REBOOT: #462 Male Hypogonadism Pearls with Dr. Bradley Anawalt: Insights on Testosterone Deficiency

Hey listeners, you're about to hear a Curbsiders Classic episode. If you heard it the first time, listen again for that space learning. But if you haven't heard it yet, then you are in for a treat. So without further ado, enjoy. And don't forget to check out our Patreon at patreon.com slash curbsiders. If you want ad-free episodes, bonus episodes, and a whole bunch of other cool stuff, patreon.com slash curbsiders. Hey Paul, I started going to the gym in my tuxedo. it's gonna be you're working on your formal i can't make it work i feel like let me tell you some more everything went well paul i don't know everything went well except for the weight lifting do you know why no because it wasn't my strong suit it's not bad not bad yeah the curbsiders podcast is for entertainment education and information purposes only, and the topics discussed should not be used solely to diagnose, treat, cure, or prevent any diseases or conditions. Furthermore, the views and statements expressed on this podcast are solely those of the host and should not be interpreted to reflect official policy or position of any entity, aside from possibly cash-like, more honest, and affiliate outreach programs, if indeed there are any. In fact, there are none. Pretty much, we are responsible if you screw up. You should always do your own homework and let us know when we're working. Welcome back to the Curbsiders. I'm Dr. Matthew Francoado, here with my great friend and America's primary care physician, maybe even, probably even the primary care physician, Dr. Paul Nelson-Williams. Hey, Paul. Hey, Matt. I like that you're hedging on this a little bit more, which I think is the right thing to do. And yeah, I'm just trying to grow your legend. Tonight, we are going to revisit a, this was episode number one, Paul, testosterone. We talked about testosterone and hypogonadism. We thought it was time we update it. And this is with a great guest, Dr. Brad Anawalt, who we heard at ACP, and we knew we needed to talk more with him about this topic. So before we introduce our co-host and tell you about Dr. Anawalt, Paul, would you remind people, what is it that we do on Curbsiders? Yeah, but before I do, just to peek behind the curtain for our audience, I actually tried to listen to episode number one, which I had never listened to before in preparation for this episode in particular. And Matt, you sounded clinically depressed. I was genuinely worried. about it just it was it was a rough scene all the way around it was not bad i'm just saying that the show has certainly evolved in the god what eight years that we've been doing it so um it's for curious listeners it's worth going all the way back to number one which might only be available on our website just to kind of compare and contrast this episode to our very first one yeah we probably didn't do enough practice episodes before we actually recorded our first episode so it was yeah you know and it featured my nemesis you started out the gate with the The great Dr. Jeff Colburn. Yeah, you got to start somewhere. Got to start somewhere. But in any case, Matt, we are the Internal Medicine Podcast. We use expert interviews for your clinical pearls and practice changing knowledge. I should also mention that on this episode, we are joined by Dr. Paul Wirtz, who put this whole thing together and wrote the episode and produced it. So Paul, other Paul, better Paul, how are you? I'm doing well. Thank you. And audience, you can tell during the episode, I really struggle with the fact that there's two Pauls. So you may struggle as well, especially if you're not watching the YouTube. But Paul Williams, would you like to read the guest bio? Sure, Matt. I'd be happy to. We had a terrific conversation with our guest, Dr. Bradley Annewalt. Dr. Annewalt is the Chief of Medicine at the University of Washington Medical Center and a professor and vice chair of the Department of Medicine at the University of Washington. He earned his bachelor's degree in anthropology at the University of Santa Clara and his medical degree at the University of California at Davis. He completed his residency at the University of Washington in 1992 and served as chief resident at the Seattle VA Medical Center in 1992-1993. Following that, he then completed a fellowship in endocrinology at the University of Washington and joined the faculty in 1995. He has been recognized with multiple teaching awards, and in addition to this, he serves as the North American Editor for the Clinical Endocrinology. He serves as a consultant for the United States Anti-Doping Agency and is on the editorial board of the Journal of Clinical Endocrinology and Metabolism. He also serves as the Associate Editor of Endocrine Reviews. He has done research in male infertility, male hormonal contraception, and male reproductive physiology. And for this episode, he talks us through male hypogonadism, his approach to evaluating the possible etiologies, determining if it's even true or not, what to do with the lab test, what test to order, and then how he conceptualizes treatment and who warrants treatment benefits most from it, and then what to do when we're treating. So a really helpful episode and something that I felt kind of shaky about before this. And I still, when I said this episode, I will feel perpetually shaky, but I feel even better after this episode. A reminder that this and most episodes will be available for CME credit for all health professionals through VCU Health at curbsiders.vcuhealth.org. And if you haven't done so yet, check out our Patreon at patreon.com slash curbsiders, where you can get bonus episodes twice monthly, ad free episodes, access to our Discord server, and a whole bunch of other cool stuff, patreon.com slash curbsiders. Brad, thank you so much for joining us. This has been a long time coming. And, you know, our first episode was a testosterone episode. We're excited to get into that with you. But first, the audience wants to know a little more about you. What's a hobby or interest that you have outside of medicine? I like really doing anything outside. I love backpacking. I play tennis. I picked up pickleball, but I'm not very good at it. And it frustrates me because the racket's not big enough. And I like to run and bike long distances. We've talked about before how we find the rivalry between tennis players and pickleball players to be funny because the pickleball players put weird lines on the tennis courts and, you know, the skills are slightly different. I feel like pickleball is more of a ping pong if you're standing on the table than a tennis, in my opinion. but yeah that's true i wouldn't say anything disparaging about ping pong i played my aunt in ping pong and i thought it was just a you know backyard game and i didn't know that she was a state champion and i hit a ball pretty hard and thought i was looking good and she decided that she was just going to destroy me so i didn't want a point for the rest of the game and i think you probably learned a valuable lesson there too. I did. Well, that's great because usually a follow-up question is what's your favorite failure, but I've already claimed that as my favorite failure of yours. So let me ask you instead. There are many. And so we do like to ask about any meaningful advice or feedback either that you've received or that you like to give people who are in their training or even late career. We'll take all the advice we can get. Yes, I think the most important thing I've learned related to leadership and parenting was something that my wife taught me many years ago when our three daughters were young. She was reading all these self-help books, and I wasn't, but I was trying to listen to her. And she talked to me about a book that was related to how you might approach your children. There was an entire chapter devoted to the following, you might be right but are you effective and uh it has been so telling for me so it's kind of a daily mantra of mine i like it was this like how to talk to your kids uh so they listen or how to listen talk how to listen so your kids will talk is it that book uh it might be all i remember is that this is universally useful whether you're talking to a spouse a friend a patient. It really doesn't help to be totally right. Yeah. Yeah. Talking to kids. Yeah. That's a lot. That's a big part of my life right now. I don't think I'm very good at it either. My effectiveness does not always seem to be there. So I feel you on that one. All right. Well, I think we should get to a case, Paul. So Paul works. Now we're recording with two Pauls. This is going to be a, this is going to be an issue for me, but they're both great. And, and the audience, Paul Williams, the audience for years has been asking, we want more Paul. No one's been asking for that. All right. Paul Wirtz, would you please read the case? Andy Rodgenus is a 45-year-old male with no known medical history who presents with feelings of decreased energy, fatigue, weight gain over the past several years, but notices that it is worse lately. It is interfering with his ability to perform well at work and notices it's taking a toll on his relationship as well. His BMI is 32 and vitals in the office reveal a blood pressure of 155 over 87. Exam demonstrates obesity and a thick neck. He wonders if his testosterone could be the problem. So in general, what is your approach to the history on a patient like this and what factors do you particularly pay attention to? I think the most important thing here is to make sure that you find out what the patient is trying to achieve. And this is a very common scenario where men of all ages come in and they just don't feel as good as they want to feel. And you've given me a history loaded with lots of clues about factors that might result in not feeling so well. And it's also a series of clues that you've given that make me worried about checking a blood testosterone level because you don't want to check a test result if you don't want to manage the outcome of the result. And so in this particular case, I said that lightheartedly, but it's almost impossible to dissuade a man who's come in to really be assessed for the possibility of hypogonadism or androgen deficiency. It's almost impossible to persuade them that we shouldn't check a testosterone. The first thing I'd be asking this man in terms of whether or not he has hypogonadism is how's his