Good review. I'm a 70 yo Intv cardiologist. Healthy and fit. I skied 78 days this past winter, while performing duties of Ski Patrol (not easy). My muscles and strength melted away. My T = 180. I started 200 mg IM q week and went to a level of 1100. Muscle blossomed. Energy level blossomed. Sexual libido and spontaneous erections blossomed. My PSA went from 4 to 5 (with free PSA of 10). I feel great. Have decreased dose to 100 mg q week. My PCP recommended working up my Prostate for CA. My response, "I'd rather feel like this and die in 3 years from Prostate CA rather then live 20 years with a low T." I'm a believer.
This was such a helpful summary! I have been practicing internal medicine and pediatrics for over 20 years now and am always looking for ways to efficiently figure out the real evidence. I don't think I have ever read a more succinct summary of a study that is pertinent to my daily practice that summarized what I needed to know in a way that I could start applying to patient care right away. Perfect combination of the stats I need to know and study background with outcomes and opinion.
Thank you for a wonderful analysis. The article is quoted in a Swedish medical paper happily and I am frustrated. I just wonder, are there raw data, protocols and statistical analysis plans available? (On top of all the other aspects you mention...)
I have secondary hypogonadism as a result of a pituitary microadenoma. Starting testosterone therapy was a life-changing experience for me in my mid 30s. It also began a journey for me as a family physician, treating low testosterone in my patients. Differentiating “real” hypogonadism from “fake” hypogonadism is not as easy as you state. There is simply a lack of great evidence. Why does expert guidance tell us to look for two levels under 300 regardless of age when testosterone naturally decreases every decade of life? For men on TRT, how does one know when it’s time to wean off, or if it’s safe for a man in his 70s to have a testosterone level over 500. I have lots of questions but little evidence based answers. In this scenario, most of us doctors depend on anecdotal experiences and perhaps what makes physiological sense. I really have liked the panels comment recently that we need to trade out the multitude of fluffy studies and invest in a few well done studies that conclusively answer questions.
Famously, the WHO states that "Health is a state of complete physical, mental and social well-being and not merely absence of disease or infirmity". I would argue similarly that medicine is not just treating disease, but promoting well-being.
As someone whose primary professional (and personal) interest is chronic pain, I've never seen anyone die of pain. We often don't have a clear etiology for a patient's pain. The treatments for pain aren't great from a cost-benefit perspective. But who would argue that treating pain isn't real medicine?
Concrete disease states are easier to study, and health promotion can descend into woo or commercialism very quickly, but philosophically, I wouldn't want to see my profession as one that only treats illness and has nothing to offer for a person without a diagnosis.
Any chance we can get an article on RCT’s studying the efficacy of CPAP machines for sleep Apnea? Seems like there’s a mini-industry selling this Medicare subsidized treatment and I can’t a handle on whether any medical outcomes are improved by this nightly intervention?
Thank you very much! I just now caught up with your reply and read the article! I just took another “sleep test” at home, awaiting results. I asked the doctor whether she could point me in the direction of any RCT results that showed a positive correlation between “number of events per hour” in the sleep test and adverse cardio outcomes, with and without CPAP. She looked at me quizzically and said yes, one study did that. I’m still waiting for it.
Well seeing it getting more and more difficult to slow muscle decline at 83, I got my primary to test and found low-T. Imagine that. PSA normal, heart seems fine despite a TIA many years ago. What to do? Primary wanted monthly shots. Not to my taste; the last thing I need is monthly visit - yearly has been fine. So then the patented gel, except every bit of my research showed quite ineffective confirmed by Primary. Settled on a 10% cream, compounded. Primary has had minimal experience with that treatment but is interested. Early days but I do know I'm fighting a battle to slow the rate of decline; at my age given other factors only seeking the ability to live independently.
While we are all different, I don't see my efforts cosmetic at all. The ad brokers enjoy preying on our desires and we are surrounded by various concoctions that purport to improve health. My exercise regime isn't keeping up with my decline so I sought a potential solution. Others might think that as well.
I have some cardiovascular issues and my sexual desire is fine at age 73. I am not depressed or lacking energy to any great degree. My soon to be wife is quite pleased and her sex drive is very strong and she's 4 years older. So all your studies are worthless as usual, and all big pharma cares about is inventing another drug that does far more harm than good.
