on a personal note, at the Center for Men's Health, by the way, we do measure body fat. We do measure ambulatory blood pressure. We actually do home sleep monitoring. And I've done more than a thousand EndoPATs. All right. So just to show you that we can actually do this at an academic center and in addition, we do recommend omega-3s, vitamin D, probiotics and magnesium. So we can actually make some advancements. I'm not telling you that every doctor at the center is at that point, but I think we're moving in that direction. I think it's pretty impressive to see that. So I am a speaker, although I have been speaking less and less for many of the pharmaceutical companies. And but I have obviously been a consultant with reference to, you know, companies that are involved with obesity management and with hypogonadism. So in a nutshell, what I'd like to discuss is, 1, the diagnosis of hypogonadism. 2, the impact of obesity on sexual function. And then to understand the bidirectionality and I think that's the operative word today, to tell you the truth. And I think that the internist really needs to connect the dots, needs to understand the relationship between hypogonadism, obesity, diabetes, sleep apnea syndrome. And specialists, and you know, in general are focused in on the disease and often miss the connecting the dot ability. They will they will deal with the your creatinine function. They will deal with proteinuria. The cardiologist will deal with whether or not you have, you know, require a stent or some form of anticoagulant. But it's the internist who really has an opportunity to put all of this together. So here are two very important conditions. I think that obesity is clearly, singularly the most important contributor to illness in this country. Of course, smoking is a bad problem, but obesity really is the number one issue. And I can't tell you that it's not recognized. Right. You will recognize people who are overweight and you recognize people who are morbidly overweight. But we are very deficient in our ability to effectively treat this condition. Whether you want to call it a disease or condition, I respect Dr. Houston's point. Most of these issues really are conditions the result of inflammatory proinflammatory genetic genomic disturbances. But what's very clear with reference to obesity is how poorly we approach these patients. It is inadequate, insufficient to basically surrender to this condition in patients who fail to respond and to what we call eating less and exercising more. How many people in this audience have patients who've tried to eat less and exercise more and how many of them have succeeded? You know, if they have, I would applaud those patients. I would guess about 5% of patients and most of us, you know, will tell a patient when they first come in. I think you need to lose weight. I'll help you with your diabetes, your hypertension, your sleep apnea and every known problem. And we advise them to eat less and exercise more in the following month they come back and they haven't lost any weight. And then you send them to a nutritionist and then they still come back and they haven't lost weight. And then you never talk about it again. And that's really the pattern, you know, that most physicians and I think that there's a new, new approach. I think it's beyond the scope of this lecture. And maybe if you enjoy this lecture, they will give me an opportunity one day to come back and actually talk about the modern approach to to obesity, from a from a more complex, a serious issue that I think we can affect the change in more and more patients, because without it, you know, we're going to fail and managing and controlling costs in this country with reference to health care. I think very few of you probably appreciate that the single most common cause for hypogonadism in the country is obesity. I mean, if you ask the average doctor, so what causes hypogonadism? They give you all kinds of. But they will never say obesity. And I will try to imply why this is actually the case and what maybe we can do about it. So the objectives are to recognize obesity is a serious disease. Don't surrender to your patients. Find out. Start reading about the new approaches. Understand some of the pharmacotherapy and some of the new nutritional advice and and go beyond telling people to eat less and exercise more. Try to understand what's really going on. Why are people fat? We actually think that people are fat because they're stupid and lazy. I mean, does that make any sense? That clearly doesn't make any sense. Okay. And explain why people fail despite their best efforts. And when I'm talking about the treatment of obesity, I'm not talking about promoting weight loss. Anybody can lose weight. Overweight people always lose weight. It's how do you prevent the weight regain that is so common in most of your patients? Of course, people will lose weight for an event, for a wedding, for a bar mitzvah, for whatever they're doing. But that's not the real long term treatment. And maybe even 5% or 10% of weight loss can reverse some of those inflammatory markers that you heard Dr. Houston talk about that that can be contributing to endothelial dysfunction, hypogonadism, a whole bunch of other issues. So with that male hypogonadism boy, a really a controversial area right now. There's so many centers and clinics that are called low T centers, as you as you know. And I think that what we're trying to do is to establish some clinical science behind this rather important entity. You know, hypogonadism, as we all studied in medical school, is a result of a diminution in testosterone production right by the testes. And there are