Compare that to something with no real off-ramp: testosterone replacement therapy. Once you're on TRT, you can permanently suppress your body's own testosterone production, and many men won't produce enough on their own afterward.
Bariatric surgery shows 25-65% significant regain rates depending on definition and timeframe. And regular dieting is even worse. Nobody would frame that as a safety issue. That's... just how weight loss works, not a unique GLP-1 problem.
Calling a return of symptoms (obesity) a "safety issue" is like saying insulin has "no safe off-ramp" because diabetics get hyperglycemic when they stop taking it.
Fear gets clicks, I guess.
How do I know that? The URL slug tells the tale.
> Fear gets clicks, I guess
I strongly suspect this is the reason the title was changed.
(although looking into it, it seems many oaths never actually say "first do no harm")
That's way better than any other weight loss program. Nothing else even comes close.
This does sound like "reversion to the mean", but saying it's "regaining weight" may be missing the bigger picture. More like "losing all previously gained health benefits."
It's less clear how "unsafe" those regressions in health markers are.
The testes atrophy over time when LH and FSH are suppressed. Even if LH and FSH return (which isn’t guaranteed) the testes need to be able to respond to those hormonal signals, but atrophied testes do not respond the same.
For someone with true intractable hypogonadism this hardly matters because they weren’t capable anyway. Many people prescribed TRT today don’t actually have intractable hypogonadism, though.
Body builders have some tricks to try to reverse this, but it’s not perfectly effective and even body builders know to cycle their steroids to avoid having prolonged periods of suppressed HPG axis activity. I was involved with weightlifting in my younger years but never dabbled with steroids or TRT. Everyone I know who did try testosterone or steroids thought they were doing it the safe way (HCG, PCT, limited cycle length) but became unable to produce enough endogenous testosterone by their 40s even with SERMs.
Men on TRT for years will have considerable testicular atrophy that is not totally reversible.
> The question is, why would someone with clinical hypogonadism cease TRT?
TRT is no longer limited to men with clinical hypogonadism. Men’s health clinics that advertise on social media, TV, and radio will prescribe to anyone who contacts them (and pays cash for the prescription and gear). In some surveys of patients on TRT, 1/4 of patients didn’t even have testosterone levels measured prior to initiation of TRT.
That's hugely problematic if true. They should be investigated and if found of wrongdoing, have their medical licenses revoked.
Some of the clinics were even prescribing anabolic steroids intended for terminal cancer patients.
If you want to read about something even crazier, look up the services that were started during COVID to be prescription mills for Adderall or Xanax. The relaxed COVID prescribing rules allowed telehealth providers to give schedule II prescriptions to new patients remotely, so services were created to advertise on TikTok and give prescriptions for a monthly fee. The FDA cracked down on these, though.
There’s even a famous story of a whistleblower who worked at one of these clinics and got reprimanded for not prescribing Adderall enough. There was a leaked memo where they pushed providers to prescribe Adderall over other options because their data showed the highest customer retention rate that way.
How about we go back to valuing ideas, regardless of their origins, if they deliver insight, value, or joy? I don’t care if someone writes something good or if the idea was stolen from something they read, or if a machine made it for them, unless the value proposition is their personal capacity for original prose.
AI gotchaism is becoming as least as tiring as the droll, tone deaf creations of LLMs.
> This patient expressed no gender dysphoria, but he got hormones, too. I asked the doctor what protocol he was following, but I never got a straight answer.
I don’t think it’s analogous at all to medical marijuana.
Then your sample is either very limited or very weird, because I test my testosterone, and my friends who did multiple cycles in the past (10–15+ years ago, and not huge competition level doses) are also within the normal range.
Can you share your longitudinal anecdata? I am considering going back on AAS for the QoL benefits, but would like to create a better mental model of long-term ramifications for testicular health.
It's my understanding that 40, it simply is expected that your hormones levels will be much lower (and that is not necessarily a bad thing). However my mind is failing to grasp what long-term damage TRT can do to the HPTA when not using an obscene amount of gear and on HCG.
Trying to figure out the mechanism. Perhaps receptor desensitization and epigenetic compensatory changes?
Studies of TRT patients have even shown that 1/4 of TRT patients may not have had their testosterone levels measured before being prescribed TRT: (Source https://pmc.ncbi.nlm.nih.gov/articles/PMC6406807/ ) Completely unacceptable given how cheap testosterone testing is, but its happening.
TRT clinics have also become a big business. Their business model relies on prescribing TRT to anyone and then charging them monthly or quarterly to continue receiving those prescriptions, which as the parent comment noted become physically necessary after TRT causes the testes to atrophy.
