Hi, everybody. My name is George Tso. This is a talk about the difficulties of testosterone replacement therapy in mayhepoconidism. It is sort of update the talk from the talk I give two years ago. I give a talk about the testosterone replacement therapy facts and controversy in like almost exactly two years ago now. And then this is a kind of update from the talk I give two years ago. I have no conflict in the no direct, you know, financial benefit and then no off labor use of medication. So these are the objective for my talk. And I'm going to start with what's a normal testosterone value. What is the effect of the testosterone replacement therapy on the fatigue and sexual dysfunction and the safety of the testosterone replacement therapy among the patient with the risk factor. I'm going to elaborate the talk on the following risk factor for the something that's embolism, prostate cancer, BPH, and coronary artery disease and ESCVD. Let me start with the case. This is a 45-year-old male who is fairly controlled type 2 diabetes, hyperlipidemia. He's a former smoker. His major complaint is fatigue, reduced libido, and irradiated dysfunction. The total testosterone is in the morning is 250 to 280 nanograms per deciliter, but he thought it is too low for his age. And he went to see the low T clinic. I'm sure you've got this kind of patient in your practice. And he was prescribed the 200 milligram intramuscular weekly. He was able to achieve somewhere around 800 to 1000 nanograms per deciliter range of total testosterone value, but he's still having the irradiated dysfunction and fatigue, and he still cannot lose weight. So he's not happy with the response, even though his testosterone replacement therapy is well within the normal range. So here are the questions. So will the testosterone replacement therapy improve the symptoms such as fatigue and sexual dysfunction, which are the most common sexual complaint? And what are the appropriate normal testosterone value for his age? So this is a life cycle of the testosterone. This is a fetal phase. The first phase is that during the fetus, there's a testosterone surge. And then there's a second phase during the neonate. And then these things responsible for the primary sexual characteristic. At the time of the puberty, another testosterone surge happened. And then this responsible for the secondary sexual characteristic. You maintain the testosterone level throughout adulthood until the 50s and 60s. Testosterone then gradually decline and settle. And then the rate of decline is 0.5 to 1% per year. It's over several decades. It doesn't decline precipitately. The mean testosterone value from the old literature is 600 nanogram per deciliter at the age of 30. And then by the time the patient has become at the age of 80, it declined up to 400 nanogram per deciliter. But you may see these dotted lines are spermatogenesis. The patient's kids still can maintain the, you know, sperm production, even though testosterone levels start to decline much earlier than the sperm production reduction. So I'm going to present the two data from both data are from Australia. One is a middle aged man, 300 middle aged men, very good in health, excellent health. There's no decline in testosterone until the age of 80. The decline in testosterone is associated with an increase in BMI, obesity, and an egg smoker status. You will see that when they plot the testosterone value against the age, it's a line is all over the place. And then this is a much older population, 70 to 89, another Australia study. The mean testosterone value is somewhere around 400 plus or minus 160. There's no significant decline in testosterone value, but the aging, SHBG increase, LH increase, and the free testosterone reduce. So these free testosterone reduction is associated with the, you know, age, BMI, and also LH. You can see this, you know, SHBG steadily increased with aging, LH steadily increased with aging, and then free testosterone also declined slowly with the rise in SHBG. So this is from the European Aging May study. This plot tells you that testosterone, low testosterone is common with the aging process, obesity, and underlying comorbid diseases. Regardless of the age, the incident of late onset hypogonadism is strongly associated with underlying poor health. Late onset hypogonadism is 10 times higher in the men with the two comorbid condition compared to the healthy men without any diseases. Low testosterone is very common in the diabetes, up to 60%. Overweight men has lower testosterone, up to 30%, compared to the lean and non-overweight patient male also. This is my favorite slide. The lower testosterone and eroditis function are the tips of the iceberg. They may be representing the underlying metabolic syndrome, diabetes, cardiovascular disease, and then there is a term, you know, I coined myself as a chronic sick gonadal syndrome. So low testosterone, in fact, it may be the presentation of the underlying poor health. We have to differentiate between the low testosterone, between the organic versus functional hypogonadism. The picture on your left is, picture on my left is a small boy with the Kleinfeld syndrome. The picture on my right is a man with the obesity metabolic syndrome. These two males, they may have a similar testosterone value, but underlying pathophysiology is completely different. So we should not treat both cases in the same way, even though both can be given the testosterone replacement therapy. Here are the causes of the low testosterone, and it can be divided into the organic and functional, and also depend on the underlying etiology. It can be divided into the primary and secondary hypogonadism. Kleinfeld syndrome, cryptocordism, testicular trauma, radiation, and these are the causes of primary hypogonadism. You may see the advanced age can be the functional low testosterone. It can be the primary and it can be the secondary. So with the aging, the patient can have a, you know, rise in LH and then primary hypogonadism. And with the aging, it can be the secondary hypogonadism, especially with the underlying comorbid diseases. And the secondary hypogonadism can be due to the, if it's organic, can be due to the, you know, Gell-Mann syndrome and the pituitary lesion and the hypothalamus tumor. Here, the most common cases we see at the clinic is functional hypogonadism. These functional hypogonadism, a lot of them are usually the secondary hypogonadism. That's why you may see the inappropriately normal LHFSH or low LHFSH. It can be the sleep apnea, OPI, and then steroid and malnutrition, obesity, type 2 diabetes, patient taking the androgen, progesterone, again, advanced age as well. So here, even though we try to divide these causes into