libido? And probably the most specific and important clue to new onset of hypogonasm or resa onset is a decline in libido. They don't usually have no libido. They don't have absence of libido, but they will have a decline. And sometimes their partners will report that, that he's just not as interested as he used to be in sex. It won't be erectile dysfunction as a primary complaint. It won't be lack of concentration or fatigue. it will be loss of libido. One clue that I teach my fellows, endocrine fellows, is that if you've never had testosterone, you won't know what it is to experience loss of libido because you'll never have had a normal libido. And so those patients that have congenital hypogonadism, patients with Klinefelter syndrome that don't go through puberty, or patients that have what we learned in medical school, Kalman syndrome, but we now call it congenital idiopathic or congenital hypogonatropic hypogonadism, they simply won't report that they've got a problem with libido because they've never had what we would call a typical libido. So for this man, the history you gave me makes me concerned he might have sleep apnea. He's got a BMI that's greater than 30, and I'll acknowledge that it's not a perfect marker for increased visceral endoposity or obesity, but it's pretty good. Another thing that I will do is measure the waist circumference, and I'll use 40 inches as my benchmark for increased visceral endoposity. The only problem with checking your waist circumference is that it's awfully hard to be consistent in the measurements. My landmarks I use are the posterior iliac spine, the top of it, So you're reaching in the back and you're feeling the top of the iliac spine, the bone. And then I measure it to the, just below the umbilicus. But the position of the umbilicus can be variable depending on how much fat the patient has. Anyway, back to this patient. I'm quite certain that because he's got brain fog, he feels tired, decreased energy. This is taking a toll on his relationships. that he's going to want to have a serum testosterone checked. And I will do that, but I do try to enhance the probabilities that I'm going to get the most accurate test that I can. And there's a couple of tricks on this. One, you want to be sure that you get it in the early morning between 7 and 10 a.m. because that's when testosterone levels are highest and the normal range is established based on normal, healthy young men assessed between 7 and 10 o'clock in the morning. You don't want to check in the afternoon. when everybody's testosterone level will be lower. I prefer to have them fast for at least six hours, particularly when I have a suspicion that they're eugonadal, that they have normal testosterone. The fact that somebody fasts for at least six hours can raise their serum testosterone as much as 50 nanograms per deciliter. So that can put somebody who's borderline, say 270, that can put them well into the normal range. And then the last thing that I would urge my colleagues is to consider the testosterone assay they're using, that the normal range of the assay they're using should be approximately 300 to 900. Ideally, the normal range should be 264 to 916. And that seems so random. Why that precision? That's the normal range for the CDC validated assays. And there are now a number of commercial laboratories that will offer validated testosterone assays. I'm going to stop there because I know you've got other questions and I don't want to spend the whole time talking about testosterone assays. When you're asking about libido specifically, can I ask how you ask that question? Like, you know, especially for someone who's been married decades and has sort of potentially other stuff going on here. Like, you know, you just, you wonder what those manifestations might look like or could appear like decreased libido, but might not be. So is there a specific way that you asked about libido to kind of suss that part out? Yeah, I try to remind myself to speak plain English, and I'll usually use the words sex drive as opposed to libido. And if I get a puzzle expression or if I get an answer that suggests that I'm not asking the question in a clear fashion, I'll ask them things like, do you think about sex as often as you used to? Are you as interested in it? I try to be really value neutral about what I mean about sex because some people don't have partners or they have multiple partners. And if I do find out, by the way, they have multiple partners, I ask them, do you have situational differences? So in plain English, do you have a greater sex drive with one partner than another? Or are there times of day or circumstances where you're more likely to have sex drive? Everybody has times that their sex drive is not very high. So what I'm looking for is a pattern where I used to think about sex all the time. And now I don't think about it anymore. Or I used to be interested all the time. And then I have to also ask them their frame of reference because universally, the men that come in to see me want to be 18 years old again. And so I'm asking them, no, I'm really most interested about two or three years ago. How were you like two or three years ago? And then I often get a very different answer. Oh, no, I'm not much different than I was two or three years ago. It's just in comparison to being 18, 19, 20 years old. That's great. I'm glad I asked. Yeah, that was a great question, Paul. This episode is brought to you by Gusto. As a new year begins, a lot of folks are trying to get their business operations together. And honestly, having payroll benefits and HR handled by Gusto feels like starting the year with a clean desk and an organized inbox so you can focus on actually growing your business. 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That's three months of free payroll at gusto.com slash curb. One more time, gusto.com slash curb. this episode is brought to you by locum story full disclosure what i'm about to say is a sponsored promotion for locum story.com but don't worry there's no sales pitch here just a friendly heads up about something you might be overlooking locum tenants it offers physicians a higher paying more flexible way to work locums lets you take control of your schedule with part-time or full-time work or even assignments on the side of your day job. It also gives you a chance to try out new practice settings, travel to new destinations, all while still doing what you love. So if this isn't a sales pitch, why does it sound an awful lot like we're selling locums? Well, here's the catch. LocumStory.com is literally just a free, unbiased resource dedicated to educating physicians about locums. That's it. There are no salespeople, no commitments, just free information. Think of it as your go-to guide for everything you'd ever want to know about locums. how it works, how to get started, and how real doctors are making it work for them. So whether you're simply curious or seriously considering a change, pop by locumstory.com to see if it's something that makes sense for you. Brad, also, like, just asking patients about, I've had patients say, oh, yeah, like, I don't have a sex drive, but I'm still, they're still having masturbation or still masturbating. And I'm like, well, then maybe it could be a relationship problem if you're, you know, if you're having issues in one area, not the other. So that's, but I like the way that you forced them to say, are you comparing yourself to yourself at 18 or is it just the past couple of years that you've had the change? Okay. So libido is really, that's an important clue that testosterone, that they might have hypogonadism more so than erectile dysfunction or fatigue. And you said, just be aware of the patient that had congenital hypogonadism. They have no point of reference. So they probably, you know, never really had a strong libido or sex drive. And then I like the point of measuring waist circumference because BMI can be a pretty unreliable thing. And I didn't realize that it could be up to 50 point difference if you make them fast or not fast. Because I do tend to get a lot of readings, people in like the 250 to 300 range. And then they, my lab says that that's low. And maybe if those patients were fasting, that, that might've fixed the problem. Yeah. In fairness, we don't have outcomes that are connected to whether or not you're fasting. In other words, we don't know if that's better. But the a priori assumption is that most men who are coming in with a borderline serum testosterone concentration are actually eugonadal, that they don't have adernate deficiency, because that's the epidemiology. that the epidemiology suggests that bona fide hypogonadism, where you can identify a cause, occurs in less than 0.5, less than a half a percent of men. So a priori, you're thinking this person's probably eugonadal. And so stacking the deck in favor of corroborating that with laboratory values is, you know, I think that's fair game because what you're really trying to do is avoid giving somebody a lifetime diagnosis and a lifetime of testosterone therapy. when they don't need it. Paul Wirtz, do you want to read the next part of the case? Yeah. So are there any labs that you would get here? Would you get a TSH? Well, you're never wrong to get a TSH. It makes patients feel that you're paying attention and they're inevitably going to be asking, might they have a thyroid problem? So I think that's fine. I think in this setting, if you decide to get a TSH, you might as well get a free T4, or total T4 as well, because if you find that the patient is hypogonadal, they have very low serum testosterone, that can help guide you as to whether the problem is in the brain, hypothalamus and pituitary, or whether the problem is in the testicles. So I wouldn't fault anybody for getting a TSH, and I have to admit that there are many, many, many circumstances when I've gotten a serum TSH knowing full well that that's not the etiology for the person's complaint. I would probably focus on a couple of laboratory tests for this man, I would get a hematocrit for two different reasons. One, you gave me a history and a physical exam. The thick neck is a clue that perhaps he has sleep apnea. And if I found that he had baseline erythrocytosis or hematocrit in the high 40s, that would lower my threshold for considering outpatient polysomnography for testing for sleep apnea. The other value of getting a hematocrit is that, of course, he may have anemia to explain these