The trick the clinics are using now is “diagnosing by symptoms”. They have a long list of “symptoms of low T” and the patient is basically prompted to check off enough boxes to justify TRT. It’s the same model as the medical marijuana card businesses where you can go in and the doctor will “find” a reason to give you the prescription.
It’s a real problem when combined with social media influencers who tell people that everything is a symptom of low testosterone and TRT will fix it.
You can't really diagnose by levels, though, unless you knew what that person's previous levels were. Setting an average across a population is not really realistic - you can't say Shaq should work to the same levels as, say, Emo Phillips.
TRT is normally used due to aging, though, so you are unlikely to have your testosterone levels spontaneously recover as you get older. You do tend to need to be on it for life, in the same way that women stay on HRT.
However, if you did need to get off, bodybuilders have "post cycle therapies" to kick start production so it seems to be possible.
Exactly. Before suggesting it. my doctor had more than a year's worth of data. (I have some blood tests done quarterly; so, he added one for testosterone.) Even then, he sent the results to my urologist.
The TRT clinics are ignoring levels or even not testing at all. They’ll find an excuse to prescribe to someone even who has clinically high levels because they want the monthly recurring revenue from keeping that customer for life.
I'm not going to say TRT clinics are the best actors here, but to an actual endocrinologist, diagnosing hormone issues isn't so simple as looking at single point-in-time measurement of total testosterone.
Testosterone levels naturally vary even for a given individual - two readings at the same time of day on different days even a short period apart can be dramatically different - and that's not even taking into consideration the fact that total testosterone levels aren't the sole (or even primary) mechanism for diagnosing androgenic endocrine issues.
Now I am worried about the long term effects, but it's been so long that if I am on it for the rest of my life and it does help me, that's good enough.
I mean, bodybuilders essentially have a whole branch of alternative medicine which they have wholesale made up, so, ah, I'd be sceptical.
* not me but I see it with men in my age range
Saying that the men's vitality clinic "pushed you" into a treatment protocol is like saying that a fertility clinic pushed you into getting pregnant.
Sure, it's a common outcome, but you had an idea of what you wanted out of it before you walked in the door.
No, it isn't. “Men’s vitality” doesn’t mean “getting pumped with testosterone regardless of indications” the way “fertility” means “getting pregnant” in either literal denotation of words or the understanding of the general population.
> Sure, it's a common outcome, but you had an idea of what you wanted out of it before you walked in the door.
Yes, but in the case of fertility clinics, getting pregnant aas definitely the outcome beinf sought. Being pumped with testosterone isn’t the outcome being sought from a men’s vitality clinic, it is (even for the people who are actively thinking about it) a mechanism (and not an appropriate one for every patient) for atteempting to acheive the desired outcome.
If you go to a fertility clinic and they don't attempt to identify the source of your fertility issues and just pump you with hormones not indicated for your specific issue, that would be wrong, too.
When I Google "men's vitality clinic", the top result I see is titled "Your experts for testosterone replacement therapy...". TRT is front and center.
> Being pumped with testosterone isn’t the outcome being sought from a men’s vitality clinic, it is (even for the people who are actively thinking about it) a mechanism (and not an appropriate one for every patient) for atteempting to acheive the desired outcome.
This is such a weird distinction to try and make.
I frequently see ads for these services, and even when they're not so explicit as that one is about what they're selling, it's extremely clear what demographic they're going after and what the hook is.
Testosterone being a Schedule III substance, "men's vitality" is the way that they can legally advertise an service that prescribes AAS. It's no more of a secret that men's vitality clinics prescribe testosterone than it is that fertility clinics are prescribing estradiol. Both of these are sex hormones that induce a specific effect on the body which the patient is looking for.
Can I imagine someone walking into a men's vitality clinic and being surprised that they're getting offered testosterone? Sure, and there's also that German couple who went to a fertility clinic because they weren't having a baby, and were surprised to learn that they needed to start having sex.
Clueless people exist. That doesn't mean that it's not readily obvious to anyone who's paying attention what these clinics exist to do, and how they do it.
17.5% maintained 75+% of their weight loss. 25% maintained 50-75% of their weight loss. 23% maintained 25-50% of their weight loss. 24% maintained 0-25% of their weight loss.
I mean that's pretty good!
* 17.5% maintained 75+% of their weight loss
* 25% maintained 50-75% of their weight loss
* 23% maintained 25-50% of their weight loss
* 24% maintained 0-25% of their weight loss.