the, all these different four quadrant, a patient can have a more than one underlying etiology. A patient can have an advanced age and then the chronic opioid use, and the patient can have a testicular trauma, and also maybe that they may have an underlying obesity and diabetes, but the patient can have a more than one etiology of the low testosterone. So low testosterone symptoms, I'm sure you heard at your clinic that it's a very common, and then these are the example of the low testosterone symptom I see at the clinic. I have no libido, it is affecting my marriage life, my testosterone level is that of the 80 year old man, I'm feeling exhausted, I can't lose my weight, and I cannot exercise like before. So these are the very common, you know, low testosterone complaint. So even though these complaints can be quite vague, and also can be quite ubiquitous, and then the diagnosis for the testosterone can be quite challenging, because of the testosterone assay issue, and also because of testosterone, the nature of the testosterone. The testosterone can have a significant interpersonal and interracial variation depending on the race, age, gender, and underlying comorbid condition, interpersonal variation. The same person can have a diurnal, circadian, and circumannular rhythm. There can be the significant assay variability, and the same assay, if they send out to the eight different labs, and then the standard sample is somewhere around 300 nanogram per deciliter, it can come back with 198 to 364. So it can have a minus 33% to plus 21% variation. The same sample, if they send to eight different labs, you have a different value. Immunoassay are widely used, but there's always a sensitivity, and specificity, and accuracy issue, especially at the lower range. Liquid chromatography mass spectrometry assay are more reliable. That's why if you are using this for the diagnosis, and then you should use a LC-MS assay, and a good LC-MS assay is a very good test to rule out or rule in testosterone low T-diagnosis. There's no universally accepted calibrating standard. After the puberty, there's no accepted age-related normal testosterone value. Some people may decline perceptibly, depending on the underlying health situation. Some people may decline very slowly, you know, depending on the underlying situation. Even then, even this, you know, different person, they may have a different testosterone baseline, depending on the genetic, depending on the race factor. So how do you diagnose a late-onset hypogonadism, or the adult low T syndrome? This is a data from the European Aging May study. This data use a nanomobile, you know, leader, and the one nanomobile leader is that you have to multiply with the 2.9, you will get the nanogram per deciliter. Somewhere around 3,000 men, they have a, majorities are overweight, only small proportion are type 2 diabetes. The 23% of the sample population, study population has a low testosterone. They use a cut of 317, but when they really use a strict criteria for the late-onset hypogonadism, you know, such as they have to have a low testosterone value, and the symptoms of sexual disorder, only 2.1% qualify for the diagnosis of late-onset hypogonadism. So they try to correlate with the symptom testosterone value, reduced libido is associated with the 317, morning erection or eroditis function is 245, and then eroditis function is 230. So these, you know, low testosterone value, symptomatic threshold can vary as well. This also, data is from the Australia Health in Men Study, the elderly men, 70 to 89, 3,690 part of Australia, they compare with the somewhere around 400 healthy men, and then they have excellent health, no underlying condition. So these are pretty healthy men, no diabetes, no stroke, no cardiovascular disease, no dementia, depression, lower limit is that they use as a cut-off, it's a 2.5% high. So 185 nanograms per deciliter, it shows that there's increased risk of frailty, type 2 diabetes, and cardiovascular disease. There is no sexual, you know, function data in this study. So if you use this data, it's fair to make the statement that if it's elderly, between 70 and older, the lower limit of testosterone should be 284 from the Australia data. How about the middle-aged men? This is a Framingham Heart Study, and then 450 healthy, lean, no diseases, no cardiovascular disease, no obesity, no hypertension, no smoking, they use the LC-MS assay, mean testosterone value is somewhere around 700 nanograms per deciliter, median is similar value, the lower limit 2.5% high is 348 nanograms per deciliter. This is associated with the symptoms when they match with the other larger cohort for the symptomatic testosterone threshold. They use a Framingham Heart Study, European Aging May Study, and Mr. Orr Study. So when they, and also for the sexual, they use a European Aging May Study. But when they compare with these larger database cohort, and the minus 2.5% high value, it's a 350 nanograms per deciliter, it's associated with these physical symptoms. So for the middle-aged men, it is fair to say that the lower threshold should be 248. For the elderly, you know, it will be fair to say that, you know, 184 nanograms per deciliter. So even in the major clinical trial, these are the major clinical trial that are done within last few years, they have different testosterone threshold. And then you may see the T4DM, this is the Australia study for the type 2 diabetes and the testosterone replacement study, and middle-aged men, 404 nanograms per deciliter. Keem's study is a 60 and older, and then it is a 400. Tom's study is 65 and older. Traverse is mostly middle-aged men, and they're somewhere around 45, and then there's a 300. These are major, you know, outcome study. Even then, you know, they use a different testosterone cutoff. Some of the studies are designed by the same, you know, principal investigator as well. And then the testosterone study is the lowest, it is 275 nanograms per deciliter. The patient population is similar to the age, you know, 65 and older, similar to the, you know, Keem's study and Tom's study. I'm going to talk about the hormone centralization program for testosterone. In this study, they use a very healthy 9,000 non-obese, you know, middle-aged adult, young adult, somewhere around age 20 or 40 men, European and American, you know, male. And then lower limit is a 264, it is a 2.5% high, upper limit is a 97.5% high, 960 nanograms per deciliter. The mean total testosterone value is 530. This is, they use a CDC certified lab with the liquid chromatography and mass spectrometry assay. So if your patient is from the European and the US descent, these are the fair, you know, normal value you can use. So how, what's the normal