Excellent summary. I don’t have to venture far before GIM topics are way out of my depth. I was surprised to find that T level actually defines deficiency, rather than high levels of the tropic hormone which seemed to be the general principle of other endocrine axes and feedback loops. Even menopause as far as I know is with high FSH and GnRH.
Great point to note that these people had T replacement, but just small smidgens of it. Given that symptoms were part of inclusions, I also could not find anything in paper about how those symptoms changed with T replacement. There was Hct cutoff of 54%, but it’s unclear why higher doses were not used, and why higher levels of T were not achieved. It would be good to know that it was because symptoms were already improved adequately. But to that end, it is also concerning that more than 60% dropped out. Anything with 60% dropout should be a huge red flag. Not to mention the significant increases in AF and AKI, as well as numerical doubling of PE.
Still, I would say low level replacement and low level attained T is probably safe from CV standpoint, PE/AF/AKI notwithstanding. But it says nothing for those in whom higher doses and higher attained T levels are needed to produce meaningful symptom improvements.
Advertising medication on TV commercials is a crime. It turns non experts into their own doctor, and we all know that “He who acts as his own doctor has a fool for a patient!”
The paternalism just jumps off the page on this essay. I love Adam Cifu but this is not a good look. The parts of the essay that deal with the science and results are excellent, as usual. But the underlying attitude is… not good. Explain the risks and benefits (or lack thereof) to patients and let them make up their own minds. No need for disparaging characterizations of patient preferences.
The one scientific point I would make is, while I am fairly good at math, it is not clear to me how the normal ranges of testosterone are calculated. The math part is easy. The question is: who is being tested and why? Is the population that is used to set the range reasonably healthy? Are the ranges similar in hunter-gather groups, etc? How do the ranges vary with age? These questions undoubtedly have answers; I just don’t know what they are.
I think the problem with this approach is taking a normal process (aging) and trying to label it as a "disease". And asking physicians to "prescribe" a treatment and have insurance companies pay for it. The data we have at this point does not support that in all honesty. If it is a situation of no good data, a balance of "pros and cons" that a patient should decide on their own - then it should be a homeopathic, over the counter preparation that you don't need a prescription for. And pay for out of pocket.
You have to realize this is totally a "Pharma" driven phenomenon - in the days before topical testosterone gel was available and the only option was an intramuscular testosterone injection, very few men were interested in even considering the issue. as soon as testosterone gel became available and was being marketed by Pharma, testosterone prescribing sky rocketed. Now it falls amongst all the other money making industries that prey on the middle aged and aging - preying on our vanities and fight against "aging" - think of all the marketing going on now- better sleep! lose weight! younger looking skin! pain relief! Just add all the claims that "low T" industry touts - it is an open market for companies dealing with these issues and big money. Each person just making up their own mind seems better-suited to over the counter, homeopathic remedies, topicals, etc. Physicians should not be using their license to facilitate big pharma and the money-making efforts of good marketing and a vulnerable, ready, target-population.
Your comment is good, and sensible, in my opinion. There are numerous public policy issues to discuss here, and probably this is not the place for a complete discussion.
But very briefly: medically, we are talking about testosterone, not delivery systems. Testosterone is extremely cheap, checking GoodRx right now, $31 without insurance for 5 ml of 200 mg/ml at CVS. This is enough for about 10 weeks for many folks, so $3 per week, without insurance. As you mentioned, this needs to be injected.
Obviously you need a prescription; this drug is tightly controlled. I think Congress itself put it on a particular list against the advice of the AMA and FDA, primarily because of concerns regarding baseball and other sports, but I might have that history wrong.
Anyway this gets into all sorts of questions about why the government is preventing 75 year old men from buying this over the counter, and if that is the right policy, and etc. And if it is, how hard should it be for them to get a Rx? Which really strays into political philosophy areas that probably are better discussed on a different forum.
Agreed! The situation "testosterone therapy" is in now does not make any medical sense. Prescribing therapeutic levels of gel or injectable testosterone is a dicey proposition - we do have to monitor blood levels and then monitor for side effects as they clearly occur! I've had patients where testosterone gel has abnormally elevated red blood cell counts to the point of danger for blood clots/strokes. We know the risks of illegal "athletic use" of testosterone. Testosterone supplementation at these levels is CLEARLY not without consequence and just should not be used without better data.
For the "lifestyle" use of just "feeling better", this should be low-dose, OTC topical application with minimal to no risk of injury and men making their own decisions. Again, physician license and higher dose should be out.