symptoms, but it's going to be an important baseline lab if you are trying to interpret his testosterone. We'll come back to that at some point. And then I would get a serum testosterone, and I get FSH and LH as well, the two pituitary hormones that regulate the testicles. It's marginally more expensive, and it can be quite valuable when they are abnormal. So if FSH and LH are quite high, then you're thinking about primary hypogonadism. And if they are below the lower limit of normal, you're really pursuing now the diagnosis of a severe pituitary hypothalamic problem. So the yield is low, but it can be quite useful. Just to clarify, so this is a guy, you know, this is someone that Paul Williams and I would probably see in clinic all the time, 45 year old, overweight or has overweight or obesity, and then not really exercising much and thinks he has low T, wants us to check. So you saying as a first round test you might check the testosterone FSH NLH without because I know sometimes in the guidelines they say wait until the second or third time to check the FSH and LH but I sometimes it just saves the patient a trip to the lab. It does. I don't feel dogmatic about this. The guidelines were written with the notion that we should be as cost-effective as possible, and I agree with that. So getting a screening testosterone alone would be perfectly sensible. But I agree with you. I'm often having to check this testosterone more than once. And the marginal cost here is pretty low. It also offers me an opportunity. When I get back these results, I draw a little cartoon about how the hypothalamus and pituitary and testicles work. and it gives me an opportunity to explain to them that the problem here is not in their testicles, it's not in their hypothalamus or their pituitary per se, but it is related to the effects of sedentary lifestyle and too much abdominal fat, and it affects the pituitary. And then I can walk them through how they can actually raise their blood testosterone with weight loss by lifestyle changes, including exercise. So it's a way of persuading the patient that they have been heard and that they have a real solution to a borderline low testosterone, which is to lose some weight through diet and exercise. And I just want to define for the audience, you mentioned primary hypogonadism. That's where the testes are just not making enough testosterone. And usually the FSH and LH are very high because they're sending a signal, but there's just no response. and then secondary hypogonadism could be the hypothalamus or pituitary or just not sending inadequate signal. Or can you define that for us, I guess, a little better than I'm doing? No, you did it beautifully, but I'm going to say it in my own words. When there's a problem with hypothalamus and pituitary, the FSH and LH will not be elevated. They may be in the normal range or they may be very, very low. They're typically very, very low when you have a pathology of the hypothalamus or the pituitary, like hemochromatosis, a tumor, hyperpalactinemia. What we commonly see as physicians is men that come in with low serum testosterone concentrations that are just a little low or they're borderline low normal, and they come back with FSH and LH in the normal range. They have suppression of their pituitary function, so they're no longer stimulating the testicles to make the amount of testosterone that they would normally make if they were healthy. And the most common cause there is, and I find this particular science that we've discovered in the last 10 years fascinating, if whether or not you're severely underweight, like patients that have anorexia, or you're overweight, the common denominator there is a problem with leptin. And leptin is a hormone made by the fat. And you have to have normal amounts of leptin to have the hypothalamus work properly and send out the message with a hormone called gonadotropin-releasing hormone to stimulate LH and FSH. and it makes sense. Your leptin is telling your body, you've got plenty of fat stores, you've got energy, you can actually procreate. And if your body weight is very, very low, I used to love the Rudyard Kipling, Just So stories. And if your body weight is really low, you shouldn't be wasting your energy on trying to procreate. You should be trying to find food. and and so that's the way you might think about anorexia or severe underweight if you think about somebody though who is overweight and obese now the leptin levels go up really high and you say well what's the problem here that should actually be really turning on the hypothalamus but what happens as we gain weight is we become resistant to the effects of leptin so it's much like diabetes where you might have very high insulin levels but your body's behaving as if it's starving. And the same thing's happening in this case with being overweight with leptin. So I don't go into that detail with my patients, but I do tell them that if they can start exercising 30 to 40 minutes, four or five times a week, and I do push them to 30 to 40 minutes, some will actually take that advice and some are already doing that kind of exercise. I ask them to push the intensity and then we go over a healthy diet. Basically, you shouldn't eat any product that has a nutrition label because it has a nutrition label. It's not nutritious. But there's a minority, but there's a fraction of men that will listen to this and take the advice to heart. If I can give you one more little tip that I just learned from my colleagues in Australia, they did a study where they looked at the effects of testosterone versus placebo, a two-year study. They recruited men that were at high risk for diabetes. They either had impaired fasting glucose, so they had an abnormal oral glucose tolerance test. And it was a big study. It was 1,000 men. And they were randomized to two years of a form of intramuscular testosterone that lasts for up to 12 weeks or placebo. But everybody was enrolled in the WW program, which is the new name for Weight Watchers. So everybody got a program that basically reminded them of the value of exercise and what to do and a healthy diet. And the two groups of men both lost a kilogram or two over the two years. And there was an effect on decreasing the incidence of diabetes in this very high risk group. But what they did that was so interesting, This is the tidbit that I think has been a really nice tip for me when I'm working with my guys that are asking about testosterone. The quality of life, how well the guys felt, their self-reported mental clarity, their sexual satisfaction and sexual function, that all improved in proportion to the weight they lost. and it was independent of whether or not they were randomized to placebo or testosterone. So I cite this effect on sexual function because a lot of the guys are really motivated by trying to improve their sex lives and improve their sexual satisfaction. And that is concordant with data looking at the effects of weight loss through lifestyle measures on men with erectile dysfunction, that they can improve their erectile function and their sexual satisfaction, not if they have no erectile function, but if they have some decrease. So I really try to emphasize the value of that. Yeah. Paul Williams, are you going to start sending FSH and LH now? Or are you already sending those tests sometimes? My practice had been more along the lines of what you would suggest. I had been doing sort of the confirmatory test. So if I get one low testosterone and do the second morning one to confirm, I'll do the FSH and LH at that time had been what I'd been doing. But often I feel like I'm just kind of making things up as I go along. I feel like if we start to do it Brad's way, we're going to start to find some Klinefelters, which we're going to talk about at some point on this. But that would be exciting if we start finding those patients because they're in our panels, as you told us at ACP, Brad. They are. I think that's, hopefully the audience will take that advice. Okay, so let me recap the lab testing. So hematocrit, a lot of different things we're looking for there. If it's high, that's going to probably push us more towards a sleep study. And we're checking FSH and LH to try to differentiate, is it primary or secondary hypogonadism? And then we're checking a testosterone. So my lab seems to default to total and free testosterone, and that's gotten me into some trouble. Do you send a free testosterone with the initial round, or is that sort of more, like, when are we sending that? Yeah, fair enough. I have to admit something to poll number one, or maybe it's poll number two. I'm not sure which, and I can't say Paul W. I don't feel dogmatic about checking FSH and LH. If you want to wait and use that as a follow-up diagnostic test, you have to look at the clinic you're in. And my clinic is enriched for patients that are more likely to have endocrine disorders. When I was in primary care, I think I would have adjusted my practice and simply checked the testosterone. So I want to be upfront about, it really depends on where you are, what your index of suspicion is. In this case, my suspicion would be low, although I must say that I still find it valuable in walking through the interpretation. It allows me to point to numbers and explain them, and I think patients find that useful. Now, coming back to answer your question about free testosterone, I think that it would be useful to get a free testosterone in any man that has diabetes, insulin resistance, or obesity. And that's because those men often have what we call pseudo-hypoglunitism. They will have a low serum total testosterone, but a normal free testosterone. And that's because these conditions of insulin resistance, diabetes type 2, and obesity all have in common, a decreased synthesis of SHBG, the binding protein for testosterone in the liver. So I think getting a free testosterone is a good idea. Now, I'm going to give the most important qualifier of the day. It has to be an accurate assay. It just has to be an accurate method. So you can do it one of two ways. You can do a calculated free testosterone. You can't do the calculation. You have to let the lab do it. Many colleagues will go online and they'll look up the formula. And the inherent problem with that is that it's dependent on the lab that you're using and the total testosterone assay. So they have to do the calculation. And this is a setting where I will go out of my way to use one of those CDC-validated total