testosterone value? Here's the food for thought. Are we going to use a healthy young adult, like T-score, compare with the, using as a baseline and then compare with your elderly man or middle-aged man, like a T-score, or can we use an age-adjusted testosterone value or same age match peer, like a Z-score, just like the bone density value. So if you say that, you know, young, healthy, young adult male is the normal reference range, we are able to use like T-score. If you use like a, yeah, we are going to use the same age match peer, we are going to use like a Z-score, or are we going to use a healthy non-obese population as a normal reference value, or are we going to use an entire population? With the obesity epidemic, you know, up to 30 to 40% of the, you know, country population is overweight or obese. And then there is a very common to have a obesity-related hypogonadism, which population, you know, group, cohort are we going to use as a normal reference range? Whenever we use for these low testosterone value in your daily clinical practice, we have to be aware of the imprecision of the assay and imperfect cut-off normal value. These values are not written in the stone number. You should know that what is the appropriate value for your own patient. It is very important to, you know, get the right diagnosis for the low late-onset hypogonadism, pick the right patient to given the diagnosis. Having the low testosterone alone, it is not good enough for the diagnosis. The diagnostic criteria is still, until currently, it is a non-universal and still controversial. It's a debatable level threshold for the testosterone replacement therapy. You saw that even the clinical trial, they use a different testosterone cut-off for the recruitment. So whenever you have a disease, the LD diagnosis threshold should be, is closely correspond to the symptoms inside. It should differentiate between the individual who is likely to get benefit from the treatment than who would not. We have to be careful not to pathologize the natural aging process. And then we have to know that whether these low testosterone are because of the underlying comorbid condition, just like the BPH. And a lot of elderly male has a BPH, that's not mean that you should treat for every single male with a BPH until unless they become asymptomatic. So that's why we have to be very careful, differentiate between it's a natural aging process or they're just a reflection of the underlying illnesses. I'm going to switch my gear to talk about the sexual dysfunction. This is the most common reason a lot of the patient check the testosterone value. Another among the sexual function, two most common problems they check the testosterone is the irradiated dysfunction and reduced libido. So not all the irradiated dysfunction are because of low testosterone. Erection is a very complex physiological process. It can be from the underlying illnesses, it can be from the neuropathy, it can be from the vasculopathy. Psychosocial and relationship issue are very common. Underlying sleep apnea and insomnia can affect the erection and sexual function as well. Medication, narcotic, steroid, antipsychotic, and then some of the medication which has antitestosterone effect like finasteride, spironolactone, they can affect the irradiated dysfunction. Chronic opioid use is a very common predictor of the testosterone prescription according to the database from the VA. Hypogonadism can occur up to the 63% of the men who are taking the chronic opioid for the more than three months. So whenever you have a patient with a low testosterone, instead of just checking the testosterone alone, we should look beyond the testosterone. And then what are the causes, what are the most common causes of underlying irradiated dysfunction? So these are the common etiology of irradiated dysfunction. You may see that testosterone deficiency, either the primary or secondary, is one of the many causes of irradiated dysfunction. It can be treated under endocrine disorder as well. Patient with a structural brain disease, especially with history of stroke and Parkinson's disease, they can have irradiated dysfunction. Patient with any chronic systemic illnesses, major organ illnesses, liver disease, renal failure, heart failure, COPD, ischemic heart disease, they can cause irradiated dysfunction. Last but not the least, and then here I put at the first etiology, mental illness and psychiatric disorder, we should not neglect these disorders as well. These are the example of the medications strongly associated with irradiated dysfunction. You may see that a lot of the medication on this table are commonly used, like SSRI, GALS antenna blocker and beta blocker, thiazide, spironolactone, and a lot of the hormone and a lot of the medication, anticonvulsant, and the recreational drug, and then alcohol, cocaine, and then some people use a very high potent marijuana, it can cause irradiated dysfunction as well. So it is very important for us to take the very good history of the medication use and the recreational drug use. Testosterone study. The testosterone study, this study is a systematically look at the sexual function. This elderly man who has low testosterone, they recruited these patients, and then they compare with the sexual function improvement. You may see the sexual function improve within the first three months, and then the plateau and the start to decline before the end of the first year. It's a one-year study, and initially there's a significant improvement in sexual activity. Before the end of the one year, the significant improvement declined as well. That's why it is very common for you to see some of the patients that, yeah, initially it worked, but now after six months or one year, this medicine, testosterone, is not working like it used to be. This is a team study. It's a smaller sample size and the longer duration of study. They look at the sexual dysfunction. You may see the similar trend, but self-improvement in sexual function, but none of them are statistically significant. Irritable digestive function, orgasm, and the sexual desire, even though the trend is on the improvement on the testosterone arm, but none of them is statistically significant. The same with the other sexual function component as well. And there's improvement trend, but statistically not significant. The last study is a traverse study. That's the largest and then the longest testosterone replacement study. Primary outcome is for cardiovascular outcome. We also take a look at the sexual function. The blue line is a testosterone arm and the black line is a placebo arm. They take a look at the changes in overall sexual activity. The patient has to answer the question, BDQ full score. And then both testosterone and then placebo, they improve the sexual function. So you have to believe in the placebo effect as well. And then testosterone treatment, 50% overall sexual has, arm has a 50% overall sexual activity improvement. But these improvement plateau out after 12 months. So that's, again, it will validate. Your patient said, yeah, initially I improved, but later on, I don't see much of the difference. When you look at the different subgroup of these patients as well, there is no difference between the older man and the younger man, 65 and older, and then younger than 65. There's no difference between the previous cardiovascular disease or no cardiovascular disease. There's no significant difference between the testosterone less than 250 and higher than 250. Again, no difference between the black and white, which are the majority of the ethnicity in this study population. This is also another sexual function. And then they take a look at the libido scoring and then sexual activity score. And the lower the score is, you know, improvement. And the higher the score is sexual function, non-improvement. Testosterone replacement therapy improves their sexual activity and libido. So you may see the blue line is the lower score. I mean, there is an improvement for these score, the changes from the baseline. And then the lower score has a much more, you know, improvement in terms of the libido. And they look at the different composite score, sexual function score, and then his Q composite score and the libido score. And all the testosterone treatment arm has a significant improvement compared to placebo. How about the erythritis function? Even though the patient has improvement in sexual function and the libido, but particularly erythritis function has no improvement. The testosterone arm is a blue and the placebo is a black. There's no improvement in both arm. How they assess erythritis function is that there's international index for erythritis function score. They have a similar result, even after they exclude the PDE-5 inhibitor groups. And then they take a look at the different testosterone value because erythritis function, they use a higher cutoff 150 nanogram per deciliter and the lower 450 nanogram. There's no difference between the two group as well. So the conclusion is that erythritis function can be more complex than the testosterone deficiency. Erythritis function can be due to the underlying cardiac issue, underlying comorbid condition. So even though testosterone level improves significantly, there is no improvement in the erythritis function. Testosterone does improve the libido and then sexual activity, but there is no improvement in the erythritis function dysfunction from the Traverse study. This is the latest data and the longest duration of study as well. What about the fatigue? This is another most common complaint, a patient complain of fatigue and depression. A lot of the mental health professional, they believe that testosterone replacement therapy can improve the depression as well. So fatigue is, because of the time, I'm going to concentrate on fatigue here. If you take a look at from the team data, there's not much of the difference in the emotional wellbeing, fatigue, and emotional problem as well from the team data. And this is a three years, 36 month duration of study in the elderly man. They use a different scoring system. And then the most common they use is a SF36 questionnaire. There's no improvement in the treatment and testosterone. What about the testosterone study? There's no improvement of fatigue. And by using the functional assessment on the chronic illness therapy scoring, there's a slight improvement in the mood and depression a little bit by using the different scoring as well. Vitality, how they assess the vitality in the testosterone study is that they assess a six minute walk. They take a look at the people with the percentage of the man who can walk at least 50 meter in the, at least increase in the 50 meter in the distance walk. Percentage of the man who had an increase in the 50 meter, at least 50 meter increase in improvement, at least 50 meter in the distance walk. And then no difference in the physical function trial sub-study per se, but when they combine with the other study, there is an improved, all the testosterone trial, there's improvement in the vitality. And treatment arm has a 20%, you know, man who can walk at least, you know, 50 meter in the distance, in the six minute walk. And compared to the placebo has a 12.6%. So it, particularly when they look at the physical functional trial sub-study, there's no difference when they combine with the other study, all the men in the testosterone trial, there was an increase in the vitality. How about the team study? And the team study, they did not see the significant, you know, physical function, and then they tend to see the significant in the, all these like, you know, physical activity scoring as well. Even though, you know, the study was a longer duration, they do not see much difference. So what is the suggestion for our patient is, we have to take a look at the non-endocrine etiology of fatigue and erythritis function, which are more common. And then we have to consider into the sleep disorder, sleep hygiene. We should not ignore the chronic insomnia and also chronic sleep apnea. And then we have to counsel about the medication side effect, which can cause a fatigue and then depression. And then we should also, you know, counsel about the psychosocial impact, which can cause fatigue and depression as well. Then the patient here, the obesity, deconditioning, it's a, you know, very common situation. It's a vicious cycle. The patient is fatigued because of the overweight and because they're overweight, they don't exercise. When they don't exercise, they become more deconditioning and even with the minor physical activity, make them fatigue more. So it's a vicious cycle. If you don't break the vicious cycle, the patient will feel more and more, you know, worsening of the fatigue. And then last not the least is, we have to always counsel about the smoking, which is a very common cause of erythritis function and low T. So people who smoke, they can have a low testosterone and erythritis function. But if you happen to give a testosterone, smoking itself can raise a tremor embolism as well. So whenever this, you know, patient complain that erythritis function, it's worth to try the PDE5 inhibitor and other, you know, measures such as MUSE, because testosterone effect on erythritis function is not always certain. And then we have to counsel about the use of non-pharmacological therapy, such as vacuum pump and penile implant as well. We