 Welcome and thanks for coming. I actually, um, I'm delighted to actually go first because then I can like pay attention to all the rest of the, um, speakers and I really enjoy this day and we, we try to make this program fresh every year so you'll see that our agenda and our curriculum changes hopefully with the times. In fact, in fact, you know, we want it to be like a fresh curriculum because really what we want it to do is like inform you to help you with the things that are, you know, coming available with information during the year because as a busy clinician, I know what it's like to like keep up with the literature and like, you know, get into a more in-depth thing when you're so busy. And so if you have comments or what things, topics that you think that we haven't covered, please feel free to email us and let us know because we want to make it the most user-adapted conference that you can spend your Saturday on even in December, which is a really busy time of the year. Okay, so that kind of speech leads to why I picked this topic for the day, which is menopause and manopause. And I know it's a silly kind of a title and I did it on purpose, but here's the reason. I've seen a rash of male patients in the clinic and I see a lot of clinic patients, both men and women, because although I'm the woman's expert, so, so. The women are bringing their husbands and their boyfriends and their fathers and men pick women too, so. But I've seen a rash of male patients who've been put on testosterone who had a lot of complications. I had patients of mine that had gone to see, you know, these low T clinics and put on testosterone. And otherwise you would have been like, no way you can't take the testosterone. I had one seminal patient where he had literally occluded his iliac veins both all the way down to the popliteals on testosterone. Okay, so I thought to myself, oh my gosh, why is no one covering this thing? And then in fact, there was a big New York Times op-ed in 2014 where there had been a study that was released and somebody, a doctor or a urologist had written this beautiful op-ed piece about low T and over treatment. And I thought, oh my gosh, you know, maybe the whole story about women and heart disease is replaying itself in the male world because of a lot of pharmaceutical sponsored stuff. So what we're going to do today is we're going to briefly review the data for women and talk about the data for men because, as I said, I think it's a story that's perpetuating itself. And we haven't done women and heart disease for hormones in a while and there's been like some new developments from some big players in the field. Okay, so that's what we have. So I was going to start out with, for women and heart disease, we're actually doing really well, okay? You can see that the trends for both men and women since really 2000, the statistics for mortality have dropped like a real rock, okay? And I love this slide because it shows that it's working whatever we're doing for prevention and for better treatment of people with vascular disease. It's working well in both men and women. And yes, we may be putting ourselves out of business by reducing the event rates and reducing the death rates and the bypass rates and the stent rates and hopefully the transplant requirements. But we will never reduce the number of transplants we do because there are so many more patients that need a transplant that can get them. So Deborah Myers, you're safe for the future in your job. Okay, the rest of us have some difficulties. So risk factors have changed, but the truth is that yes, biological risk factors, hypertension, tobacco use and family history haven't really changed that much, right? Metabolic risk factors, baseline haven't changed, but how we take care of those metabolic risk factors have changed dramatically. And I would submit to you that one of the main reasons that we have this decline in mortality over the last 16 years is because more people take cholesterol drugs, okay? We have the same level of patients that have hypertension, probably even more as people become more obese. There's more diabetes. There's more insulin resistance. There's more sedentary activity, and yet the disease rates of death have gone down dramatically. Most likely because we're better twofold, better able to prevent disease by the good care that we're providing to our patients. And half of the benefit is also from what we do in buildings like this where we take better care of the patients once they become ill. So the techniques and the streamline approach to how we care for people have improved outcomes. So statin use is up dramatically since 2000. You can see that age over 65, it's gone to nearly 40% in females, about a third. And even in that age group, 45 to 65, that middle age group rates are increased really from very low rates in 2000 to widely accepted, 13 to 16%. People think that if you look at risk factors by obesity, if you look at how people live near the poverty level, the obesity statistics, this is actually interesting, is that people that are below the poverty level are not getting any bigger. They don't have any excess money to get any more bad food. Actually, the obesity rates are increasing at one to two times the poverty level because then there's a little bit extra money. And then people adopt that, you know, kind of really bad American diet in that age group. And so those obesity levels have