ramifications from this. You know, for most men, having a low testosterone, especially very low testosterone is associated with certain clear cut clinical signs and symptoms. Right. You know, low libido, poor erectile dysfunction. But it goes beyond that. You know, over time, you start getting osteoporosis. And, you know, osteoporosis is a serious disorder even in men, even though it may present ten years later than the typical female. But also increasing in body fat, predisposition to diabetes, sleep apnea. There's a whole host of other factors, other things that happen, increased morbidity from cardiovascular disease. So hypogonadism is not a good thing. Low testosterone is not a healthy state. And for me, I will oftentimes measure a serum testosterone, not because I want to actually even treat the patient. I use it as a biomarker. I see a low testosterone and as an indicator of insulin resistance, of inflammation. There's something wrong when I find about testosterone in a male patient. Right. And it may be as simple as stress, maybe as simple as the fact that they're taking some medication. You know, you know, there are a whole host of medications. So the lowest testosterone, I'm getting ahead of myself because I can't help myself. This is how how I teach medical students and residents. You know, I can't stand using the slides. You know, if I get a testosterone in my office of 125 in a 42 year old male, you know what the first thought is that I have? How many opioids is this guy taking? All right. Because that's what you find the lowest. I'm not thinking that he's got a prolactinoma, he's got a pituitary tumor. That's what the third year medical student is thinking. Okay, I'm not diagnosing hemochromatosis sarcoid. I'm thinking terms of opioids. That's what this person is doing. Okay. So I think that as a as a marker, it's very important. Even if you decide you're not going to treat patients with low testosterone. And that's a much more complicated decision because of the lack of really solid clinical data on safety in every population and risks of cardiovascular disease. The controversy over prostate cancer. So forget about the controversy. Just think in terms of testosterone as a marker. Just as an aside, if you said to me, Stephen, I have a 60 year old man coming to your office and you want to give him a $25 million life insurance policy, but you could only ask him one question, right. And only ask one question. What would that question be? Nocturnal erections, Right. I would ask him, do you wake up with erections? Because if he's waking up with erections on a regular basis, it implies the proper orchestration and integration of vascular neural hormonal sleep. And those are really important. So I actually think that's probably the best question you can ask. I had this one relatively healthy gentleman. You don't mind if I, you know if I move away from my slides a little bit. Okay. You're going to have a lot of science today. So so this young, healthy guy, I mean, he was fit he was in his forties and and I asked him to be, you know, are you having morning erections? And he said he actually he’s not. And it just it didn't make sense to me until I asked him, well, let me ask you a question, you exercise? He says, oh yeah, I exercise six days a week. And I said, when do you exercise? He said, I exercise in the morning? I said, So what does that mean? He said, Well, I get up at 4:30. Well the morning erections generally occur at 6. So he actually was waking up before he had a chance to have a morning erection. So that's just an aside. He didn't have a medical problem. Okay. So, you know, when you look at the definition, it's a clinical symptom. You have to have low, low libido. You may have low spermatozoa. And the issue is whether there's a disruption in the testicles or what I think is this the key in the future in this whole field, is this really this hypothalamic pituitary axis. And that's where the money is going to come and that's where the business of medicine is going to come in the future. So it's really not in the testicles, but rather in this very interesting hypothalamic pituitary axis. Many of you heard of this protein called KISS peptide. No. Good. Least I could maybe teach you one thing. Okay. This this, by the way, this this product, that's a product of a gene KISS1 gene KISS peptide. Actually, the reason is called KISS peptide, because I thought it was fascinating was it was discovered in Hershey, Pennsylvania with a okay so that that's it is nothing more sexual than that. It's it's and by the way it was originally actually discovered as a as a protein that reduces the likelihood of cancer cells melanoma to metastasize. It was called metastatin. Okay. Which I think is interesting. But they're actually now showing that this particular gene and protein is involved with puberty and involved with with testosterone and hypothalamic gonadal function. I thought it was fascinating. I'll have a slide at the very end about it. All right. So as you know, testosterone deficiency, as I said, it's clearly an important hormone and affects multiple organs. I think the important thing besides the the sexual arena in which it affects erections and libido, especially, is body fat and moods, irritability, bone density, muscle development. It's obviously an important hormone. Okay. So when you look at patients who, quote, have testosterone deficiency, it's basically first on clinical complaints, right? I mean, you ask a gentleman if they're if they're having problems with libido, erections. But as I said, there are certain patients who, you know, predictably are going to probably have very low testosterone and may not actually