Thanks for the comment and I totally take your critique to heart. I get my bias here, it is just not the kind of medicine I like to practice -- that does not make it wrong or bad. I do feel uncomfortable with us all paying for unproven therapies not for diseases, illness but for potential improvements for subjective symptoms.
The population used to determine the range is possibly non-representative of a 'healthy' population. So the question is whether the results in the population tested are generalizable to the entire population of men.
I would argue that we are living in a toxic soup of chemicals, along with birth control in the water that there is no healthy population anymore. I read elsewhere that average testosterone levels have decreased by 40-50% for the average man since the 1980's. Average ranges on standard blood tests have been coming down in huge jumps just since 2014 when I first started looking into testosterone replacement. To @Edward Brown's point, how do we compare to the typical hunter gatherer male in testosterone? Just because everyone's levels of testosterone have been plummeting in the west, does not mean that those are healthy levels.
I literally cannot live without my HRT. I was hospitalized twice for suicidal ideation in menopause with never ever having had any such problems before. I can sleep. I don’t have debilitating anxiety. I want to have sex with my husband. I feel GREAT. I will take this quality of life any day over living to 100 and feeling like dog poop. I get a pellet of low doses of estrogen and testosterone, plus take oral progesterone. Pray to God I never have to stop.
There is a lot of good stuff in here: what "medicine" means by "a little low" and "normal range", "cosmetic medicine", how advertising and society fetishizes via medicalization, and poor study design (by deviousor incompetent design (who knows) which is a form of scientism. ("The study" and "numbers" (regardless of rigor) as the new white coat and stethoscope: shamanistic signalers of authority.)
Since you swapped with Dr. John, I hope he reads this and sees it as evidence against his theory that Hayek and the free market can cure medicine. The market will not drive out snake oil. Real science and real evidence based medicine might.
PS a few less spontaneous erections in 50s, 60s etc is a feature not a bug.
Good review. I'm a 70 yo Intv cardiologist. Healthy and fit. I skied 78 days this past winter, while performing duties of Ski Patrol (not easy). My muscles and strength melted away. My T = 180. I started 200 mg IM q week and went to a level of 1100. Muscle blossomed. Energy level blossomed. Sexual libido and spontaneous erections blossomed. My PSA went from 4 to 5 (with free PSA of 10). I feel great. Have decreased dose to 100 mg q week. My PCP recommended working up my Prostate for CA. My response, "I'd rather feel like this and die in 3 years from Prostate CA rather then live 20 years with a low T." I'm a believer.
This was such a helpful summary! I have been practicing internal medicine and pediatrics for over 20 years now and am always looking for ways to efficiently figure out the real evidence. I don't think I have ever read a more succinct summary of a study that is pertinent to my daily practice that summarized what I needed to know in a way that I could start applying to patient care right away. Perfect combination of the stats I need to know and study background with outcomes and opinion.
Great talent! I look forward to more!
Thank you for a wonderful analysis. The article is quoted in a Swedish medical paper happily and I am frustrated. I just wonder, are there raw data, protocols and statistical analysis plans available? (On top of all the other aspects you mention...)
I have secondary hypogonadism as a result of a pituitary microadenoma. Starting testosterone therapy was a life-changing experience for me in my mid 30s. It also began a journey for me as a family physician, treating low testosterone in my patients. Differentiating “real” hypogonadism from “fake” hypogonadism is not as easy as you state. There is simply a lack of great evidence. Why does expert guidance tell us to look for two levels under 300 regardless of age when testosterone naturally decreases every decade of life? For men on TRT, how does one know when it’s time to wean off, or if it’s safe for a man in his 70s to have a testosterone level over 500. I have lots of questions but little evidence based answers. In this scenario, most of us doctors depend on anecdotal experiences and perhaps what makes physiological sense. I really have liked the panels comment recently that we need to trade out the multitude of fluffy studies and invest in a few well done studies that conclusively answer questions.
Famously, the WHO states that "Health is a state of complete physical, mental and social well-being and not merely absence of disease or infirmity". I would argue similarly that medicine is not just treating disease, but promoting well-being.
As someone whose primary professional (and personal) interest is chronic pain, I've never seen anyone die of pain. We often don't have a clear etiology for a patient's pain. The treatments for pain aren't great from a cost-benefit perspective. But who would argue that treating pain isn't real medicine?
Concrete disease states are easier to study, and health promotion can descend into woo or commercialism very quickly, but philosophically, I wouldn't want to see my profession as one that only treats illness and has nothing to offer for a person without a diagnosis.