increased. So what about menopause? So menopause really, honestly, women are at low risk for heart disease before menopause. So in fact, if you call and you say I'm having chest discomfort or can you see the patient, I'm going to ask how old they are and I'm going to be thinking, you know, are they perimenopausal? Have they had early menopause? As a way of measuring what their innate cardiac risk is for, you know, how quickly do you need to assess the patients? What about menopause increases the risk? So we know that menopause or menopausal women have a two to four fold elevated risk of heart disease. And menopause interacts with all the other risk factors for heart disease. It increases the weight, makes women a little bit more sedentary. It raises the blood pressure. It raises the glucose and LDL cholesterol levels increase. HDL levels tend to reduce a little bit over this period. And so all these things elevate a woman's risk for developing heart disease. It is thought that the menopausal or, you know, before you go through menopause, a woman is relatively protected from developing vascular disease. And that may be the reason why women develop heart disease full fold 10 years after men. Okay. So if you look at that ASCVD score, risk calculator score, and I'm going to ask how many people out there are using the risk calculator scores? It's catching on. It's a little cumbersome when you see the patient because you don't always have the laboratory when you see the patient. I find that to be one of the stumbling blocks. So what I tend to do if I've seen the patients before is we will calculate what their ASCVD score is based on this year's weight, and this year's age, this year's, you know, blood pressure, you know, and then use last year's cholesterol. But I will say, okay, this is the nuance of working in the field, is that you don't know what to do about the lipids when they're at that perimenopausal period because the lipids really are changing. If a woman is, you know, five or 10 years from menopause, their lipids, if they're not on drugs, their lipids are pretty stable after menopause. And I find that the, that's maybe a good paper. The ASCVD scores don't really change that much, but it's something I think that it's a little cumbersome. I find it effective, and I think that the patients like the information about is that you're just not like Willie Millen just deciding, you know, without any data. They can look it up themselves, and I sometimes give them, you know, the website, and I sometimes actually print out if the printer is working that's connected to my computer in the office. I print out what their ASCVD score is so that they can take it home, and I encourage them to play with the score. Like, you know, if your blood pressure were better, it would be better. If your LDL were lower, you would have a lower score. So I find that helpful. Okay, so let's go to women in heart disease and look at hormone trials. So I lived through this error, and I worked at the Brigham where Joanne Manson was a researcher for the Women's Health Initiative. And I was around the people that were studying this. And so during my fellowship in formative years, I mean, we really thought hormones were really good for you. And here's the reason why. All the observational studies looking at women pre-hormone and after-hormone or comparing hormone use that hormones, when given to women in the post-menopausal period, had a lower relative risk of heart disease. So these studies, you can see the blue dots are for estrogen replacement therapy and the yellow dots are for hormone or estrogen plus progesterone therapy, showed, you know, a pretty substantial effect on outcome for heart disease. The caveat, and this is what you have to understand, is when you look at these natural, I mean, observational studies, women that take or are willing or eager to take hormones, take hormones when they go through menopause, right? Because there's no reason to take, the main reason that you'd want to take hormones is if you have symptoms of menopause. So if you're far out from menopause, you've probably survived and you're not having that much symptoms long-term. So these studies are of women that started hormone when they went through menopause, right? It probably be age of 50, 51, 52, which is the average median age for menopause in our society. So the observational studies are different than the treatment trials for hormones. The thought was, why are hormones good for you? And one of the biological mechanisms is that estrogen encourages LDL to come down. Okay? It brings up the triglycerides. It raises the HDL a little bit, but the thought was that by reducing LDL cholesterol, it was having some beneficial effect in the vasculature. So the nurses' health study, many nurses here participated, actually my nurse, MC, is still in the nurses' health study, which I think is so cute, was a primary prevention study of coronary disease. They looked at healthy postmenopausal women, and it had a huge number, 28,000 nurses, which were kind of eager to participate in the study because the nurses' health study followed the very famous physician's health study by a few years, which came out with some very important findings and changes in the management of primary prevention. It's the study for which we demonstrated that aspirin was beneficial for heart patient or for primary prevention of heart disease in U.S. and British physicians