testosterone assays. If I get myself into the quandary of, do I think this person with a borderline serum testosterone, total testosterone is hypogonadal or not, then I'm going to go and use a CDC-validated total testosterone and do a calculated. The other thing you can do is you can measure it by equilibrium dialysis, and that's very expensive. It's time-consuming. Most labs don't do it, so you'll get an answer back in two weeks. So I almost never use that assay. I almost always use it calculated. Do you know if the national lab chains, when you send people to those, do they use the validated, recommended testosterone-free in total? The big ones do. You actually can stipulate, you can look in the lab menu and say you want a CDC-validated, or you can look for one that has that normal range that it gave you, 264 to 916. LabCorp is one of the ones that primary care docs use quite frequently. That one has a good validated assay. Mayo Clinic does. So, really, any of the big commercial assays, commercial labs will have a CDC-validated assay. So, I think it would be prudent in this man to go ahead and get a free testosterone. If you want to start with a total and then have it come back 265 or 260 and then get your calculated free testosterone, I don't object, but I do like to save my patient the time. And so I really, in my clinic, I have so many patients that are overweight or have diabetes that I go ahead and just get a free testosterone whenever I'm going through this evaluation. Do you find it useful to get the, so SHBG, sex hormone binding globulin, just to prove to the person that, oh yeah, you know, this is why your total T, see, this is low. Your sex hormone binding globulin is low. That's why your total T is low, but you have a normal free T. So do you get all of them or just the free and total? If you're using a lab that does a calculated free, they should give you an SHBG. And if you get back a total testosterone and a free testosterone and no SHBG, you should be suspicious that they are doing a direct measurement of free testosterone. And I think we're going to get into that in one of the cases, but I'll say it now. They are worthless. They're cheap, fast, and inaccurate because as much as 30% of patients will have an inaccurately low free testosterone with those methodologies. So if you don't have an SHBG, you should be suspicious and ask if you had a testosterone that was done by a platform method by direct measurement. And it'll actually, if you look carefully, the lab will report usually direct. Oh, okay. That's, that's helpful. We're not used to looking at free hormone levels, right? You know, for a lot of the times we, we don't use those because like vitamin D and things, they're a little bit more volatile and harder to interpret, but this is the case where we are. Okay. Yeah. The best example to help remind you is free T4 and total T4. We all check free T4 now, but before we did that measurement, we were often fooled by pregnant women and patients that are taking medications that raise thyroid-binding lab. And so it's the same concept. Okay. Paul Williams, any other questions you want to ask about this guy's lab testing here? no no so i think did we get his labs back so he we talked to him about nutrition counseling physical activity we refer him for a sleep study his am testosterone comes back at 283 but let's let's say his hematocrit was was normal tsa thyroid tsh was normal anything else that we need to do here just just do a second round of testing brad what would you do next well our Pre-test clinical suspicion was low for hypogonadism, and we've confirmed, depending on what lab you're using, but he's either normal, 283 is normal in a validated assay, or it's low normal, or slightly low normal. But all three of those I'm going to interpret as eugenadal. And I'm going to have my conversation that we had a few minutes ago about the advantages of it's hard work, but you will feel better. You'll think better. Your quality of life will improve. And that's where I would start with this. And I see these patients back now in primary care. Of course, you always see them back, but I do see these patients back. And I said, look, I'm going to, I'm going to see you in three or four months and we're going to follow up on this. I'm going to see how you're doing. And that helps spur them on a little bit. I can't say that it's a magic wand and makes everybody transform into regular exercisers, but many do. I've been surprised by some of the guys that take this really to heart. And I haven't focused on waist size, not weight. I ask them about whether or not the loop of their belt is getting a little loose and they're having to tighten it. That's actually a better predictor of loss of visceral adiposity. And it's less frustrating to them because sometimes they will lose waist circumference, but their weight will remain pretty much the same. And so it's a better end point for me to have them see a reward. This episode is brought to you by MedStudy. You forget 70% of what you learn within four days. It's not motivation. It's how memory works. Most QBanks are built for mass repetition, not efficient retention. Other platforms make you manage spaced repetition, installing plugins, manually scheduling reviews, serving you a thousand items to review each morning. MedStudy's QBank with Personal Trainer is built around spaced retrieval. It reviews content at exact intervals your brain needs. MedStudy automatically tracks what you've learned and surfaces reviews at the right time. You just log in and study. No plugins, no manual tracking, no guesswork. MedStudy users pass at rates 2% to 7% higher than national ABI averages. Try the MedStudy QBank for yourself. Curbsiders listeners get 15% off with code CURB15 at medstudy.com. This episode was brought to you by the Sanford Guide. Infectious diseases cases can get complex quickly. Sanford Guide was born as an antimicrobial therapy Grand Rounds handout over 50 years ago to make ID treatment easy to understand. Millions of health professionals have used the guide, and it continues to grow as an essential tool that individuals, work groups, and even entire hospital systems purchase. While the book can be intimidating for the occasional user, the Sanford Guide antimicrobial app is the opposite. Physicians, pharmacists, NPs, PAs, even students just learning the basics love the clinically actionable, continuously updated infectious diseases treatment guidance. This isn't an encyclopedic reference to scroll endlessly, and it's not an AI-generated summary. Everything is intentionally written in a succinct high-yield format from the start. Sanford Guide experts stay on top of all the evidence and distill it into guidance that's easy to understand. Search for Sanford Guide in the app stores. And Curbsiders listeners can get 20% off the already very moderately priced yearly subscriptions directly at sanfordguide.com. Go to sanfordguide.com and use the code CURB at checkout. I find that, you know, there are so many people now asking us for these weight loss medications, and they're just asking, you know, what can I do to lose weight? And some of the people that just need to lose 20 pounds, I say, you know, listen, what you need for weight loss is not these fancy new drugs, these things are free. They're just very hard to do. The exercise, the eating right. Maybe if they're drinking 12 beers a week or something, I say, if you stop drinking 12 beers, you'll probably get at least halfway there. But it's hard to do that. So I do empathize with people. But the weight loss thing is, I know it's on everybody's mind. Everyone's trying to lose weight for the most part, unless they're older and sicker. And then we're just praying that they can gain some weight. Right. No, I agree. That's a common second question that happens with these patients. And I return to the goals of what the patient has. It's generally not weight loss per se. Sometimes it is. I mean, the patients that are coming in asking because they're curious about whether or not they have a low testosterone, oftentimes their goals are to have more energy, clearer thinking, better sex lives, in part because they've been listening to the quote-unquote low-T marketing that is so ubiquitous. Those patients aren't usually asking me up front for a GLP-1 analog or the GLP-1 GIP combination. When we get to that, I have to educate them that, Yes, those are very effective weight loss drugs for most people. They also cause loss of muscle mass, which is often one of the endpoints they want to go the other direction. They're actually seeking to have more strength and more muscle. And they also have a loss of bone density. And then the other kicker, actually one of my patients is an older man came in. He's a real character and he loves donuts. and I said, you know, one of the problems with these medications is we're finding that they take some of the pleasure away from some of the things that we like. One of the reasons why they're effective at weight loss is these people will report, I just don't have the same urge to eat as I used to. And that applies across the board. It's one of the reasons that there's speculation about some increased depressive symptoms when patients take GLP-1 analogs. And one of the reasons that these drugs appear to be effective for tobacco sensation is they just take away the pleasure, take the pleasurable edge off of activities that they like. So I use that as a, you know, you came in here asking for greater pleasure out of life, more muscle mass, more energy. And I think we're going the wrong direction here. Let's see what we can do with changing your lifestyle. It's a lot of work. It's a lot of conversation. Yeah. Yeah. Well, we have America's primary care physician, Dr. Paul Williams here. Paul, I feel like you're good at that conversation with a patient, counseling. My literal favorite thing. Yeah, it's actually the reason why I'm in primary care. Yeah, I will say before we sort of close out this case, that apropos of none of this, by the way, is that this is someone who I'd also be screening fairly heavily for depression just because the world's on fire. So they have weight gain and they feel bad. They're actually reporting that they feel depressed. So it's certainly testosterone should be a consideration here, but I would also be just triple checking to make sure that we don't need to consider something else for them instead. Yeah, I would just say, Bravo, it's such an overlap between