can, should always work with the mental health professional as well. The psychosexual therapy counseling and couples, you know, sexual counseling can be always helpful. But this is a follow-up case. So this gentleman, you know, came back with the total testosterone 701,000 nanogram per deciliter. He has been maintaining that range, but he noticed that his hemoglobin went up and hemoglobin went up. And then he's getting the, you know, regular therapeutic phlebotomy. At some point within the last few months, two things happened. He was diagnosed with the DVD on left leg and his father had diagnosed with prostate cancer. So he was concerned about the safety, long-term safety of the testosterone after he saw the TV advertisement. So this TV advertisement, you know, show that, you know, there's FDA warning statement, show that testosterone replacement therapy, you know, can cause a heart attack and stroke. You know, this issue in the 2015. And then once this FDA warning statement, you know, was issued, then all this TV advertisement started to pop up. So this patient asked me that, you know, what should I do? Is the testosterone safe for my heart? Is the testosterone safe for my prostate cancer? And may I, you know, will I get the testosterone, prostate cancer in the future with the testosterone replacement therapy? So these are the potential side effects of the testosterone replacement therapy. I'm going to concentrate my talk on the venous thromboembolism, prostate safety, and then cardiovascular risk. But let me start this, you know, topic with the venous thromboembolism, VTE. Testosterone can cause erythrocytosis. It is no fact. It's also depend on the testosterone replacement therapy dosage and the circulating testosterone level. The short-acting injectable forms are very common. Erythrocytosis is more common in the older men than the younger patient. Hypothesis for the cause of the venous thromboembolism is testosterone can cause a hematocrit, increase the viscosity. Testosterone replacement therapy can cause platelet aggregation and coagulation. Testosterone replacement therapy can stimulate the thrombosate A2 concentration in the platelet, and also testosterone can convert it to estrogen, which itself is a risk factor for the venous thromboembolism. However, at what hematocrit value the risk of the neuro-occlusive or the cerebrovascular event can occur, it's still not unclear. We use a hematocrit cutout of 55. It is more of a safety target set by the expert opinion. There is no strong evidence. There is no good data that, you know, looking at the hematocrit less than 45, you know, 55, more than 55, and which can cause, which group can cause increase in the, you know, stroke or the venous thromboembolism. There is no very good data. And these are the erythrocytosis data from the, you know, major outcome study. Traverse trial, they use a 1% gel. Then they have to titrate the dose whenever the patient has a hematocrit, high hematocrit. So that's why only small number of the patient can has a, you know, hematocrit more than, you know, 54, because they have to titrate down the dose. And then they always adjust the dose in the blind, double blind fashion. So that's why, you know, there's only small number has increased in the high hematocrit. Testosterone trial has only small number, seven patient out of the 788, they use a gel as well, E4DM. They use a high dose of testosterone, testosterone and decanoate. This is every three month testosterone injection. They use a high dose of testosterone, and also they aim for the high testosterone value, which I'm going to elaborate in the next few slides, that there's a much more higher incident of the high hematocrit. Up to 22% on the treatment arm has hematocrit more than 45, 54%. And the placebo arm has only 1%. Definitely, this slide tells you is, gel has a lesser incident of the retrocytosis. Injection has a higher incident of the retrocytosis. Higher dose has a higher incident of retrocytosis. If you aim for the higher level of testosterone, there's a higher chance of having the retrocytosis. This data is from the UK primary care database. And then venous thrombolysis happened within the first six months of the initiation of therapy. And the risk is a slightly 1.2, adjusted risk ratio on the testosterone arm, compared to the people who never got the testosterone. It is not statistically very significant, but when they limit to the first six months, and it become a statistically significant. Also, what you can take away from this slide is, the risk of the venous thrombolysis is much more highest in the first six months of the initiation of the testosterone replacement therapy. This data is from the United States data, and it's a case control data, and the 30,000 men, more than 40 years of age. And then for commercial claim database, they use venous thrombolysis, diagnosis ICD-9 code, and the prescription of the anticoagulant prescription, within the first 60 days after the diagnosis. In match control is those people who never had the diagnosis of venous thrombolysis, or the PE. But however, from this insurance claim database, just also a recent therapy, did not show any association with the increase in the risk of the VTE risk. Part of the Veteran Affair Database, this is a retrospective cohort data. They look at the people with the DVT and PE among the 70,000 veterans. These categorized into three group. Group one is those who got the testosterone replacement therapy. Subsequently, they had a normal on treatment testosterone value. The group two is those people who got the testosterone replacement therapy, but they continue to have a low testosterone on treatment. And the group three is who never received the testosterone replacement therapy. They compare the risk of the VTE risk instead of risk in three group, the same, no difference. Out of the PE and DVT-free survival, no difference as well. But this is a meta-analysis. This data is a little bit old already. And since they don't have a latest data, T4D and traverse data, and then even then these meta-analysis did not show significant increase in the testosterone, significant VTE in the testosterone treatment therapy group. This slide show the more recent randomized control data from the venous thromboembolism. Testosterone trial. It has 170 subjects, 65 and older. They use a gel for one year. Median testosterone value they achieve is a 500. And the venous thromboembolism, they got is only four on the treatment arm. And then placebo is five, pretty much the same. T4DM is Australia-based study. It's a middle-aged man, mean age is 60. And then they use a testosterone anticannulate, which is every three month injection, now acting testosterone, intramuscular for