after the age of 65. But in the nurses' health study, they looked at, it was a non-randomized survey questionnaire that was mailed out. They looked at current users of hormone and compared them to never-users, and they found that there was, in fact, a 40% reduction in coronary or arterovascular risk compared to the non-users, and a 50% reduction in all-cost mortality. They found that there was a loss of benefit after five years when the hormones were stopped and that those that had a natural menopause benefited more than those who had a surgical menopause. So here's the data. When they looked at it, that 28,000, and they looked at them over a longer period of time where they enrolled more nurses. So in the end, they had 70,000 nurses, and there was. This is actually an important study because it shows that if, I love the study because it's going to show something important that's going to be helpful when we look at the male data. We're going to look at stroke and heart disease deaths and compared to never-users, and this is dose-dependent risk, is that over a primary dose of 0.625, there was certainly an increased risk of stroke. There was a protective, thought to be a protective effort by the hormones to prevent heart disease. And this led the way to the HRS trial, which was a secondary prevention trial. Now, I was involved in clinical trials in this period, and really what they did in this trial was they took like a treatment trial for heart disease, much like they would have done for cholesterol drug treatment. So you take a population that you think is at risk that's older because really what is, if you're going to fund a study, you want to have the smallest number of people followed by the smallest amount of time because it costs less money, right? So they ran these trials for secondary prevention for hormone, much like they ran the cholesterol drug treatment trials. They took a population of women that were older, that had already gone through menopause and had been off hormone for at least a decade. So they took a riskier population of women, and they randomized them to estrogen or progesterone, or with progesterone in two groups. So there was HRS1 and HRS2, but long story, they had an average age of 67, so it was older women, and they looked at a four-year follow-up, and then the HRS2 trial was like a registry after the HRS1 where they followed women even longer for 6.8 years, and they had hard end points. They looked at CV death and MI, and here's what they showed. They showed really that the hormones really didn't make that much of a difference, but there was a little bit of an excess risk in that first four years for more women in the group that got the hormones, had more heart attacks and more deaths, and the study was stopped early, because it was clearly not going to show benefit. And even followed long-term, which was a beautiful thing that they did, because a lot of people would have said, well, maybe you didn't treat them long enough. So they enrolled and kept following the patients, half of them for another 2.8 years, and still no benefit. So this really was a wake-up call, and I remember it was like 2002. It changed how we practiced. So if you looked at the data for venous thromboembolism, or PE in the HRS trial, clearly there was excess risk of venous thromboembolism. Excess risk in the first year, the second year, the third year, the fourth year. All the years, excess venous thrombus, venovascular disease. So clearly a risk factor for DVT and PE. So then that led to the Women's Health Initiative, the WHOI, which was the first primary prevention randomized trial. But again, so this becomes a little bit more complicated, again they enrolled women at average age 63. So why did they wait? Okay, so the other rule about clinical trials is you want to run the trial as economically conservatively as you can, but you also don't want patients dropping out of your trial early because of side effects. So what they didn't want is people that were seriously symptomatic from vasomotor symptoms that got randomized to placebo to drop out of the trial and cross over to your active treatment. And they also didn't want women to bleed. So they started the trial in older post-menopausal women, average age 63, again, 10 years after the menopause. So nothing like the natural observational trials where women were started in the 50s. Does that make sense? Different kind of populations. So this was actually quite important actually as a trial. It was funded obviously by the NIH and was well done trial. They ran two concurrent trials. So they basically ran a trial for women that had a uterus and they ran a trial for those that had a hysterectomy. So the women and those two groups were not exactly the same. So they can't be co-mingled. The women that had the hysterectomy tended to be more underserved and more minorities. In this group, they got unopposed estrogen and they enrolled almost 11,000 women. This trials was stopped on time. It's almost seven years. Those that had a uterus, a bigger cohort, almost 17,000 were a lower risk group. Remember, they didn't have the ASCVD score. But if you look at the risk pool, that pool of patients was lower. This group got both estrogen and progestin in order to protect the uterus from uterine cancers, risk of the unopposed estrogen. And this study was stopped early because of risk greater than the benefit. The average age in this trial was 63. The