complain because they've kind of given up and they're no longer involved in relationships. So they may no longer be interested in sexual function. And so they may not complain of a libido issue, although in my experience with the younger guys, guys would like to have an erection if they were on a deserted island. But that's some point. You know, they just kind of certain men give up. And so they may not say to you, I'm having an issue, especially men who have weight issues, which we will talk about. So, you know, the problem is either going to be in the testicles as a result of some injury, mom's trauma. Right. Or some genetic disorders like Klinefelter is, you know, you have a young person who has low testosterone, has some infertility issues, looks a little strange, and they have very high gonadotropin, some low testosterone. You want to do a carrier type, You want to check whether they have a genetic issue. And of course, there are a few individuals who actually have normal testosterone, but their testosterone is not affected. The some something and these are rare. You know, people have had who are on androgen blockade for prostate cancer or people who have receptor problems, but those are unusual. So the key is when you when you are diagnosing testosterone based on whatever reason you're suspected that the patient may have a low testosterone, you of course, you measure testosterone. And it's important. Just remind you that you measure you do a morning testosterone. This is a especially important in younger men where there is a circadian rhythm to testosterone secretion. It's less so in the older gentleman, but it makes sense to do it in the morning. Okay. And it's also because of the fluctuations in testosterone, it could be 20 to 30% on any given day. It's important before you commit somebody, especially if you're going to commit somebody to treatment with drugs that are both expensive and potentially harmful, you want to really be certain of the diagnosis and you don't want to be doing testosterone on somebody who's just been operated on for their gallbladder, you know, or somebody who's just recovering from influenza or somebody who's been in a car accident or, you know, you've got to do this in a steady state when it's reasonable for their hypothalamic pituitary axis to be in a steady state. So don't do this in an unusual time, you know, try to find a period of calmness and not a lot of chaos in the person's life. And at that point, if you do measure a morning level, which is low, repeat the level a week later, two weeks later, another morning level. And at that time, I would also add one of the gonadotropins, LH FSH. You know, I measure FSH, though, a lot of people measure LH. And then if you really want to be sophisticated, you can measure a prolactin level. And if you're really, really sophisticated, you know, if you're convinced that this person really is low, you can measure a ferritin level as well, because as you know, hemochromatosis may actually be a diagnosis and it's easy to diagnose with a ferritin level, so then you can do some genetic testing to to confirm that or some sort of MRI of the liver. But it'll make you look like a genius if your diagnos this condition. So how common is it? It's also very controversial. It's just about as common is when you're going to be looking for it. All right. If you have old or if you take an older population, if you take men 50 and older who are overweight, you probably find it in an insanely high number. I mean, 30%, 40%, 50% depends on your population. You know, if you take younger, you know, you're going to you know, especially if they're younger, they're healthy, they're fit, they're going to the wellness program, they're going to a wellness center. They eat asparagus all day long. You know, you're going to rarely see it. Right. But in the in the typical patient who comes to quote a clinic, oh, my God. And they and if you went to a diabetes clinic, I would say was the exception, you know, in that population that doesn't have a low testosterone. All right. So clearly, there's an age related phenomena as well. Okay. So hypogonadism, it's a combination of both the clinical symptoms and biochemical diagnosis. All right. Once again, you know all the target organs, it's pretty obvious, you know, in general, there are sophistication. You know, you know, we generally look at 300 nanograms per deciliter as the lower level of normal and an 800 above it. Obviously, you know who has a testosterone producing tumor, you can have 2000. I mean, you know, they're taking, you know, testosterone supplements. Obviously. So we're really looking at that lower level. And so, you know, it's hard to say, oh, you know, is it possible that somebody has a level of 320, you know, doesn't have hypogonadism? And somebody with with a level of to 280 is normal. This is a range, this is a clinical diagnosis. And there are reasons that the levels may actually not be exactly correlating with the clinical picture because as you know, testosterone circulates primarily in a bound form. It's bound to both albumin loosely and more tightly to something called sex Hormone binding globulin in only 2% is actually free, and in theory, it's the free form that is the active component that binds to the androgen receptors and that starts a cascade of events in the mitochondria and does all the good things that we know testosterone is supposed to do. So there are a confusing at times where the numbers don't seem to match because of alterations in the sex hormone binding globulin. And there are conditions, as you can see, where there is a an increase in the level and there's a, you know, indications where they're