two years. Mean testosterone value is 490. And then they do have two on the absolute value, two on the treatment arm. There's no VTE on the placebo group. So Traverse study, they use a gel, 1.62% gel, and the 22 months duration. Median is lowest among all these study, 300 and 380. And then treatment arm VTE has a slight, devein thrombosis is a slight increase, even though statistically not significant. PE also, pulmonary embolism also increase, in the treatment arm, absolute number increase, compared to the placebo. But even though these numbers are not statistically significant. How about the other venous, peripheral venous thrombosis? It's pretty much the same in both group. From this study, what you can see is the testosterone has increased in the number of the venous thromboembolism in the DVD and PE for the absolute case incident, but it is not statistically significant compared to the placebo. So what is the suggestion for our patient? So we got to counsel this patient, if this patient is a non-smoker, so it is not that effective for him. If the patient still smoke, we have to counsel the smoking cessation, because smoking itself is a common risk factor for the erythrocytosis, venous thromboembolism, and then erectile dysfunction. And also we always have to screen for the secondary erythrocytosis, and then venous thromboembolism risk, such as sleep apnea, COPD, and smoking. These are the very common cause of the secondary erythrocytosis. And also we got to treat effectively for the sleep apnea and COPD. We should screen for the JAK2 mutation for the polycythemia. And also we also ask about the family history of the venous thromboembolism. And then we should use a gel and patch formula compared to the injection, if the patient has a high risk for the thromboembolism. And then so we should also can reduce the dose and reduce the frequency of the testosterone release therapy, and gel is proven to be relatively safer compared to the injection. And then we can cut down the dose, lower doses relatively safer for the erythrocytosis and VTE from the data. And last is that we can always counsel about the therapeutic phlebotomy. What of the prostate? So this, our patient has a concern about his prostate. So his question is, can the testosterone release therapy raise the PSA? Can the testosterone release therapy can cause a urinary symptoms? Can the testosterone release therapy cause a prostate cancer? So these are the quite common question from the patient and then from the other provider who are prescribing the testosterone replacement therapy. And the last question is, can a patient with the known prostate cancer take the testosterone replacement therapy? How this come up with the testosterone is a major driver for the prostate cancer. And this is a paper from Dr. Charles Higgin. He's a Nobel Prize winner. His paper is a case report studying the case with the metastatic prostate cancer who underwent the archiectomy. They take a look at the serum alkaline phosphatase as a marker for the bony mats. And then he established a concept of the prostate cancer as the androgen dependent cancer. And then testosterone injection, can activate or stimulate the prostate cancer, his assumption was. And then he established a dogma that testosterone is a major driver hormone for the prostate cancer growth. But it never proved as a, testosterone is a sole etiology of the prostate cancer, even though it can be the driver for the prostate cancer growth. And then we use that androgen deprivation therapy as a mainstay for the prostate cancer treatment. How about the PSA? The testosterone trial, it shows the PSA increase from the baseline. More than 5% of the patient who are taking the testosterone has a more than 1.7 nanogram per mil. And the 2.5% has a more than 3.4. Absolute testosterone value, four and higher, which is also the cutoff for the urology referral or the prostate biopsy, PSA more than four nanogram per mil. It's a relatively small number, but definitely it has a much more higher on the treatment arm than the placebo. Almost 2% on the treatment arm, compared to 0.3%. How about the incident? Incidents total only four patient has a Gleason score of eight. Out of three, three patients are on the testosterone replacement therapy and one patient on the placebo. But this study is too short to make the final conclusion for the prostate cancer incident, because it's a one year duration study, it's too short to see the prostate cancer growth and the prostate cancer activation. What about the lower urinary symptoms? This is from the RIME study. They take a look at the international prostate symptoms score change over the time. It's a three year study compared to the testosterone group and placebo group, there's no difference. The similar finding noted at the Traverse T4-DM and the testosterone trial as well, all these major testosterone trial, significant lower urinary tract symptom has no difference between the treatment and placebo arm. What about the prostate cancer? Androgen play a role in regulating the prostate growth and the differentiation of the prostate gland. Androgen deprivation therapy is a mainstay of treatment for the hormone sensitive prostate cancer. However, there is no strong correlation between the endogenous testosterone level and the risk of the prostate cancer. Who has a high endogenous testosterone level? It's a young, healthy adult male. But they don't have a prostate cancer. Prostate cancer is a disease of aging. The prostate cancer incident increase with aging and also where the low testosterone is very common. So endogenous testosterone is not unlikely the driver for the prostate cancer growth. So meta-analysis, they take a look at the different meta-analysis. They did not see the testosterone replacement therapy has no association with the increase in recurrence or progression of the well-treated prostate cancer. The catch is well-treated prostate cancer. Of course, if the patient has active prostate cancer or the metastatic prostate cancer, we should not be treating them with the testosterone replacement therapy. It is possible that we may be dealing with a lead time bias. So the men with the 65 and older, they may have an underlying or subclinical prostate cancer. And then they may develop the newly diagnosed prostate cancer and the with or without testosterone replacement therapy. But who we screen these PSA more aggressively is those who are taking the testosterone replacement therapy. If the gentleman with a 65 year and older, if they're taking the testosterone, we may be screening the PSA for every six months or every one year. And it depends on the underlying trend. If the patient is not taking the testosterone, we may or may not screen them quite aggressively like those who are taking the testosterone already. So the more you screen aggressively, there's a higher chance of the detection of the subclinical disease and the subclinical prostate cancer or subclinical BPH. So are we digging up the clinically non-significant disease reservoir, which may or may not be clinically significant over the years. So the more you screen, the more you pick up the testosterone-induced PSA. From the previous slides, you notice that testosterone does increase the PSA value and also it can lead to the prostate biopsy. It can create the more diagnosis of the subclinical prostate cancer or the mild prostate cancer, which might have been missed. How about the patient with the occult prostate cancer? Can they develop the aggressive prostate cancer after we started using the testosterone replacement therapy? There are not many good paper. This paper is a smaller study and short duration, but this is a well-done study. 