primary outcome was non-fatal MI, heart disease death, safety outcomes were breast cancer. And then they did this thing called a global index looking at how many fractures did you have, how many colon cancers. And they were trying to figure out, overall, was this kind of treatment beneficial to the woman? I mean, maybe she got less breast cancer or maybe she got less fractures. Maybe she died less of heart disease. And here's what the results showed. So in the patients who got estrogen and progestin, the heart disease risk was elevated by 29%. So you can see that here. The stroke rate was elevated by 41%. The venous thromboembolic disease risk was twofold. And this has actually been a very stable number for all treatment trials for women and heart disease. Total CVD was 22%. Fractures were actually down because estrogen improved the bone health and decreased fracture rate. Cancer was basically null. Death rate was null, but the global index was in the wrong favor of the hormones. And the trial was stopped and all the press was like, hormones are not indicated for primary prevention. They're not indicated in secondary prevention after hers. And there's some excess risk to take an estrogen and progesterone for women that have an intact uterus. When it's prescribed in your 60s. That's really what the outcome data shows. If we look at the annualized heart disease risk by year, the risk was the highest in the first year for a woman that's been without hormone and then you give her hormone. And then the risk kind of was basically undulating and followed the placebo group pretty well. If you look at what is the excess event rate per event in this study, estrogen and progesterone, there were seven additional heart disease events. There were eight extra strokes. There were eight pulmonary embolized. There were eight invasive breast cancers. There were six less colorectal cancers. There were five less hip fractures. So the global index was, you know, not in favor of the woman by 19 excess events. And because of this data, it really halted the practice of women receiving hormones. I mean, and women, their doctors just like stopped them cold turkey. I mean, there was a lot of like turbulence in the medical field during this period. If you looked at more in depth at the data, how women responded to hormone therapy was really, and what the risk group was like, really had a lot to do with how many years past menopause were they when they received the hormones. So for women within that 10 years of menopause, even with estrogen and progesterone in this study, and I know it's a subgroup analysis, and I'm leery of saying anything about that, but in that group, they appeared to be safer from hormone exposure than women who were over 10 years after menopause. So clearly, you would never treat some woman 10 years post menopause with hormones, but I would make the observation to you, we wouldn't treat that woman with hormones really anyway, because really the predominant reason to treat a woman is for symptoms, and symptoms occur early and they abate over time. So it kind of nullifies why we really treat a woman, but at this time in the period of, you know, medical knowledge, we really thought estrogen or progesterone would be beneficial long term for a woman, and we clearly demonstrated, especially in older women, and for those post 10 years after menopause, hormone treatment is actually adversely affecting their health. But it took, you saw how big the numbers were in the trial, it took thousands of women in a trial followed for four years before that data became obvious. Okay? I'm making the case for the men. Okay, so if you looked at the women only arm, actually it was much better, which suggests that the progestin added to the estrogen added a lot of the risk. So overall heart disease risk was null in women that had no uterus with treatment with just estrogen alone. But still you see this excess risk of stroke with estrogen alone, excess risk of PE. In this case there was an excess risk of, oh, venous thrombolymbolism, and overall hip fractures and overall fractures were down. If you look at it again, timing of when you give the hormone to the women without a uterus, then you see this gradient of risk by age and by time from onset from menopause. Not as robust as the one, the graph with the estrogen plus progesterone, but still an adverse risk as women grow older. And if you look at the number of events, you can see them and this is just for inclusion in your syllabus. It just shows you across the board elevated risk in women. Again, markedly changed by their timing from menopause. Again, I'm making the big case about hormones in all the trials showed an elevated risk of stroke. If estrogen alone, estrogen plus progestin, and I think the takeaway message is that hormones for women are not good long, long term for the prevention or for the elevation of your health. Certainly there's excess risk from all the data that we've seen, even the observational trials and from primary and secondary prevention randomized control data that shows that yes, indeed hormones increase your risk of stroke and your risk of venous thromboembolic disease. And because of those things, I warn women every time I see them at the risk of the hormone and you have to look at the risk-benefit ratio. Certainly this data is helpful in reassuring that for women that are going through menopause that have the most symptoms, taking