depression and all these other syndromes we're talking about. You have to think about that first. And before we leave this case, let's, and I can't remember if we read you this lab yet, but we had it written this way. And I feel like I have seen something like this that confuses me. So if I get the first testosterone and it was in the 280s, and let's say I was following my lab, my lab said 300 or less is low. So I get it again and it comes back. The total is 334. but also I got one of those free assays and what's what we don't know if it's calculated or not but it said the free is comes back at eight it's low so how do you explain that so if it's a normal total and a low free are we worried about that or how do you talk to patients about that yes there there are two answers to that question the first one is that when you see the free testosterone in single digits, it's almost always a direct method. So that's a big important clue that you probably have an inaccurate method So I going to make that number different I going to make that number say 33 So now it and I confirm that it an accurate method that we used a good testosterone assay and we've calculated the free testosterone and it's a little low. That's a quandary. That would be a setting for this particular patient. It would still make me quite comfortable that he has, that his primary problem causing many of his symptoms and causing the low testosterone is that he's overweight and we still need to take the same approach. The other thing that I would say for us doctors, which is harder to convince patients of, but when patients are truly hypogonadal, they will have a concordance usually of the free and the total testosterone. So they won't have a total testosterone that's well in the normal range and a free testosterone that's really a little low. The patients who get the most benefit from testosterone therapy will have a low total and a low free. So that's helpful for us as clinicians, but it's less helpful to the patient because they're going to say, well, I thought you told me the free testosterone was the active form. And I say, yes, but we still are going to take the same approach to help raise your own natural production of testosterone. I will say if you use an accurate measurement of free testosterone, an accurate method, you will less often see this discordance. Yeah. I got to look back and now that you've taught me this, cause I wasn't aware of the direct and the calculated and cause I feel like I have seen that discordance and it confused me and it confused the patient. They were asking me about it and, and probably that's what was going on. Okay. Well, let's say that, uh, we, we did convince, uh, Andy, our patient, our first patient, he was one of those patients that really changed things. His testosterone went up, let's call it 60 nanograms per deciliter. He was happy with the numbers. He felt better. He lost some weight. And let's go on to another case. And this, I have to say, I'm a big fan of this name. So Paul Wirtz, I'll let you read this one. Yeah. So Sir Toley is a 68-year-old male. He's got a history of BPH and CAD with a PCI two years ago. He presents due to decreased libido and erectile dysfunction over the past one to two years. It is now affecting his intimacy and causing distress in his relationship. He is very active. He runs six to eight miles three times per week and goes to the gym daily. His AM fasting testosterone on two occasions comes back at 370 and 395, but the free is 30, which is low. So how do you approach next steps in a patient like this, including navigating a risk-benefit discussion? Well, this patient has a much more classic story and presentation for bona fida, hypogonadism, and handkerchief deficiency. He's got a decline in libido. It's affecting his relationship. Presumably, his partner is reporting that the low libido is bothering them. We have a patient that has coronary artery disease and has BPH, so we're going to have to talk a little bit about the risks and benefits if we start testosterone therapy about prostate symptoms and prostate disease and cardiovascular disease. But this is somebody that I would have a much higher index of suspicion that they have bona fide hypogonadism. There's one other relatively new finding in the past few years, which is that we know that the effects of aging start as early as 30 or 35 in lowering serum testosterone. So we all slowly are declining about a half percent per year. But there is an inflection point at about 65 or 70. And that the prevalence of primary hypogynetism begins to increase quite a bit after age 65. It may be as high as six or seven percent of men over age 70. So if you find that the patient has a low testosterone and a high FSH and LH, those men don't get better. They don't get better with weight loss. Their labs stay the same, and they have probably real primary epigonetism that's related either to aging or, Matt, you brought this up a few minutes ago, undiagnosed Kline-Filter syndrome. And we miss Kline-Filter syndrome about half the time. And we know that because in countries that are civilized and have national health care systems, like in Scandinavia, they can follow patients throughout their lives with a single health care registry. And they have determined that they are missing. So, Kleinfeldscher occurs in about 0.2% of the male population, and they only find it about half the time. So, that means we're missing it. So this man, I'd be quite concerned that he has hypogonadism, and I'd want to measure testosterone. In this case, I would want to be sure I measure FSH and LH because of this increasing prevalence and incidence of primary hypogonadism after age 65 or 70. It's something that surprised me. The total testosterone here for this guy is in the 300s, but is free is low. But is it true that as you age, your sex hormone binding globulin goes up? That confused me a little bit. Yeah, fair enough. So let's assume, again, we've got an accurate assessment of the free testosterone, and it's low. There are a couple of things that can raise your sex hormone binding globulin. One of them is that it increases as you age. And so I think your assessment that this discordance could be due to the fact he has high SHBG related to aging. His total testosterone is misleading you because with SHBG being high, his total testosterone, his body is trying its best to make more testosterone. It rises, but the free is low. So another interesting aspect of this is if you have primary epigonadism, like men with Kline-Filter syndrome or men over age 70 where they may develop primary epigonadism, the luteinizing hormone, LH, increases the aromatization, the conversion of testosterone to estrogen. And this is why you see with primary epigonadism more gynecomastia. Interesting. And you will also see higher SHBG levels. men with Klinefilter syndrome will have SHBG concentrations that are high and sometimes quite high. So there's two possible contributors here. One is age and the other one is indeed has primary hypogonadism. He may be making a little more estradiol and raising his SHBG. So for acquired primary hypogonadism, is this almost like equivalent to premature ovarian failure or where just like the testes just, they don't have Klinefelters, but the patient just for whatever reason, the testes just stopped making as much testosterone or incapable of making as much testosterone? Yeah, I wouldn't want to use the term premature ovarian insufficiency because it's a more gradual process than what happens in the setting of primary ovarian insufficiency. But What happens with aging is we get a dual defect. Our hypothalamus doesn't pump out as much GnRH. We only have about 1,000 neurons that make GnRH, and so for a variety of reasons over time, they may either decline in number or in function. And then the other problem that happens is the leitig cells decline in function in number. And we think that that might actually be due to, as men age, it might be related to ischemia and loss of leitig cells. So let's say we're convinced that this patient has hypogonadism. We want to treat him. Can you talk to us about the options there? And what does that conversation go like when you talk to a patient about treatment? Yeah, if I can emphasize one point here, I think he is hypogonadal. And I'm going to believe that free testosterone now and not the total because of his convincing story. So it's important actually to interpret these labs in the context of whether or not you think the patient's hypogonadal. And so I want to freely admit to you that I'm really convinced by that declining libido. I would evaluate them for cause. So if his FSH and LH are high, we can diagnose primary hypogonadism and we can move on. But if they're not high, then we have to evaluate for pituitary tumors, hyperprolactinemia, Cushing syndrome. So we can talk a little bit about that, but I don't want to dodge your question about prescribing the testosterone. We'll come back to the, when do you get an MRI and prolactin? Yeah, let's talk about the treatment a little bit. So, in this case, the questions that come up from clinicians more often than patients is, what's the risk of testosterone to the heart and to the prostate? And we now have had four randomized controlled, placebo-controlled trials in the last 10 years that have allowed us to answer that question a little better. Now, these trials were all done in patients that didn't have identifiable disorders that would cause hypogonadism. So, they didn't have Kline-Filter syndrome or pituitary tumors. But nonetheless, we've got some good data. And if you look at all four of these studies, the testosterone trials, the T for diabetes study, the Traverse trial, and then something called TEAM, which was a three-year study looking at markers of atherosclerosis. In those studies, there was no significant increase in lower urinary tract symptoms in patients that had mild or moderate symptoms. They excluded patients with severe symptoms, so we don't know about those patients. And there was no increase in prostate cancer. Now, these studies weren't designed to look at whether or not increase the risk of prostate cancer. They weren't long enough. They didn't have enough patients, but there wasn't a concerning signal that maybe they would increase prostate cancer. And then finally, the biggest study and the most important one for cardiovascular risk was the Traverse trial that was published about a year and a half ago now. And I don't know, because