75 hypogonadal men, they got the prostate biopsy. 55 men has a subclinical disease called the PIN, Prostate Intraepithelial Neoplasia. 20 men without any PIN. When they take a look at the PSA and testosterone value one year after the testosterone replacement therapy, they repeat the biopsy and they monitor with the Digidirector exam, PSA value. And there is no significant increase in PSA nor the prostate cancer risk one year. Of course, it's only one year and that is a smaller study. You cannot extrapolate this data into the larger population. What about the T4-DM? This is a group from Australia. They give a testosterone in the middle-aged man and then they see the testosterone replacement therapy improve the risk of diabetes, but testosterone improve that insulin sensitivity. And then they use a testosterone anticannabate, which is a higher dose. They aim for the higher value of testosterone value. You do see the increase in PSA value on the treatment arm has a significant increase, 23%. And then this is a major reason for the people who has a cessation of the study medicine. Five patients, they stopped the study medication and three patients, they stopped the study medication. However, when they take a look at the prostate cancer incident, lower unit tract symptoms, and then the BP, there's no difference. There is a slight difference in the BPH-related hospitalization. Eight on the testosterone treatment arm and then three in the placebo. Of course, they are not statistically significant. What about the Traverse study? There's no difference in the testosterone diagnosis because the event rates are very low, but in order eligible for this study, they excluded a patient with a high risk for the prostate cancer. They exclude the patient with the high unit, lower unit tract symptom score. And then so they handpicked those people with the low risk for the prostate cancer and then low risk for the invasive BPH. And then that's why this study, the whole study has the event rate for the prostate cancer diagnosis, very low. Incident rate is a 0.4% in both group. And then 12 in treatment arm, 11 in the placebo. But how about the high grade prostate cancer? It's a slightly five patient in the testosterone replacement therapy, three, but the both are not statistically significant. How about the IPSS score? International Prostate Symptom Score, no difference. Again, they don't enroll those patient with the highest score to begin with. And then there's a small minor increase in PSA value on the treatment arm. So these are the most significant increase in PSA noted in the first year. After four years of the testosterone therapy, the PSA has not increased significantly. And then both arm has a change in IPSS from the baseline. And when they take a look at the acute urinary retention, any invasive surgical procedure and the prostate biopsy, any new pharmacological treatment for the BPH, there's no difference between the two arm as well. So here are the answer for the question. Can the testosterone replacement raise the PSA? The answer is yes. And then can the testosterone replacement cause a lower unit stress symptom? Answer is no. And then can the testosterone replacement therapy cause a prostate cancer? No, but only for the, we have only the short-term data. Again, even the unit stress symptoms, that a lot of the study, they excluded the patient with the underlying risk factor for the lower unit stress symptom and then significant BPH. So these patients are not studied. If the patient, your patient has a significant BPH already, this information may not apply to your patient. Can the patient with the testosterone prostate cancer, known prostate cancer, take the testosterone replacement therapy? Yes. Low-grade cancer in remission, who are well-treated in remission, and then it should be the shared decision. I always talk to the patient urologist. I always get the blessing from the urologist before I start the testosterone replacement therapy. And then, again, the traverse data does not apply to the patient with the known prostate cancer because of those patient with the high PSA and the men without the, you know, you know, confirmed, you know, hypogonadism patient. So they cannot apply for the, these patient with underlying risk factor already. This traverse, you know, they excluded the patient with a high PSA and then high IPSS, underlying prostate score, and they are already excluded for this study. The last topic is cardiovascular risk. The background literature is a little bit fuzzy until recently, and then those are the pharmacoepidemiological study, and then they give a contradictory result. The randomized controlled data, such as T4-DM testosterone trial team study show no increase in cardiovascular outcome. Tom trial premature terminated due to the concern for the cardiovascular safety, but it is underpowered and not designed for the CV outcome. And the team and testosterone trial show the conflicting data on the surrogate markers, such as coronary artery intima thickness, tax code, and the coronary blood volume. These studies, they study the similar population, but they give a different result for the surrogate marker for the ESCVT. So these are the placebo-controlled randomized data for the cardiovascular outcome. Tom study has 209 men, 65 and older, with the limited mobility. And the baseline testosterone value is somewhere around 100 and 350. They use a testosterone gel, 100 milligram of placebo for six months. The primary outcome is a lower extremity strength and physical function. The treatment arm does improve the physical activity, but the study stopped because of the increase in cardiovascular risk on the treatment arm, such as AFib and then weight gain, heart failure concern. Team study, it is 200 