hormones early may be safe. And here's some more data about the stroke risk. And so basically, I think we've summarized the WHOI in saying that there's elevated risk of breast cancer for those that received the progestin compound. There was definitely an increased risk of heart disease, particularly in the first year. There's elevated risk of stroke and the global risk was increased. For those that take estrogen only, it may be safer than those that take estrogen and progesterone, but still there's an increased risk of stroke and certainly no long-term benefit in these women. So basically, hormones are contraindicated in women with established disease for sure. Hormones should not be initiated for primary heart disease prevention. This is no statin drug and estrogen increases clearly the risk of stroke and venous thrombosis and hormones should be considered early after menopause for the relief of vasomotor symptoms. And honestly, the rule kind of in the community is hormones should be taken at the smallest dose amount of time and then encourage other kind of lifestyle modifications to help with that. Now, this brings up one important point about the timing hypothesis. So I know that people in the field thought that and you can tell, I kind of share that feeling that maybe those trials weren't really the treatment, randomized trials weren't really and didn't really capture what we really do in the real world by treating women with hormones when they go through menopause. The problem now is that we have two major treatment trials of women that showed harm, right? Which means that nobody's really going to be too eager to fund a trial of women for treatment effect of hormones even if you wanted to try it in people that are going through menopause. Does that make sense? An earlier treatment trial might have given us a different outcome and the timing hypothesis kind of addresses this. The question is whether estrogen when given to a woman as she go through menopause someone that has not withdrawn from estrogen may actually slow the development of atherosclerosis by improving lipids and endothelial function and the question is, can you prevent that? And so there's this whole thought that the observational and the clinical trials were disparate populations where the clinical trials were in older women the observational trials were in younger women menopausal symptoms were excluded in the treatment trial but those were the people that were included in the observational trials and then the timing since menopause obviously is much shorter in a treatment trial of women and then the whole question about the treatment of people post menopausal with symptoms and the observational trials they got estrogen for I mean I still see patients that just like refuse to come off their estrogen and they may be like close to 80 and you're like really I'm really not thinking it's benefiting you anymore and they're very hesitant to change their dose for those that have done well they don't want to come off they think it's the fountain of view in this whole question about obesity so if you look at those relative risks again you can see that in young women that get hormone, either estrogen or progesterone if they get it young and stay on it they did well but there may be some bias in these groups that those young healthy people that were really interested in their well-being were healthier enough to be exercising some intrinsic bias in these observational studies these were healthier vainer eager beaver women that were keeping their body weight down and less diabetes and making themselves healthier in other ways which could help to explain some of these findings the WHI took those primary prevention women that were randomized to hormone and when the study was halted they got money and they went out and calcium scores on over a thousand patients that were enrolled in the clinical trial which I think is a really a very fine test and I think some of you I've given a lecture here about calcium scoring looking for plaque as a marker of who has coronary disease so you might expect if somebody were to have more events later they'd have more of a calcium score when they're younger so they went back and they didn't have a lot of money they wanted to look at that early group of women age 50 to 59 who went through menopause recently and were randomized to WHI and were studied on the hormones for 7.4 years and they obtained calcium scores 1.3 years after the WHI initially stopped the mean age at the time of the calcium score was almost 65 and why calcium score is a marker of how much plaque you have and it's an inflammatory kind of marker that you can get that's actually very stable between measurements so it's like there's not a lot of error in the measurement it's like the calcium goes into a plaque and it sparkles so it sparkles under the X-ray so you can count the sparkles and it's a marker a pretty validated marker of elevated cardiac risk it's a pretty cheap test in the community it costs about $150 most insurance won't pay but it's I love it it helps me a lot and so you know who has plaque and in this study the women that got the estrogens alone actually had lower plaque mean scores and also had a significant p-value oops had lower plaque numbers so with some thought that this timing of when you give the hormone would maybe affect a surrogate marker for outcome and most I'm going to skip this one because this kind of