It's ironic that one of the effects of this drug seems to be reducing the impact of impulsive behaviors, reducing cravings from other drugs and alcohol and cigarette addictions.
The hat trick for someone might be to get on one of these GLP-1 regimens, wean themselves out of whatever crisis/crises they are in, end their GLP-1 regimen with a heroic mushroom trip, and physically move to a new environment, where they don't have any of the default triggers or patterns to fall back on, and everything is fresh and can be built up from scratch.
I think the medicalization of human agency is one of the great evils of our time. The implication and impact of doctors, bureaucrats, and bean counters making sweeping policy, regulation, and legal decisions on behalf of the peasants and peons who just don't know better. The casual dismissal of fundamental basic principles is outrageous, especially in service to the politics and idiotic tribalism.
Our complex modern society has a daily buy-in.
Some people were born and/or raised for it and the cost for them is nothing.
Others need to soothe the pain of shoehorning themselves into it by chain-smoking while working a jackhammer or shoveling cereal into their face while programming.
Yes, these behaviors are technically within their control, but are you really going to suggest that we can solve the underlying problem(s)?
Obese people typically do not try to become obese. Most obese people have tried to lose weight and find that they lack the tools and skills needed to succeed, and many of the ones that do succeed only do so temporarily.
Why is that?
It's a question with no simple answer, and no single answer.
Evolutionary biological drive to acquire calories.
Psychological dependency on food.
Inability to differentiate satisfaction from "being stuffed", likely due to environmental factors like negative education as a child or poverty mindset in parents.
The perceived difficulty of altering diets for longevity.
Self-hate.
I'm sure there are scores more reasons for this, and no single concept or mindset is large enough to fully accurately embody the breadth of reasons why people remain obese in a world that actively disincentivizes obesity in every measure of life satisfaction.
People outside of that fail to empathize with the plight of obese people. They blame them for living a life that is generally unintentionally thrust upon them.
They do not see obesity as a disease but as a choice and then mock or dismiss them for being obese, even though by all metrics it is a disease.
People tell obese people to diet like they tell alcoholics to quit drinking or drug addicts to quit using drugs and honestly believe their words have contributed value to humanity, but unlike drug addicts or alcohol, there is no cold turkey for obesity other than death.
People must eat. That includes obese people.
If you can figure out a way for a crackhead to smoke crack 3 times a day until they feel satisfied with how much crack they have smoked without remaining a crackhead, then you might be able to figure out how to get an obese person to eat 3 meals a day until they feel satisfied without remaining obese.
TRT cessation does not inherently cause men to have suppressed hormone levels after. With precautions and extra steps like HCG to maintain leydig cell/testicular function, preventing atrophy, one may safeguard against that risk.
Coming off TRT, yes you will have lower levels as your HPTA has been suppressed by exogenous hormones. One may speed up this recovery using "PCT" (post cycle therapy), which involves taking a SERM (selective estrogen receptor modulator, e.g. enclomiphene) to resensitize and restart your HPTA. However this is not always necessary, and if one takes a look at the HARLEM study, most users return to their baseline levels within a year of going cold turkey.
In the cases of true permanently lowered levels of hormones, I believe the two most common reasons are: using other AAS besides testosterone (1) and lifestyle or health factors that correlate with the need to be on TRT (2).
With 1, this can be seen in users of decadurabolin (deca), which notoriously has hormone receptor active metabolites that last around for atleast a year, continuously suppressing the system. Or trenbolone (tren/cattle bulking hormone) which is inherently neurally and endocrinically otherwise toxic.
With 2, you hop on TRT because there is some reason your hormones are not at healthy levels. Whatever the reason is, it is still there, and once you've stopped bandaiding the issue its effects resurface.
---
I have also used many GLP-1s (semaglutide, tirzepatide, and retatrutide). No there is no off-ramp, but the only effects I've noticed are a return to my baseline of appetite, and neurological state.
N.B. GLP-1s are good for impulse and behavioral disorders like ADHD, which it did help. However, I have decided to not take it due to the negative effects on personality and reward seeking behavior.
They are neuro-active in the brain, and their effects I've decided are not worth it.
The obesity likely is the main culprit-- if I had to guess. Fat stores act as sites for testosterone to be aromatized to estrogen -- so if your E2 is elevated that would be a marker.
1. There is an off ramp for TRTs but some people have, “true permanently lowered levels of hormones.”
2. For GLP-1s, “there is no off-ramp, but the only effects I’ve noticed are a return to my baseline.”
To clarify my original post, I consider the ability to return to baseline to mean there is an off-ramp and permanently impacted to mean there is no off-ramp.
