Thank you for this! My brother is considering taking testosterone. I am sending this to him, so that he can be more informed! The theme of many of SM posts is that the system meant to treat/improve our health is a mess of conflicts on interest, fraud, lies, and over promises.
Really appreciate this breakdown, especially the point about non-inferiority design being the wrong tool here.
Slightly tangential, but I've been curious about how this intersects with the well-documented secular decline in population testosterone levels (Travison et al. 2007, MMAS data, replicated in Danish cohorts and a 2025 meta-analysis spanning 1971-2024). It seems to be age-independent and not fully explained by rising obesity/BMI, the cause is still debated.
Correct me if I'm wrong, but doesn't this raise an interesting wrinkle for the "low T" diagnosis conversation? If population-wide averages are shifting downward for reasons we don't fully understand, our reference ranges (built from population data) could end up drifting along with it, potentially medicalizing what's actually a population-level shift rather than individual pathology. Not saying TRT marketing isn't still the bigger issue you're describing, just wondering if the moving baseline adds another layer to why "low T by the numbers" doesn't necessarily mean symptomatic androgen deficiency.
Those low T clinics typically use injectable testosterone, so this study wouldn’t even apply to common practice. My patients definitely expect injectables if they request treatment. The other practice I hate is stacking prescriptions/treatments, for instance I am now seeing patients being sent for therapeutic phlebotomy for the polycythemia caused by injectable testosterone given based on symptoms and not a medical diagnosis/indication. What are we doing?!
Excellent analysis. I imagine that it would be possible to elicit one of the symptoms from practically all males over 40. I have to wonder whether a relatively low grade prostate cancer might be stimulated by raising the T level and become a significant harm given enough time.
Don’t forget the autopsy studies showing indolent prostate cancer at below 5% incidence below 30yrs old, with numbers listed as 20% in your 50’s and over 58% in your 80’s. As someone said, testosterone is like Miracle-Gro to prostate cancer. And, when it happens to you, the incidence is 100%. Remember a peer saying low-T was the fibromyalgia of men 🙈. “ we need more studies “
Some time ago, I had a young male patient on "T" for "cosmetic reasons". He had polycythemia and a PE! Similarly, I had a female w menopause on estrogen patch with a DVT. A recent article from NEJM now finds risk associated with the estrogen patch delivery method, previously thought to be safe. https://www.nejm.org/doi/full/10.1056/NEJMra2202438.
This cosmetic approach to care is simply a means to sell more drugs which patients seem happy to eat or apply, sometimes at high cost and high risk. And, when there are negative consequences, we can sell more drugs for those diagnoses as well. Thus continuing to grow our trillion dollar healthcare industrial complex.
I think I am an interesting outlier. For past 20 years my total and free have been 80 and 12. I have supplemented for 19 years 9 about 300mg/month) I recently wen off supplementation and my numbers went back to80 and 12. Even at age 80 when I lifting big weights and keeping total T at 700 I noticed no benefit from testosterone injections. I am now 85 ( 6' 2'', 175) and off supplementation. T at 80 and 12, and I can dead lift 200lbs the same as 5 years ago. I never felt any advantage in testosterone injections. I I often wondered about Tour riders who certainly were using exogenous T, and surmised that it was for recovery not for strength.
My position is that I refer out anyone interested in “low T”. If I think someone may have hypogonadism, I will start the work up and if it’s negative, I’ll leave it at that and if it shows they might benefit from testosterone replacement, I always refer to one of my endocrine colleagues just to back me up with an expert opinion. I’m happy to continue the medicine for the patient and follow him. And I always tell the patient that you’ve always got the endocrinologist to help follow also.
I agree with the criticism of fundamental study design re: non-inferiority. That should be reserved for scenarios testing tradeoffs. So if they’re testing for non-inferiority in CV outcomes…where is the upside? Was it better for “symptoms” (soft endpoint as that is)? And this highlights the flaw of the study…since it used homeopathic doses that induced huge dropouts due to presumably perceived uselessness for symptoms among study subjects.
So at best, this study tells you when you use homeopathic doses of T in folks who don’t really even have low T, there seems to be no CV price to pay.
As I’ve also learned from SM over the years, what we need are post marketing registries to properly assess long term safety.
The study author’s surprise at this study being used for marketing bespeaks a level of naïveté that is disturbing.
We have many patient populations using or “ abusing “ these compounds. Great black market out there too. If they really care about their health, maybe they’ll agree to be subjects in such study. Just a thought.
One consequence of the cosmetic testosterone treatment is polycythemia. The patient then becomes a regular volunteer blood donor to reduce their hemoglobin. In order to donate we request they get a physician note indicating they can safely be phlebotomized.