goes again this shows that there's this aged variant variable on a gradient of risk in older versus younger women and it really remains unanswered quite honestly because I think people are going to find it problematic to run a trial of the right magnitude to answer the question but there is intrinsic data like mice models that estrogen itself inhibits progression of established lesions in the vascular and I'll say to look at I'm going to go to this one important case the elite trial because it was a New England journal article two years ago where they actually was earlier in this year where they took 600 post-menopausal women with no coronary disease and they treated them this is mainly in California so those people are kind of healthier they looked at two groups women that had been through menopause within six years and women who were over ten years from menopause and they looked at their treatment outcomes after being on hormone therapy and they used both hormones with uterus without uterus estrogen plus progesterone or estrogen alone and they looked at crotted entomal thickness and they did demonstrate that plaque growth was slower in the estrogen treated group taking hormones within six years after menopause compared to the group that had been ten years so I think that it's very clear that if you've been past menopause very clearly there's excess risk for women that are I think that the corollary would maybe be for women that are at ASCVD score higher that hormones would not be a good idea for those women even for prevention of vasomotor symptoms and so I kind of restrict the treatment or the counseling of women to treatment with hormones to those that are asymptomatic without heart disease who've been through symptomatic through menopause within the last six years really because after that you kind of already gone through it and then to restrict the hormones to that group that's in the low risk category because there are women out there that are suffering with vasomotor symptoms and honestly the best treatment really is hormone and if they're at low risk for heart disease I'm really kind of okay with letting them take it but again you don't know how long you need it until you withdraw the hormone and see how your symptoms are so I strongly advocate for taking the low dose that settles down your symptoms for the shortest amount of time and then to wean the dose off okay so what about menopause okay so there's this robust commercial advertisement to men about taking testosterone and I mean we are seeing young men I mean like one of my fellows last night told me see I'm the girl heart doctor so I have a different experience in my clinic than the male heart doctors that one of my colleagues is seeing men that are like all on taking the testosterone and makes me very worried knowing what I know about women and heart disease and hormone replacement therapy what we are increasing or are we increasing the risk in our male counterparts who may be at higher risk of disease anyway at similar age just because they're men right so what about menopause is it real I mean is it a manufactured disease to elevate the treatment of men to spend more money on testosterone products is it real is it worthy is it valuable is it safe and the answer is we don't have much information so I'm going to go through the data because there's going to be more data coming out so I'm preparing you for your reading of the literature in the next few years because people are interested in this more now than they have been so what are the symptoms of menopause well men will tell you they have low libido they're fatigued they're depressed they may have loss of muscle mass they may have more fat deposition and the signs of male menopause may be this loss of body hair low real androgen deficiency will cause low bone mineral density it'll cause gynecomastia it'll reduce the size of the testes reduce muscle strength and unfortunately it increases your fat mass so what's the relationship between age and hormones and men well guess what men when they're young make a lot of testosterone huge numbers look at the numbers 900 nanograms per deciliter it's a huge number and we all know men in their 20s act much differently than men in their 70s and I have a college student it's kind of scary to see this okay so it declines over time and this has been well demonstrated in multiple trials which came out in 2008 shows the relationship between age and hormone but it also shows the relationship between testosterone free testosterone and LH and sex hormone binding globulin so you get an idea what's the cause of why the testosterone declines in the male as he ages so with age there's definitely a component to end organ testicular production failure okay because the LH goes up okay obvious right so it has to be that the end organ has stopped producing very much like the end organ ovary and the woman stops producing hormone clearly it's not like the woman where it stops almost 100% by the age of 55 and a woman clearly in men they produce hormone much longer such that men can reproduce with children I can make some funny comments I'm gonna restrict my comments about men having babies in their 70s you know they can still have produce children and heirs but seriously after age 70 testicular production of testosterone declines so age is important in this decline in testosterone but the most important factor that makes testosterone decline is