I'm actually not that long ago, it was a year ago. But the Traverse trial showed that in the 5,200 men that were randomized to placebo or testosterone, that there was no increased risk of strokes, heart attacks, deep venous thrombosis. There was a numeric difference. about twice as many men had pulmonary amylai than had on the testosterone arm than the placebo arm, but the total number of pulmonary embolus events was just under 40, so it was a small number, but nonetheless, that's a worrisome sign, and it makes me more concerned, even more concerned, about prescribing testosterone to somebody whom I do not think has hypogonadism. So I don't think this man has any really serious signals that make me worried about the risk of testosterone therapy. I think he'd have a benefit. He's at the age where I need to have a conversation with him about prostate cancer screening. And I would treat him just like any man. I use ages 50 to 70. I'm open to conversations about different ages than that. but I use 50 to 70, 40 if they have a family history that makes me more concerned, but 50 to 70 is a rule of thumb, and they need to have a life expectancy of at least 10 years. And so I would have a conversation about the risks and benefits of prostate cancer screening, and if he opts to proceed, I would advise him that in general the PSA won't go up very much. It goes up about 0.2 to 0.5, but up to 5% of men will have it go up as much as three or more. So there's going to be some people that will have their PSA go high, and it doesn't mean that they have prostate cancer. I mean, if it goes to 20 or 30, that's a different case. But if it goes to four or five, it doesn't mean they have prostate cancer. It's just one, they're in the outlier of being much more responsive to androgens. So I'd have that conversation, and depending on what he wanted to do, we would proceed with PSAs or not. I wouldn't do a digital rectal exam unless the PSA is abnormal. So it's, the AUA is now called that a second-line screening test. In other words, you wait until you have an abnormal PSA. Yeah, most patients are happy when I tell them about that part of the prostate cancer screening. And most of my colleagues are happy to hear that I say it's a second line diagnostic test too. Yeah, I'm with them on that. The other thing you mentioned back to the beginning of our conversation, the hematocrit, so if that's above 52%, I think is the number line drawn in the sand on the guidelines that you would probably think twice about giving testosterone replacement therapy? I think I'd reframe this. Most men with hypogonadism are either going to be a little anemic or they're going to be in the normal range. And if you see somebody in the high 40s, that raises two questions. Are they truly hypogonadal? That would be a mark against that. Or do they have undiagnosed sleep apnea? So this would be somebody that if their hematocrit is 47, 748, I would recheck that hematocrit, certainly within three months, but I might even check it in a month or two, knowing that they're not going to have the full effects of testosterone. But if it starts to go above 50, I'm certainly going to be screening them for sleep apnea. And I might even do it right out of the gate. If they give me symptoms that suggest they have sleep apnea, I would, in that case, I would forestall prescribing testosterone. I would treat their sleep apnea. And if they're correctly treated, particularly in these days when we have these much more comfortable masks and much more tolerable devices, they may actually have resolution of hypogonadism. Now, that wouldn't be true for primary hypogonadism, by the way, though. Okay. Yeah, that was a question I had because there has to be so much overlap for these patients and obstructive sleep apnea and undiagnosed. And I guess, how does that impact when you would treat or if you would treat? Would you go through the sleep study and actually ensure that they're on, you know, positive airway stuff before actually treating for hypogonadism or sort of what is your order of treatment or does it even really matter all that much? I think it depends. And the patient that has primary hypogonadism, they have hypogonadism and treating the sleep apnea is not going to make any difference. And I think you can decide whether you want to treat and see if that unmasks sleep apnea or you can wait and do your polysomnography and then wait for the results, treat that and then start testosterone. But either way, you're going to wind up just, if they have primary epigenosis and you're going to wind up treating with testosterone, you know, independent of the diagnosis. So the confusing answer is it depends. And what benefits, so we largely just talked about the risks. What benefits would you say they might glean from this? Because, you know, the patients often, they're coming in with brain fog and low energy and those sort of things. So which ones can you promise them might get better? So Paul has his favorite question or favorite part of medicine. This is one of my favorite questions related to testosterone. You need to divide the men that you've diagnosed with hypogonadism that you've decided to treat in two camps. One is, do they have very severe hypogonism, androgen deficiency. So that would be reflected by very low serum testosterone concentrations. And then the other one is, do they have an underlying etiology that you can identify like a pituitary tumor or Kline-Felter syndrome? So for the men that have really low serum testosterone or they have unidentifiable cause, they're in a totally different group. This is like treating those guys or patients with TSHs of 70 and delayed deep 10 reflex returns and yellow skin. I mean, these patients get better and they feel great and they thank you and they remember you forever. The patients that have a serum testosterone that's just a little low and don't have an identifiable cause are much more like those patients that you see with serum TSHs that are 11, 12, 13, they may or may not experience a significant benefit. Many do not. And this explains why many of these patients stop taking testosterone on their own within a year, that those patients that don't have bona fide hypogonitis, some often will quit taking it. In fact, the majority do more than half. I like that comparison because that's very clear to me because we've all seen the patient that's borderline in a coma from hypothyroidism that then just like it's totally life-changing when they get on medication and then you've seen the patient with, you know, almost subclinical, barely clinical hypothyroidism that it's harder to notice the benefits, I guess. That's exactly right. Okay. So I know, you know, we can't keep you forever. I'm sure you have other stuff to do this evening. So we promised that we would talk about MRI and you said pituitary hormones, prolactin. So the man with really low serum testosterone, is that what makes you think? Like, let's say their FSH and LH are normal or low and their total testosterone is really low. Then is that the time when you get the pituitary MRI or think about those other tests? I can give you a list of criteria and a rationale that I think you can remember. We can all remember. Oh, perfect. I love it. The first one is how low is their testosterone? If it's very low in the setting you're describing, you'd get a cell imaging study, usually an MRI of the pituitary. If they are younger than age 50, you would have a very low threshold for getting a cell MRI. And the reason for that is that the prevalence of low serum testosterone and what looks like secondary epigonidism is so much lower in men that are younger. Whereas if they're older, you've got a whole bunch of guys out there with age-related, obesity-related, what looks like secondary epigonidism, and the yield is very, very low. Prolactin is your other friend, your other signal. If they even have a slightly elevated prolactin, they get an MRI. But if their prolactin is normal, they're young, sorry, their prolactin is normal, they're older, and their testosterone is not very low, you do not need to get an MRI. And then the last one is if their pituitary gonadichopins, their FSH and LH are undetectable, that's a clue that you've got something squashing them and that it's not just related to aging. So age, if they're over age 50, prolactin, if the prolactin is normal, if they have a testosterone that is not very low, and if the FSH and LH are not suppressed below the lower limit of normal or undetectable, that's a setting where you can skip the pituitary imaging. And that's probably 95% plus of men over age 50. I can deal with that, Paul. I know Paul always has a low threshold to know what he doesn't know and then send people to the specialist when needed. But Paul, any questions about that? That's pretty clear to me. No, that's actually very straightforward and consistent with what I've done. So that's actually really helpful. Oh, good. So what are we going to put Sir Toley on to treat his hypogonadism. So before we get started on the treatment, I just want to add one more thing in here. Remember in the very first case, we checked a hematocrit. And if Sertoli has a low hematocrit on top of everything else, that also is a predictor that he's going to have a more significant benefit. Those are the men in the Traverse trial that if they came in with anemia, they reported increased energy when they are given testosterone. So that would be one other reason for checking the hematocrit in this particular setting. I would recommend for this particular patient that he either use IM testosterone ciptonate, which is the testosterone formulation that we prescribe either as an injection once a week or every two weeks, or a transdermal gel. And it really depends on what the mechanism is to pay for the choice. The gels are a lot more expensive and the injections are a lot less expensive. And so if you have circumstances where the patient doesn't have access to insurance or it's not possible for them to pay for a gel, IM testosterone is terrific. It's a tried and true remedy and it's much less expensive. and you can teach these guys how to self-administer the IM injections and it works great. I will also tell you that about 30%, maybe even as high as 50% of men prefer injections over the gels. They actually like the fact that they can kind of feel the testosterone. They claim they can feel the testosterone levels rise up and so they like that. The other reasons to think about IM testosterone