men, 60 and older, the range is 100 and 400 nanogram per deciliter. They use a testosterone gel, 75 milligram for daily, for three years, it's a longer duration. They take a look at the surrogate marker for the carotid artery intima thickness and the tax code progression. There is no difference in MACE, but this study is not designed for the MACE. There's no difference in their primary outcome, carotid intima thickness and tax code. So this is a detailed data from the team study. You can take a look at it. There's no difference between the treatment arm and placebo in terms of the coronary artery calcium score and then coronary artery intima media thickness. The testosterone study is a, you know, again, similar study, 65 year and older, they use a testosterone gel, so 50 milligram daily for one year, it is a sub-seven sub-study, and then one of the sub-study is to take a look at the progression of the non-calcified coronary artery plug volume, there is no difference in MACE, again, this study is not designed for the MACE, there is an increase in the coronary artery non-calcified plug volume on the treatment arm, but there is no difference in CAC score. T4-DM is testosterone replacement therapy for the diabetes remission. 1000 men, middle age, with newly diagnosed diabetes or impaired glucose tolerance. Testosterone value of less than 404 nanograms per deciliter. And then they give undecanoate, you know, one gram, and then placebo in two years. The prevention or the reversion of the vision of the diabetes there's no difference in maize. The last trial is a traverse study. I'm going to elaborate a little bit about this study. This is the largest and longest cardiovascular outcome study. And then testosterone replacement in hypogonadal men with a high underlying risk patient. It's a phase four study. It's already FDA approved medicine. 5000 patients in the middle age, 45 and 80 year men. Testosterone value, 100 and 300. They should have hypogonadal symptoms and evidence of cardiovascular disease or the high risk cardiovascular patient. Primary outcome is first occurrence of the cardiac death, non-fatal MI, non-fatal stroke. We have other sub-study, anemia, fracture, depression, diabetes progression, and prostate cancer. Traverse study, median duration of the testosterone therapy is the 22 months. And then mean follow-up is 33 months. Majorities are white. The median age is 63 and the mean BMI is 35. There are significant number of patient with a diabetes and then a lot of them are overweight and that significant numbers are hypertension. Baseline testosterone value is at 227, a little slightly lower than the 300 cutoff. And then target value is 350 to 750. They try to maintain the hemoglobin less than 54. They have to cut down these hemoglobin value whenever they reach the 54 and higher. And testosterone replacement therapy median achieved is at 326. You may notice that, so here is the oldest modest increase, 100 nanogram per deciliter modest increase. 61% stop the study medication and then 18% did not complete the study. 20% withdraw from the study. It is different from the other outcome study, much, much higher withdrawal rate because the patient has expectation compared to the other lipid study. And this is like, they have a sub expectation. But they designed the study very well that there's still the statistically significant even after the significant withdrawal. And the retention and the adherence are much more lower than the most of the CV outcome study. The primary composite outcome, there's no difference between the treatment on the placebo. And there is a slight increase in the pulmonary embolism. There's increase in the non-theta arrhythmia. And then AFIT increase and then AKI increase as well. These, even though they are not significant, they are slight, you know, or just numerically increase in significant value. Let's take a look at the, you know, individual cost of the primary outcome, cardiac death, non-theta MI, non-theta stroke, no differences. And then the question is who might benefit from testosterone replacement therapy? Testosterone replacement therapy is safe. Yes, it is safe. It does not cause MI and stroke and heart attack, but who might get the benefit? Is that this study is the majorities are white and they have a significant number of 54% has underlying cardiovascular disease and almost 70% has a type one or type two diabetes. Who might have a benefit? Is a younger patient, black population, no underlying cardiac disease and no diabetes. So the take home message is from this testosterone study, who has no underlying diseases might have a more benefit. It favor the testosterone replacement therapy. So how about the question? Is the testosterone replacement therapy safe for the patient with increased cardiovascular risk? Yes, but the traverse data cannot apply to the general population. It has a stringent inclusion exclusion criteria. It's not included the organic etiology and it does not include the testosterone misuser. It is safe for the short term because it's a median duration is two years duration. And then that's a modest increase in the median testosterone value from the 227 to the 326. So such a modest increase can be achieved by the lifestyle change, weight loss and diabetes control without the testosterone replacement therapy. So they try to limit the maximum testosterone value to the 750 and then they cut down the dose whenever the patient hit the hematocrit 54% and higher. So most of the traverse patient receive the standard cardiovascular care. There's a very high number of the statin use, very high number of the aspirin use, LDL values are not bad, you know. And so this, you cannot imply these traverse data to the general population. I'm going to close my talk. It's, you know, while we are searching for the fountain of youth for most of our patient, we have to be careful. And whenever we prescribe the testosterone replacement therapy, our first rule of thumb is do no harm first. So we got to pick the right patient, appropriate patient who might get the benefit from testosterone replacement therapy. Testosterone replacement therapy may not be for the, you know, every single patient with the low testosterone we see at the clinic. So picking the right patient is the most appropriate. Last is we have to follow the, you know, our old do no harm first. Thank you very much. If you have any question, please feel free to email me at this number. Thank you. Thank you very much for the Endocrine Society for the such opportunity.

testosterone replacement therapy

hypogonadism

testosterone levels

fatigue

sexual dysfunction

venous thromboembolism

prostate cancer

cardiovascular disease

late-onset hypogonadism

patient evaluation