obesity okay and so they look at the same hormone levels testosterone free testosterone LH and sex hormone binding globulin and they broke it down by BMI so BMI less than 25 is pretty normal in America well no no I shouldn't say normal it should be normal it's not common right so BMI 25 to 29 which is really kind of normalish but it's called overweight and those over 30 are called obese although that is skewed by our population as well and they looked at the testosterone levels the LH levels the free and the sex hormone binding globulin and you can see that as the BMI's increase there's no real step up in the luteinizing hormone level which means that it's not just an end organ effect it's not that obesity suppressing the testes from making testosterone it's because obesity interferes with the hypothalamus pituitary axis to make hormones so it's interfering on top of age as men grow older they grow fatter you see how this rolls in together and it makes their testosterone levels drop even more so in fact it turns out that obesity has a much greater effect on male production of testosterone much much more than age in that if a man goes from a BMI on average from a BMI of 25 or less to over 25 he drops his testosterone concentration equivalent to 15 years of life okay so one could make the argument that if you want to have robust testosterone levels you need to stay skinny okay and that would help you the most so how do we make the diagnosis what's the real diagnosis of androgen deficiency you have to have symptoms of you know manopause and a subnormal testosterone level collected in the morning between 8 and 10 am why because testosterone has a diurnal variation and it's standardized at the highest level in the morning it's lowest at night and treatment is strongly discouraged for because if you don't need it if you don't really have really low testosterone levels because this is the funny part of the story if you treat a man with testosterone you're going to turn off his hypothalamus to pituitary to test his axis so that you're going to suppress his innate ability to make testosterone right so you're going to turn off his ability to make it and testosterone exogenously shrinks the testee size and makes less you're going to make that man less manly by giving him hormone and you're going to make him an addict to the hormone that you've given him which isn't good okay I should have been a lawyer okay so what are the contraindications you can't take it if you have known prostate cancer or breast cancer obviously so you have to check the PSA and make sure it's less than four but in men that are at high risk of prostate cancer like African American men or men with first degree relatives with prostate cancer you don't want to give the hormone to any man with the PSA over three it turns out that testosterone treatment makes BPH symptoms much worse and a BPH scale for BPH and a BPH scale of over 19 is going to do really poorly with testosterone it causes erythrocytosis so you don't want to give it to a man with a hematocrit over 50 because hormones increase your risk of venous thromboembolism right and thick blood increases that risk as well okay you shouldn't give it to a man that has untreated sleep apnea which is going to highly be prevalent in your population of these overweight older men because it makes sleep apnea worse you shouldn't give it to untreated heart failure people with known heart disease or people with the prior history of DVT PE okay that makes sense because it causes erythrocytosis sleep apnea there's a warning about DVT heart disease and these warnings have come out in the last two years okay so have we taken the diagnosis of adult onset hypogonadism and made it a disorder or are we just letting these advertisers have a robust marketing strategy and make you feel like you have a disease which in fact you just got older and got fat so what about the prescriptions for testosterone well guess what we're talking about like a serious billion dollar baby okay it's now administered in five forms patches gels injections over three million prescriptions since 2012 for androgel alone testosterone boosting cells are like off the chart I've got young men coming in asking for testosterone and so like I was like somebody I beg Dr. Willerson to do in his itinerary for the like the male and he was like I don't know if we want to get into that testosterone stuff and I was like you do you really do because it's a problem so I decided I tackle it so I'm brave I went for it so there's a warning from 2003 where the National Institute of Aging noted that there was scant evidence to support the idea of male menopause caused by transmission testosterone especially in men as they reach their 30s this rapidly growing use of testosterone by men seeking to fend off the effects of aging had outpaced the scientific evidence and so guess what some scientific studies have come a meta-analysis a meta-analysis of 27 small small remember how many people were in the women treatment or observational trials they were thousands and thousands before we got the right answer so what I'm suggesting to you that if this kind of risk is coming out in men in these small trials what's it going to look like in a big randomized trial which is why the industry is not going to support a trial to show that their drug is harmful you get it so it's going to take like the NIH maybe somebody in Europe to perform a trial so