One of the best books I have ever read about the founding of synthetic hormones, the politicization, and the cosmetic medicine trend is Bob Ostertag's Sex, Science, Self: A Social History of Estrogen, Testosterone, and Identity. https://a.co/d/03zRlUrp. From testosterone synthesis in the 1930s, the hormone was theorized as "rejuvenation" for males. Hitler wanted to corner the market to fuel his ideology. There is the terrible history of synthetic estrogen and testosterone used for so-called "gay cures" in jail or court order home treatments (Alan Turing), male rejuvenation movement in 1960s and 70s with the Harry Benjamin Society (now WPATH), and now the modern day trans movement and military screenings. As long as it continues to be marketed as a "happiness" therapy and/or "rejuvenation", I envision ongoing blockbuster sales. The polypharmacy interactions are understudied and ignored.
Devil's advocate. There are benefits to testosterone therapy: sexual function. If informed consent presents the known upsides at the time of the trial, the latter, along with the postulated downsides (CV outcomes), the trial participant is not uninformed. Now sexual function may or may not be weak tea, but it's a value choice for men. On this premise, a non-inferiority trial could be justified.
It’s my understanding that testosterone only helps with desire not with ability. That’s why we have Viagra. Can someone give me a reference disproving my ideas?
Dr Feelgood and Dr Lexus have thriving medical practices without corporate compliance requirements, call, cash payments only or a direct manager with no medical background telling them what to do. What’s not to like ?
Pretty bizarre to have GYN prescribing testosterone to the spouses and when the side effects arise, they do not deal with them …. Informed consent, hmmmm. The same way we can choose not to ride a motorcycle or go in a “ shark-proof “ cage because we do not want the possibility of harm, we can just walk past the aisle with all the treatments for Lookatmeitis. Last one out turn the lights off.
So, let the poor schlub who sees these ads beware?
Don’t we, as physicians who understand what the literature does and does not say, have a responsibility to do what we can to educate patients, and advocate for responsible drug advertising? Or, better, work to get rid of it altogether?
Responsible drug advertising is an oxymoron. I always advised my patients to disregard it. Also explained that a genie doesn't leap out of a bottle of cleanser and mop the floor for you.
Your Venn diagram is something I have been preaching for years. I would label the left circle 'pharma funded trials' and the right circle 'investigator initiated trials'
Thank you for this! My brother is considering taking testosterone. I am sending this to him, so that he can be more informed! The theme of many of SM posts is that the system meant to treat/improve our health is a mess of conflicts on interest, fraud, lies, and over promises.
Really appreciate this breakdown, especially the point about non-inferiority design being the wrong tool here.
Slightly tangential, but I've been curious about how this intersects with the well-documented secular decline in population testosterone levels (Travison et al. 2007, MMAS data, replicated in Danish cohorts and a 2025 meta-analysis spanning 1971-2024). It seems to be age-independent and not fully explained by rising obesity/BMI, the cause is still debated.
Correct me if I'm wrong, but doesn't this raise an interesting wrinkle for the "low T" diagnosis conversation? If population-wide averages are shifting downward for reasons we don't fully understand, our reference ranges (built from population data) could end up drifting along with it, potentially medicalizing what's actually a population-level shift rather than individual pathology. Not saying TRT marketing isn't still the bigger issue you're describing, just wondering if the moving baseline adds another layer to why "low T by the numbers" doesn't necessarily mean symptomatic androgen deficiency.
Those low T clinics typically use injectable testosterone, so this study wouldn’t even apply to common practice. My patients definitely expect injectables if they request treatment. The other practice I hate is stacking prescriptions/treatments, for instance I am now seeing patients being sent for therapeutic phlebotomy for the polycythemia caused by injectable testosterone given based on symptoms and not a medical diagnosis/indication. What are we doing?!
Excellent analysis. I imagine that it would be possible to elicit one of the symptoms from practically all males over 40. I have to wonder whether a relatively low grade prostate cancer might be stimulated by raising the T level and become a significant harm given enough time.
Completely agree with you, excellent recap.
"When you pray for rain, you gotta deal with the mud too. That's a part of it." (D. Washington)
Perfect for Big Pharma related discussions.
Chris
Don’t forget the autopsy studies showing indolent prostate cancer at below 5% incidence below 30yrs old, with numbers listed as 20% in your 50’s and over 58% in your 80’s. As someone said, testosterone is like Miracle-Gro to prostate cancer. And, when it happens to you, the incidence is 100%. Remember a peer saying low-T was the fibromyalgia of men 🙈. “ we need more studies “
Love the term "fibromyalgia of men".
Some time ago, I had a young male patient on "T" for "cosmetic reasons". He had polycythemia and a PE! Similarly, I had a female w menopause on estrogen patch with a DVT. A recent article from NEJM now finds risk associated with the estrogen patch delivery method, previously thought to be safe. https://www.nejm.org/doi/full/10.1056/NEJMra2202438.
This cosmetic approach to care is simply a means to sell more drugs which patients seem happy to eat or apply, sometimes at high cost and high risk. And, when there are negative consequences, we can sell more drugs for those diagnoses as well. Thus continuing to grow our trillion dollar healthcare industrial complex.