Any chance we can get an article on RCT’s studying the efficacy of CPAP machines for sleep Apnea? Seems like there’s a mini-industry selling this Medicare subsidized treatment and I can’t a handle on whether any medical outcomes are improved by this nightly intervention?
This is a huge paper on the topic. Maybe a future "favorite article."
https://jamanetwork.com/journals/jama/fullarticle/2643307
Thank you very much! I just now caught up with your reply and read the article! I just took another “sleep test” at home, awaiting results. I asked the doctor whether she could point me in the direction of any RCT results that showed a positive correlation between “number of events per hour” in the sleep test and adverse cardio outcomes, with and without CPAP. She looked at me quizzically and said yes, one study did that. I’m still waiting for it.
Well seeing it getting more and more difficult to slow muscle decline at 83, I got my primary to test and found low-T. Imagine that. PSA normal, heart seems fine despite a TIA many years ago. What to do? Primary wanted monthly shots. Not to my taste; the last thing I need is monthly visit - yearly has been fine. So then the patented gel, except every bit of my research showed quite ineffective confirmed by Primary. Settled on a 10% cream, compounded. Primary has had minimal experience with that treatment but is interested. Early days but I do know I'm fighting a battle to slow the rate of decline; at my age given other factors only seeking the ability to live independently.
While we are all different, I don't see my efforts cosmetic at all. The ad brokers enjoy preying on our desires and we are surrounded by various concoctions that purport to improve health. My exercise regime isn't keeping up with my decline so I sought a potential solution. Others might think that as well.
I have some cardiovascular issues and my sexual desire is fine at age 73. I am not depressed or lacking energy to any great degree. My soon to be wife is quite pleased and her sex drive is very strong and she's 4 years older. So all your studies are worthless as usual, and all big pharma cares about is inventing another drug that does far more harm than good.
Excellent summary. I don’t have to venture far before GIM topics are way out of my depth. I was surprised to find that T level actually defines deficiency, rather than high levels of the tropic hormone which seemed to be the general principle of other endocrine axes and feedback loops. Even menopause as far as I know is with high FSH and GnRH.
Great point to note that these people had T replacement, but just small smidgens of it. Given that symptoms were part of inclusions, I also could not find anything in paper about how those symptoms changed with T replacement. There was Hct cutoff of 54%, but it’s unclear why higher doses were not used, and why higher levels of T were not achieved. It would be good to know that it was because symptoms were already improved adequately. But to that end, it is also concerning that more than 60% dropped out. Anything with 60% dropout should be a huge red flag. Not to mention the significant increases in AF and AKI, as well as numerical doubling of PE.
Still, I would say low level replacement and low level attained T is probably safe from CV standpoint, PE/AF/AKI notwithstanding. But it says nothing for those in whom higher doses and higher attained T levels are needed to produce meaningful symptom improvements.
By andropause I think you mean
Man o pause
A rose by any other name...
Advertising medication on TV commercials is a crime. It turns non experts into their own doctor, and we all know that “He who acts as his own doctor has a fool for a patient!”
Great read Adam. I also love your last line. Remember the line: knowledge comes but wisdom lingers. Ben Hourani
The paternalism just jumps off the page on this essay. I love Adam Cifu but this is not a good look. The parts of the essay that deal with the science and results are excellent, as usual. But the underlying attitude is… not good. Explain the risks and benefits (or lack thereof) to patients and let them make up their own minds. No need for disparaging characterizations of patient preferences.
The one scientific point I would make is, while I am fairly good at math, it is not clear to me how the normal ranges of testosterone are calculated. The math part is easy. The question is: who is being tested and why? Is the population that is used to set the range reasonably healthy? Are the ranges similar in hunter-gather groups, etc? How do the ranges vary with age? These questions undoubtedly have answers; I just don’t know what they are.
I think the problem with this approach is taking a normal process (aging) and trying to label it as a "disease". And asking physicians to "prescribe" a treatment and have insurance companies pay for it. The data we have at this point does not support that in all honesty. If it is a situation of no good data, a balance of "pros and cons" that a patient should decide on their own - then it should be a homeopathic, over the counter preparation that you don't need a prescription for. And pay for out of pocket.