besides the benefit of being less expensive and the convenience. Some guys prefer once a week or every two weeks, but the other benefit is there's no risk of secondary transfer. So if this man is a grandfather and is taking care of, say, a baby granddaughter or baby grandson, he might prefer to have IM testosterone as opposed to applying a gel to his shoulder. And if he's got bare skin, they're potentially exposing the child to secondary transfer of testosterone. There have been some case reports of boys having early puberty and girls developing some acne and hirsutism from secondary transfer from the gel. And then the last thing that is helpful in thinking about gels versus injections is the risk of erythrocytosis So the risk of erythrocytosis is much lower with the gels probably because the peaks of the testosterone are not as high than they are with the IM injections And in fact if they get erythrocytosis on the injections, one tactic is to switch them to a gel. There are a lot of other therapies out there. There's oral, there's buccal tablets that were never very popular. There is a nasal gel. Patients don't really like that very well. That sounds terrible. It is terrible. If we lived outside of the United States, the other therapy that we'd strongly consider, it's the second most popular one in the world, it may even be the most popular now, is this injection of testosterone that lasts 8 to 12 weeks, but it's really expensive in the United States. And is this a start low, go slow situation with the dosing? I love that question. I remember I taught one of the great clinicians I've ever known. I said, well, you want to go low and start low and go slow. And he said, well, would you want to do that if you were feeling really terrible? Wouldn't you want to get going? And so the short answer is no, I think in general with endocrinopathies, you can get right to the right dose unless the person is frail or you're concerned that they're at great risk of a significant adverse effect. If this man had severe lower urinary tract symptoms, then I would start low and go slow. But this guy, I mean, he's more vigorous than I am. This guy was running five times. I mean, you know, if he's hypogonadal, let's start him on a proper dose. It doesn't mean I would start him at the top of the dosing curve, but let's get going. Okay. All right. So we start him on the IM weekly or every other week injections. He loves it. His symptoms improve. And I think we have one more case that I definitely want to get to. So Paul Wirtz, will you read the case? Yeah, absolutely. So T. Lowe is a 30-year-old male. Presents with fatigue, low libido, and difficulty concentrating. He has no medical conditions and takes no medications. His BMI is 24. Exam shows a muscular build with normal testicular exam. Actually slightly small, 10 cc by orchidometer. Testosterone is low on two occasions, 282 and 267. The FSH and LH are high. He endorses using some pro-hormones to build muscle in the past during high school, but he doesn't know what he took. Those days are long behind him, and he now works as a firefighter. He anticipates attempting to conceive a child in the next three to five years, but possibly sooner. So does this patient need any further workup? Well, this is a difficult case. The fork in the road here is that testicular size assessment. If his testicles are 10 cc, they're clearly small. And so there's one of two possibilities that he has a form of pre-pubertal onset of hypogonadism because the normal testicular size is 15 milliliters and his are 10. And so you'd be concerned that this person has Klinefilter syndrome that we missed. The other possibility with the history you gave to me is that he was taking more than just pro-hormones. he was taking hormones and he took them for many years and his testicles which started at 15 shrank down to 10 because they will shrink as much as 30 to 40 percent and that what we're saying now is a man who is in the prolonged recovery phase of androgen misuse or abuse so the other important thing is that fsh and lh and you said it was They're low normal. Is that right? They're elevated in this case. I think they were high in this case. Okay, thank you. So now we're back to this person I'm thinking has Kline-Filter syndrome, and they're one of these patients that have been missed. And he probably actually felt better when he was taking, if he was taking hormones. And so it's important for us to think about the possibility that somebody taking androgens is actually treating undiagnosed hypogonadism. he doesn't need further workup in terms of declaring him hypogonadal. He's got symptoms. He's got labs consistent with primary hypogonadism. And if you want to be truly parsimonious, you could say you're done. He's got primary hypogonadism. Most experts would suggest that you should do karyotyping to confirm whether or not he has Kline-Filter syndrome. and I've always been a bit of, oh, I don't know, I'm cheap about labs and I don't like to do them if I don't need to. And I've asked some of my colleagues, well, why would we do that? And the major values are the following. One, you have a clear diagnosis. I mean, there isn't, you now can give the person an answer. It has implications for fertility. This man is young and he may want to conceive. And knowing that he has Klinefelter syndrome means that you know that he's going to have to, if he wants to be fertile, more likely than not, he's got no sperm in the ejaculate and that he would need to engage with an assisted reproductive technology specialist, somebody who does assisted reproduction. And surprisingly, about 40 to 45 percent of men with Klinefilter syndrome will have small nests of sperm in the testes when you look under the microscope. So the technique is they open up the testicle, they take a microscope and they can see the little nests, and then they take those sperm out of those areas, and they can use them for a process called ICSI, where they inject the sperm directly into the egg. And the logical follow-up question is, doesn't that raise the risk of having boys with Klinefelter syndrome? And to date, there has not been a boy with Klinefelter syndrome born from that technique. And we think that the sperm that we're seeing in the testicles of these men simply don't have that double X chromosome, and they get selected against in this setting. So I think there's a strong argument to be made for giving this man a lab order for a serum karyotype. It costs about $1,000 and at least $500. And so, again, if you're in a circumstance where you can't order that expensive test, I think you can make the diagnosis presumptively, particularly if their testes are really small. And really small is two or three cc's. And if they have like the unicoid proportions where their lower half is longer than their upper half and their wingspan is taller than their whole body? I love bringing up the unicoid proportions. probably the most useful is measuring their legs and comparing them to their wingspan. As a practical basis, I don't think everybody needs to do that. I think you can rely on the testicular exam, the labs, and the probabilities. So if you have the time and the interest, yes, I think you can go through that exercise. I love the physical exam, but that's one where I think the benefit is mostly to ivory tower geeks that are... I hate to tell you who your audience is right now, Brad. I wanted to follow up on, because you mentioned the 30, so if someone is taking testosterone prescribed, like our previous patient, where we're giving him the IM injections and his testes size, let's say it was normal, it was 16 cc's, would we tell him he would expect a 30 or 40% decreased size in his testes? And is that reversible if he stops the testosterone? If you are giving a normal man testosterone for any length of time, the shrinkage of the testicles will range from 5% to 35%. And it can be enough that if the man is examining himself on a regular basis, he would notice it. Most men don't notice the size of their testicles. And so I don't actually advise the patients that they're going to have their testicles shrink. And I often wonder if maybe they're not checking too much if they notice. Okay. Yeah. I mean, if they have true hypogonadism, primary or secondary, I guess, and you're treating them, well, I guess it doesn't matter that much if the testicles are going to shrink in size. It doesn't matter. Maybe I've had one patient notice and ask me and was like it was a younger, a younger patient that was like pretty distraught about it. Yeah, no, there's a group of patients out there that we see. We know the data on this because we've been working for 25 years on a male hormonal contraceptive that's based on testosterone. So I've treated hundreds of guys. And so we've actually measured testicles pre, during and post. And yes, they will recover if they stop. But these are normal guys. And yeah, there are some guys out there that it distresses them. Okay. All right. Let's change this a little bit. Let's say that this same 30-year-old person, they had low testosterone. They had low FSH and LH. And they're asking us about quamaphene or HCG. They're concerned about fertility. Dr. The surefire way of treating secondary hypogonadism, so somebody that you diagnosed with hypogonadism based on symptoms and a really low testosterone and their FSH and LH are low, is to give them gonadotropins back because they lack LH and they lack FSH. And so we give HCG, and people are going to say, wait a minute, that's not LH. HCG has LH-like properties, and it's why when women get pregnant and the HCG levels go high, that they continue to produce estradiol during pregnancy. And so you give HCG and you inject it two to three times a week subcutaneously. And men that have gone through puberty and have testicles that are 10, 12, 15 CCs at baseline, those patients will respond to HCG alone and often have sufficient sperm production that they may conceive. If they don't, we add in FSH. Now I'm going to come back to the most controversial thing, which is clomiphene. Clomiphene works by, it's a CIRM, it's like raloxifene, it's a selective estrogen receptor modulator, and it tricks the brain into thinking you don't have any estrogen going through the blood. And the brain's major feedback mechanism is estradiol. So the FSH and LH concentrations will go up, and it works beautifully in young, healthy, normal men because they have a normal pituitary and they have normal testicles. If you