where they decrease. And you can see the list right over here. And that's those are the times where you may want to measure the free testosterone. And some people measure free testosterone all the time. But in general, if your levels are above 346, you know, on a morning level, likelihood as a patient is not hyper gonadal and that their depression and their libido and their erectile issues probably due to some other factor, a million other factors. Right? And if their levels are generally less than 230, there's a great likelihood that they are really clinically hypogonadal. And of course, if the levels are really, really low, as I said, think of opioids, think of pituitary issues, and then the prolactin levels are going to be pretty important. But I think the key is measure it more than once and measure it in the morning and measure the gonadotropins, because I think that's going to help you differentiate the primary versus the secondary. And if it's really secondary, it behooves you to find out what the potential etiology is. As I said, you know, a pituitary issue or some other condition. This is, of course, is the algorithm that's in most charts. And it's really not that complicated. You know, you, you know, signs and symptoms. You measure a morning level, you repeat the level. If it's very low, you know, you measure the gonadotropin. If it's not, you know, you just proceed during this this algorithm. And it really helps you determine, you know, and this is important if you're going to be treating patients. You know, the current approved drugs for the treatment of hypogonadism is testosterone. And it's you know, testosterone comes in all different forms that many of you I know were familiar with, whether they're one type of injectable or this and, you know, a newer type of injectable, which is extremely long acting. And there are a whole host of topicals and these even a buckle form. And of course, there are other drugs that are actually not FDA approved for the treatment that is often used to try to affect, you know, these are non testosterone treatments that are used to increase testosterone levels such as clomiphene or 8CG, some of the aromatase inhibitors and all of their action is really based on what I said to you earlier, the hypothalamic pituitary axis, which I think is where the money is going to be in the future as opposed to testosterone, which is fraught with some issues. So as I said, the key is is suspect that a patient may have it. Then measure at a couple of times. Measure gonadotropins. Measure prolactin and you may need to do a carrier type and then you then at that point, you have an opportunity to have a really thorough discussion because that's really the most difficult part. You know, who really is a candidate? How many patients are truly bothered by this? You know, you don't treat numbers in medicine, all right? You try to treat the patients and you try to treat their symptoms and you try to reduce, you know, at least increase the likelihood of benefit over risk. You know, I'm not going to take, you know, you know, an older man with a slightly lower testosterone who's got a PSA of four and decide, I'm going to give him testosterone to correct a number. That just doesn't make sense. I'm not going to take a 28 year old with a slightly low testosterone and give him testosterone and knock his sperm count to zero. You know, you've got to be you've got to be a real doctor and try to figure out, you know, who's going to be the best candidate and the most appropriate treatment. And I think that a big problem today is that a lot of people are initiated on treatment and they're not followed appropriately. So they never actually achieve testosterone levels in at a level that is adequate to make a difference. And so the patients will tell you that they don't feel any different then they stop the treatment. And then they continue, obviously, to have low testosterone, which once again is not a healthy state to be in. And of course, the other problem is we're not dealing with this is what I said to you before about the free and total testerone and what happens with testosterone, how it's it's aromatase to estrogen. And guess what really likes to aromatase testosterone to estrogen. And those are fat cells. They're really good at it. And what do you think happens to those estrogens? You know, the estrogen molecule, it goes back and it feeds on the hypothalamic pituitary axis, turning off LH and FSH production. And for the diminution in testosterone production, you have DHT, you know, which is an active testosterone molecule, which then also binds to androgen receptors. As you know, sometimes we block DHT production in dealing with prostate issues and and hair loss. You know, so it's an interesting biochemistry. And I think this is really the important slide as I see it. Look, at the risk of having hypogonadism or at least of having low testosterone obesity, number 1. Diabetes, number 2. How many patients do you see every day in your office with obesity and diabetes? Right? A lot of patients, which I'm telling you then clearly you're going to if you're measuring it in everybody, once again, you're going to be over diagnosing. If you measure it in very few people, you're under-diagnosing. But I target this population, the obesity population, the diabetes population. And you just think about everything that doctor, you said I was talking about with hypertension and endothelial dysfunction and inflammation. That's really the basis. That's how you connect the dots with all of these diseases, hyperlipidemia. They're all doing the same thing. They're all creating inflammatory interleukins, molecules and alterations in