I think I am an interesting outlier. For past 20 years my total and free have been 80 and 12. I have supplemented for 19 years 9 about 300mg/month) I recently wen off supplementation and my numbers went back to80 and 12. Even at age 80 when I lifting big weights and keeping total T at 700 I noticed no benefit from testosterone injections. I am now 85 ( 6' 2'', 175) and off supplementation. T at 80 and 12, and I can dead lift 200lbs the same as 5 years ago. I never felt any advantage in testosterone injections. I I often wondered about Tour riders who certainly were using exogenous T, and surmised that it was for recovery not for strength.
My position is that I refer out anyone interested in “low T”. If I think someone may have hypogonadism, I will start the work up and if it’s negative, I’ll leave it at that and if it shows they might benefit from testosterone replacement, I always refer to one of my endocrine colleagues just to back me up with an expert opinion. I’m happy to continue the medicine for the patient and follow him. And I always tell the patient that you’ve always got the endocrinologist to help follow also.
I agree with the criticism of fundamental study design re: non-inferiority. That should be reserved for scenarios testing tradeoffs. So if they’re testing for non-inferiority in CV outcomes…where is the upside? Was it better for “symptoms” (soft endpoint as that is)? And this highlights the flaw of the study…since it used homeopathic doses that induced huge dropouts due to presumably perceived uselessness for symptoms among study subjects.
So at best, this study tells you when you use homeopathic doses of T in folks who don’t really even have low T, there seems to be no CV price to pay.
As I’ve also learned from SM over the years, what we need are post marketing registries to properly assess long term safety.
The study author’s surprise at this study being used for marketing bespeaks a level of naïveté that is disturbing.
We have many patient populations using or “ abusing “ these compounds. Great black market out there too. If they really care about their health, maybe they’ll agree to be subjects in such study. Just a thought.
Just one more Dr visit and paperwork.
One consequence of the cosmetic testosterone treatment is polycythemia. The patient then becomes a regular volunteer blood donor to reduce their hemoglobin. In order to donate we request they get a physician note indicating they can safely be phlebotomized.
One of the best books I have ever read about the founding of synthetic hormones, the politicization, and the cosmetic medicine trend is Bob Ostertag's Sex, Science, Self: A Social History of Estrogen, Testosterone, and Identity. https://a.co/d/03zRlUrp. From testosterone synthesis in the 1930s, the hormone was theorized as "rejuvenation" for males. Hitler wanted to corner the market to fuel his ideology. There is the terrible history of synthetic estrogen and testosterone used for so-called "gay cures" in jail or court order home treatments (Alan Turing), male rejuvenation movement in 1960s and 70s with the Harry Benjamin Society (now WPATH), and now the modern day trans movement and military screenings. As long as it continues to be marketed as a "happiness" therapy and/or "rejuvenation", I envision ongoing blockbuster sales. The polypharmacy interactions are understudied and ignored.
I think about this book quite a bit these days. It is very relevant in the context of the modern day trans movement.
Devil's advocate. There are benefits to testosterone therapy: sexual function. If informed consent presents the known upsides at the time of the trial, the latter, along with the postulated downsides (CV outcomes), the trial participant is not uninformed. Now sexual function may or may not be weak tea, but it's a value choice for men. On this premise, a non-inferiority trial could be justified.
Valid points. But non-inferiority studies always set my BS meter flashing red.
It’s my understanding that testosterone only helps with desire not with ability. That’s why we have Viagra. Can someone give me a reference disproving my ideas?
Good question. I hadn't heard that before. If true, wouldn't the testosterone merely increase sexual frustration?
Dr Feelgood and Dr Lexus have thriving medical practices without corporate compliance requirements, call, cash payments only or a direct manager with no medical background telling them what to do. What’s not to like ?
Pretty bizarre to have GYN prescribing testosterone to the spouses and when the side effects arise, they do not deal with them …. Informed consent, hmmmm. The same way we can choose not to ride a motorcycle or go in a “ shark-proof “ cage because we do not want the possibility of harm, we can just walk past the aisle with all the treatments for Lookatmeitis. Last one out turn the lights off.
So, let the poor schlub who sees these ads beware?
Don’t we, as physicians who understand what the literature does and does not say, have a responsibility to do what we can to educate patients, and advocate for responsible drug advertising? Or, better, work to get rid of it altogether?
Responsible drug advertising is an oxymoron. I always advised my patients to disregard it. Also explained that a genie doesn't leap out of a bottle of cleanser and mop the floor for you.
If the airplane mechanic is to be a passenger on that plane , can same be done with Pharma ?
The cat still has no bell on
Wow - you sound rather ‘testy’… 😜
Roid-rage ????
Your Venn diagram is something I have been preaching for years. I would label the left circle 'pharma funded trials' and the right circle 'investigator initiated trials'
I always dis count Pharma funded trials by 30%.
Maybe "usually pharma funded trials" and the right circle "usually investigator initiated trials"?