there have been 27 trials nearly 3,000 older men there were 180 cardiovascular risk and guess what testosterone had an odds ratio for increasing risk of 1.54 which really is just a 54% increase which isn't that great but they had a lot of healthier people because in this when they looked at a retrospective cohort of 56,000 men relative risk for MI was 1.36 in the three months after starting testosterone so it's little bit like the estrogen story where the added risk was really at the beginning of the treatment because it makes the blood a little bit stickier and if you already have plaques and you make your blood sticky you might be more likely to form a thrombus the risk was 2.2 fold higher in men when given testosterone the age of 65 compared to men less than 65 it was still 2 ok so that's an absolute risk of 6.25 or 10 cases per 1,000 patient years and pre-treatment serum testosterone weren't even included in this because most of these men didn't have their serum testosterone check they just decided they needed testosterone does that make sense they just went for it they just went for it so there is actually some studies looking at retrospective data in men here's the first one, 8,700 with low serum testosterone less than 300 which is low they were subsequently prescribed testosterone and they had a composite higher risk of all cause mortality MI and stroke compared to men that never saw testosterone hazard ratio 1.29 and these men were mostly older and 80% of these men had coronary disease the authors of the study wanted to reflect that it was just a small absolute risk of heart disease only 1.3% overall which I would submit to you is actually a generous risk ok remember in cardiology trials an absolute risk of 1% changed which you know the TPA dose we use for decades ok so 1% can be a lot of people if you're giving it to a lot of people out there so the testosterone trials this is important because this is new data there was they know that this is going to be a big problem for the public and they know it's going to cost a lot of money to answer the question so the urologists got together and they decided that instead of funding some huge amount of 20,000 30,000 men on testosterone they'd look to see first whether the testosterone treatment made any beneficial effect to mood, libido muscle mass and oh by the way we'll look at some heart disease risks because if we prove that it's not really making you feel better nobody's really going to want to take it anyway I think that's kind of reasonable that's what came out in the New England Journal and there was an editorial this year these are called the testosterone trials it's like a series of 7 double-blind randomized trials at 12 sites but there's 3 main trials one's a sexual function trial, one's a physical function trial and one's a vitality trial they were received these patients received testosterone gel or placebo for one year they were all older than 65 they all had serum testosterone levels lower than 275 on two episodes so they followed the rules it took forever to enroll only 1.5% of those that were reviewed because it was so hard to find men that made these criteria which is testosterone levels on two occasions lower than 275 with all the symptoms they excluded prostate cancer high risk cardiac patients why'd they do that because they don't want to have people dying in their trial so they excluded high risk cardiac patients because they're worried they excluded severe depression and what did they find it increased sexual activity sexual desire and erectile function but no difference between the groups on physical function or a 6 minute walk no benefit of vitality and their rates of adverse events were basically the same between group so in conclusion for women menopause increases your cardiac risk it increases your risk of DVTPE it clearly increases your risk of stroke it increases CBD risk in patients with established disease and it increases CBD risk in women over 60 over 10 years past menopause it is safe in women with low clinical risk it should be given only to symptomatic menopausal women in the smallest dose for the shortest possible time and what do we know about menopause and androgen deficiency is that testosterone levels decrease with age and more importantly they decrease with obesity androgen deficiency treatment with testosterone probably increases the risk of DVTPE probably increases the risk of heart disease and clearly increases the risk of prostate cancer may have some beneficial effects on sexual function but the jury is out on physical function and overall vitality so I'm going to leave it there and let you think about it I think that the questions aren't fully resolved like I personally I'm 50 I'm worried about it and I think there may be a role that hormone plays for women as they go through menopause that may actually may actually be preventative I'm holding out hope it may be true in men but I'm actually very cautious about given people treatment for which there's unknown benefit and clearly unclear previously ill defined risks especially to men that are at risk so in my population they're at risk and those are the guys that have the most erectile dysfunction because they have heart disease so one of my colleagues he really needs to like not suggest that the testosterone is going to make these guys healthier because it may be making more heart disease so I'm going to leave you all with that perfect