leptin that are the result of these inflammatory conditions. And so when you measure inflammatory markers in your blood and the more sophisticated you are, the sense, the more sensitive you are, you know, the regular we measure CRP but that's like kid stuff compared to what's really available out there. To understand why these conditions would clearly be responsible for changes in testosterone, inflammation, really the hypothalamic pituitary does not like inflammation. Okay. I also find it how interesting that sexual function and obesity and fertility and puberty are so linked, you know, with that with with hormones that are released by fat cells. You know, fat cells do more than just store fat cells. I mean, fat you know, they are they're an active endocrine organ that is releasing a tremendous amount of toxic substances. And so when I see patients who are significantly obese, especially visceral obesity, I'm thinking they have a toxic dump and they're really releasing all of these carcinogens, thromotic agents. It actually makes me anxious when I see them because I realize, you know, what a dangerous situation there in. I actually had this young man, 35 years old, his wife, just had a baby and the guy was 35 pounds overweight. And you know, it was clear that I was getting worried about this guy, you know, And I just hope that you can make a change and explain to him or at least try to remove the barriers to his obesity, whether it's his lifestyle, his schedule, his circadian rhythm. There's the fact he's a shift worker. You have to come up with a eating program that makes sense for him. You can't tell somebody to eat no carbs, you know, no potatoes, bread, rice and rolls for the rest of your life. Who's going to do that? Right? But you have to figure out some modalities, some nutritional supplements may And clearly the new pharmacotherapy that I find very interesting, once again, all of which have side effects, but these are the conditions that I see in the office every day. So it's not surprising you're going to see a lot of patients with low testosterone. As I said earlier, the free free testosterone is when you're a little confused, when you really know the patient has it and the numbers just don't pan out, sometimes it's helpful to do that. Same thing with SHBG. Sometimes if they don't make sense, if you levels are are high and you know the patient is has at least you suspect they're hypogonadal, you know, if you measure the SHGB gene is very high you realize that their free testosterone is probably not going to be normal. Okay. The important thing is monitoring of your patients. Of course, any time that you intervene and you give people drugs or treatments, then you're going to have to understand the ramifications. With testosterone, you have growth of the prostate, you have polycythemia, you know, and of course, the controversy about cardiovascular risk, which is not answered at this point. So you want to have a good discussion with the patient saying, look, you know, that low testosterone contributes to cardiovascular disease and there's a suggestion that maybe treatment with testosterone may be an issue. Okay. You also know that when you take testosterone away from patients in prostate cancer, they are at increased risk for obesity and cardiovascular disease. So it's really a little bit of a quagmire, but it's important to have a discussion about it. But now I think that the interesting thing is this relationship between obesity and and hypogonadism. And I think that a lot of this stuff really deals with, you know, 1) fat cells, as I said, promote the production of more estradiol estrogen, which have a negative feedback on the gonadotropin and hypothalamic area which then results in low testosterone. Leptin which is released by fat cells and leptin resistance which occurs in patients with obesity affects the hypothalamic pituitary axis. Leptin also actually directly impinges on leydig cells. These adipokines that are released by the obesity cells are really also major contributors to diminution in in gonadotropin, which ultimately affect testosterone production. The one good for you know adipokine that is release adiponectin and you know by fat cells goes down with obesity so you can't win. Obviously you know the issue is going to be you know what do you do about it? Well, if you can get people to lose weight in some way and this miraculous, in my opinion, I congratulate everybody who loses weight. I tell them I'm trying to lose 3 pounds and I can't do it. I'm asking them to lose 30 pounds. But there's no question that when they lose weight, their testosterone levels will go up. And it's this that's very clear. So this Kisspeptin very interesting. Decrease secretion is a common pattern linking obesity, testosterone deficiency and environmental influences. It's encoded by this KISS1 gene and it's involved with initiation of puberty. And it's a very interesting, you know, graphics that you can see. And they show that things like leptin and, and, and some of the inflammatory markers will downregulate Kisspeptin which ultimately then causes a diminution in testosterone production and infertility in women. So there's some studies using Kisspeptin to induce ovulation in women. So with that, I hope that you understand that there is a very bidirectional relationship between hypogonadism and obesity. Don't surrender to obesity in your patients. Do everything you can to to promote and create alternate approaches. 5 or 10% may make the difference between their being on testosterone and improving their libido and improving their sleep apnea. And once again, I really appreciate your time and your courtesy. Thank you very much.