give it to older men, it doesn't work as well. And if you give it to somebody with bona clomifida, hypothalamic, pituitary, or testicular disease, it will do nothing. It will do nothing for a Klinefelter's patient, and it won't do anything much for somebody who has undetectable LH and FSH. I don't object to somebody using clomiphon and seeing if it will work in that setting. My concern about it is it doesn't have the decades of track record that HCE does, and the cost is about the same for both the modalities. And usually these patients want to get started on something that's going to work for sure. And I know I can tell them HCG will work for sure. Whereas the clomiphene may take a bit of time. And then the last thing about clomiphene, if there's been some case reports of clomiphene causing central retinal vein thrombosis, and the concern is like any of the CIRMs that it may actually increase deep venous thrombosis. So I just prefer to use HCG, but I don't jump up and down and shout if somebody wants to try clomiphon. Dr. Paul Williams, will you be prescribing? Absolutely not. You know the answer to this. That's what I have friendly neighborhood endocrinologist for, man. Right. Yeah. And Paul Wirtz is in a city where I know there's billboards everywhere, advertising, and there's a lot of young people around. And that's something that some people ask about. Certain crowds ask about that. And I've certainly had those questions at parties and things. And so it's good to have some answer. So Paul Wirtz, anything else you really want to get to here? I know we're sort of towards the end of our list of questions, but anything that we're missing that we should ask about? I guess just like the monitoring options in terms of like, how often do you check the different labs and the testosterone levels? And then eventually like, how do you potentially come off of these would be the only other thing. Those are two important and very different questions. The monitoring, I've changed my practice over the years. Initially, we only had IM injections, and we just would treat people based on their symptoms. And now I do monitor testosterone concentrations episodically. I monitor them after a change in dose, and I monitor them usually once a year. I don't try to target precisely the middle of the normal range because it can't be done. that was born out in the testosterone trials where they went through all sorts of shenanigans to have everybody between 400 and 700, and it was not possible. And for those of you who've tried to do it, you will drive yourself to the brink of drink. So you target just the middle of normal range. You do take note of symptoms and whether they perhaps haven't had as much improvement as you'd like, and their testosterone is on the low end of normal range, you might increase that dose up. And the way you check, the time that you check it for a gel is you check it usually six hours, four to six hours after application. It doesn't matter too much the timing, but it will be higher four to six hours after application versus checking it before application. And that allows you to err on the side of not over-treating if you check four to six hours afterwards. And if it's anywhere in the normal range, you should declare victory. And the other lab that is useful is hematocrit. That's your bioassay for excess. So if the hematocrit is too high, if it's 50% or higher, you lower the dose and you ask the question, do they have sleep apnea? For injections, you check halfway between the interval. So if they're on weekly, you check it three and a half days after the injection. It should be somewhere in the normal range. And then for my testosterone junkies, which I do have, I have guys that want to take more and more. I will check a nadir or trough level of testosterone. And that's useful in two settings. It's useful in guys who are taking high dosages and to prove to them, you got plenty. That testosterone is, you know, at the very bottom, It's still in the middle of normal range or it's even at the top of the normal range. And that's useful in some guys that in both my trans populations and my cis populations, there are some people that are slow metabolizers or hyper metabolizers. And so they get erythrocytotic. They don't have sleep apnea. And they're on a low dose of testosterone. I check their trough level and it's in the middle of normal range or even high. And they're just slow metabolizers. and then some of them are rapid metabolizers. So that occasionally the trough levels are useful. And the trough for injections would be like the day before they're due or the day they're due and then for gels? Ideally for a trough and for the gels, you do it right before they would administer the drug. So you just have them come in whenever they can. I mean, it doesn't matter what time of day they give the injection. So you just say, wait for your injection, get your blood drawn, then take it. and then for the gel, it's right before they would normally apply it. Oh, that's good. Yeah. Because as much reading as I've done, this is why I love doing the show. I didn't read this anywhere, you know, in any of the just like common sources you'd read about this, but this seems just very practical, the way that you thought about like when you would check the levels. So I really like that. And then your last question, I think last question was, can they ever stop testosterone? And this gets to another important concept. At the very beginning of evaluating somebody, it was implicit in what we talked about, and you were all right on top of this. But you asked the question, does the patient have primary or secondary hypogonadism? And the other question is, is it likely to be reversible or likely irreversible? So, Klinefelter syndrome is irreversible, and they're going to be on it for a lifetime. The patient that we talked about that we weren't sure what the cause was, that had a low libido, and if we decide to treat that person, that person has reversible, potentially reversible hypogonadism. And the quandary is if you start testosterone therapy in that person and you continue it for any period of time, you can turn off their access. And the longer you treat and higher the dose, the slower they are to recover. If you've diagnosed somebody with hypogonadism, that you think might be reversible, the person who's overweight or has another reversible etiology, it's troublesome to start testosterone. So that patient you diagnosed with sleep apnea, and you think, gosh, maybe the sleep apnea is the cause, treat the sleep apnea, reassess, don't start the testosterone. I think that's a really important point. Paul, as America's PCP, I think you need to let everyone know about this. You should be out there Or on Twitter, whatever it's called. Yeah. So can I give you just one more? May I give you just one more example? Sure. Because in primary care, you're treating patients that are on chronic corticosteroid therapy or chronic opioids. And that's potentially a reversible cause of hypogonadism. But, Paul, if you're seeing this patient and you know this patient has been on Suboxone or has been on chronic opioid analgesias for years and is not going to come off, and you diagnose that person with hypogonadism and their LH and FSH are normal, and you say it's all due to the opioids, you might decide, yeah, this is technically reversible, but I don't think they're ever coming off. and they have a low libido, you just say, you know, we're going to treat, and you document that in the chart. This is potentially reversible, but in my opinion, you know, my diagnosis is this is irreversible because we cannot get them off as opioids. Because this is a chronic lifelong treatment. That makes a lot of sense. And same thing would apply with, you know, corticosteroids. You've got somebody who has polyrheumatica, polymyalgia rheumatica, PMR, and they're on prednisone and they never get down to lower than 10 milligrams and they're there for years, that might be another example of somebody that you diagnose and say it's potentially reversible, but I don't see that happening. I'm gonna treat them. All right, well, this has been fantastic. I'm sure we're leaving some questions on the table, but we have to let you go. So if you wanted to give the audience a couple favorite take-home points to make sure they definitely remember those things, what would those be? Let's see. I'll give you five take-home points. Your clinical assessment is absolutely vital to making the diagnosis of hypogonadism versus eugonadism. And libido is your most specific symptom of hypogonadism. Your third one is the America's PCP, Dr. Paul. You need to think about other etiologies for nonspecific symptoms, and in particular, you need to think about depression. Four, the only really important part of the physical exam is measuring the testicles. And you can get a prato-orchidometer for $20 online, little wooden beads, handsome wooden beads, and you'll be able to diagnose Klinefelter syndrome. And then five, you want to use an accurate testosterone assay, particularly in the setting where you have a patient that you think is ugonadal and has a borderline value. Love it. Amazing. This has been another episode of The Curbsiders, bringing you a little knowledge food for your brain. Yummy. Editor, leave all that in. That was magical. Still hungry for more? Join our patreon and get all of our episodes ad free plus twice monthly bonus episodes at patreon.com slash curbsiders you can find our show notes at the curbsiders.com and sign up for our mailing list to get our weekly show notes in your inbox this includes our curbsiders digest which recaps the latest practice changing articles guidelines and news and internal medicine and we're committed to high value practice changing knowledge and we want your feedback so email us at askcurbsiders at gmail.com a reminder that this and most episodes are available for cme credit for all health professionals through VCU health at curbsiders.vcuhealth.org. I wanted to give a special thanks to our writer and producer for this episode, Dr. Paul Wurtz, and to our whole Curbsiders team. Our technical production is done by PodPaste. Elizabeth Proto does our social media. Jen Watto runs our Patreon. Chris the Chew Man Chew moderates our Discord. Stuart Brigham composed our theme music. And with all that, until next time, I've been Dr. Matthew Frank Watto. I've been Dr. Paul Wurtz. And as always, I've been Dr. Paul Nelson-Williams. Thank you and goodbye.