You have to realize this is totally a "Pharma" driven phenomenon - in the days before topical testosterone gel was available and the only option was an intramuscular testosterone injection, very few men were interested in even considering the issue. as soon as testosterone gel became available and was being marketed by Pharma, testosterone prescribing sky rocketed. Now it falls amongst all the other money making industries that prey on the middle aged and aging - preying on our vanities and fight against "aging" - think of all the marketing going on now- better sleep! lose weight! younger looking skin! pain relief! Just add all the claims that "low T" industry touts - it is an open market for companies dealing with these issues and big money. Each person just making up their own mind seems better-suited to over the counter, homeopathic remedies, topicals, etc. Physicians should not be using their license to facilitate big pharma and the money-making efforts of good marketing and a vulnerable, ready, target-population.
Your comment is good, and sensible, in my opinion. There are numerous public policy issues to discuss here, and probably this is not the place for a complete discussion.
But very briefly: medically, we are talking about testosterone, not delivery systems. Testosterone is extremely cheap, checking GoodRx right now, $31 without insurance for 5 ml of 200 mg/ml at CVS. This is enough for about 10 weeks for many folks, so $3 per week, without insurance. As you mentioned, this needs to be injected.
Obviously you need a prescription; this drug is tightly controlled. I think Congress itself put it on a particular list against the advice of the AMA and FDA, primarily because of concerns regarding baseball and other sports, but I might have that history wrong.
Anyway this gets into all sorts of questions about why the government is preventing 75 year old men from buying this over the counter, and if that is the right policy, and etc. And if it is, how hard should it be for them to get a Rx? Which really strays into political philosophy areas that probably are better discussed on a different forum.
Agreed! The situation "testosterone therapy" is in now does not make any medical sense. Prescribing therapeutic levels of gel or injectable testosterone is a dicey proposition - we do have to monitor blood levels and then monitor for side effects as they clearly occur! I've had patients where testosterone gel has abnormally elevated red blood cell counts to the point of danger for blood clots/strokes. We know the risks of illegal "athletic use" of testosterone. Testosterone supplementation at these levels is CLEARLY not without consequence and just should not be used without better data.
For the "lifestyle" use of just "feeling better", this should be low-dose, OTC topical application with minimal to no risk of injury and men making their own decisions. Again, physician license and higher dose should be out.
Thanks for the comment and I totally take your critique to heart. I get my bias here, it is just not the kind of medicine I like to practice -- that does not make it wrong or bad. I do feel uncomfortable with us all paying for unproven therapies not for diseases, illness but for potential improvements for subjective symptoms.
"Low" is just outside 2-3 standard deviations. Depends a bit on the test.
As mentioned, the math part is trivial.
The population used to determine the range is possibly non-representative of a 'healthy' population. So the question is whether the results in the population tested are generalizable to the entire population of men.
Ranges are derived from healthy populations. It is up to the doc to determine if it is reasonable to apply this range to the individual patient.
I would argue that we are living in a toxic soup of chemicals, along with birth control in the water that there is no healthy population anymore. I read elsewhere that average testosterone levels have decreased by 40-50% for the average man since the 1980's. Average ranges on standard blood tests have been coming down in huge jumps just since 2014 when I first started looking into testosterone replacement. To @Edward Brown's point, how do we compare to the typical hunter gatherer male in testosterone? Just because everyone's levels of testosterone have been plummeting in the west, does not mean that those are healthy levels.
I literally cannot live without my HRT. I was hospitalized twice for suicidal ideation in menopause with never ever having had any such problems before. I can sleep. I don’t have debilitating anxiety. I want to have sex with my husband. I feel GREAT. I will take this quality of life any day over living to 100 and feeling like dog poop. I get a pellet of low doses of estrogen and testosterone, plus take oral progesterone. Pray to God I never have to stop.
Thx
I’m a subject for replacement via weekly injection for over ten years. Monitored and tested biannually.
I’m 75. Annual Cardio check ups.for 20+
Etc
Etc
Couldn’t speak more highly!
Thank you.
There is a lot of good stuff in here: what "medicine" means by "a little low" and "normal range", "cosmetic medicine", how advertising and society fetishizes via medicalization, and poor study design (by deviousor incompetent design (who knows) which is a form of scientism. ("The study" and "numbers" (regardless of rigor) as the new white coat and stethoscope: shamanistic signalers of authority.)
Since you swapped with Dr. John, I hope he reads this and sees it as evidence against his theory that Hayek and the free market can cure medicine. The market will not drive out snake oil. Real science and real evidence based medicine might.
PS a few less spontaneous erections in 50s, 60s etc is a feature not a bug.