2. Yes
There is no "off ramp" for GLP-1s in my experience, because the off ramp is so insignificant to not worth a mention. You just don't take another dose after a week has passed from the previous one, and you're back to baseline. Same way there is no off ramp on taking aspirin -- just don't take it.
As someone diagnosed with ADHD, I wasn't aware of this (although I haven't had reason to research GLP-1's). Is this just your N=1 or an effect proven in studies?
The struggle doesn't stop when you stop losing. My personal experience was that it takes about 2 years for the new 'normal' to kick in. (I lost 60lbs when I was in my early 20s and kept it off until today. The 'after' period was as taxing as the 'losing' period, but in a different way)
At that point only can you 'relax' a bit around your body's cravings for calories.
This has already been studied extensively:
https://pmc.ncbi.nlm.nih.gov/articles/PMC5764193/
It's not the worst thing in the world to be on a medication for a couple years rather than a few months, but long-term study of this class of drugs is certainly warranted and necessary.
So weight loss was actually maintained for most people -- the hard part is finding a healthy daily lifestyle which can maintain the drastic effects of GLP1s.
This information isn't new -- weight regain has been studied before and I've written about it before:
https://glp1.guide/content/do-people-regain-all-the-weight-l...
The missing piece to this article is just how bad the alternative is -- never having the cardiovascular and metabolic benefits is clearly not the best strategy (and if simply changing patterns was so easy, people would have done it already).
GLP1s don't work for everyone but they're pretty close to miraculous in effect given the balance of positive and negative side effects. Making GLP1s cheaper & more tolerable then figuring out how to actually deal with the complex web of how to keep the weight off sustainably for most people seems like the right way forward here, not avoiding potentially life-saving medication because you may not be able to get off of it as fast as you want (if you can afford it).
BTW, there is already generic Liraglutide, and legal workarounds for getting compounded Semaglutide that already mean no one pays the $1000 that was in the zeitgeist a while ago. Even Lilly Direct and similar outfits from Novo sell for $500/month, with the $150/month pricing coming soon[0].
[0]: https://glp1guide.substack.com/p/negotiations-are-underway-f...
> So weight loss was actually maintained for most people
That's the key. They may have come up from their lowest, but they still better off.
There’s also the perverse incentives wrt broader society. Enabling the average person to control their physical health is orders of magnitude better for society and orders of magnitude less profitable than the current trends.
Maybe a setup where glp drugs are nationalized and only used to further understand why we have an obesity epidemic and eventually finance changes to combat it? Ideally the drug makers would do this without requiring government intervention, but I doubt they will.
* Almost everyone has access to a wide variety of delicious food, which we on average enjoy eating more of than is required to maintain a healthy weight.
* We don't want the government to forcibly restrict people's food access.
* Research consistently shows that voluntary portion control works occasionally in the short term and not at all in the long term.
* Many people have proposed specific ingredients or nutrient classes that can be adjusted in a person's diet to resolve obesity, but none to date have checked out.
In principle, I suppose, there could be some crazy diet hack we don't yet know about. But why should we expect that to be the case? To be honest, I think a lot of the existing discourse on this topic was just wishful thinking, because before GLP-1s the bottom line was not "some people need a pharmaceutical intervention" but "some people are just gonna be obese and there's nothing we can do to help them".
Japan does not have an obesity epidemic. The US has an extreme obesity epidemic. There does not seem to be any good genetical explanation, there might be cultural based behavioral explanations, but Japanese communities in the US are also more obese than ones in Japan (although less obese than the general US population).
So it is clearly entirely possible for a society to have plenty of easily accessible delicious food, with no major government restrictions in place, and not have an obesity crisis. And there seems to be some particularly bad environmental and/or cultural factor in the US driving the abnormally bad obesity epidemic there, and no intervention before GLP-1 has managed to reverse the trend (not that there have been many). There are a lot of theories about this topic, but no clear scientific consensus beyond "all very sweet things are probably maybe bad".
PS: I am aware that Japans "fat-tax" exists and is technically a form governement restriction, but I would assume that it plays a relatively minor role overall.
i think it’s due to the increasing prevalence of dairy
Yes, you can loose weight without it, I did, I'm even in the healthy range now.
No, you don't have to, if you need medicine help, take it.
When I lost weight, I had my first real job that I liked so much, it didn't felt like one, 11 weeks of vacation per year, a nice enough apartment I couldn't be evicted of, great emotional support and advices and support from a doctor.
The only thing draining my willpower every day was the calorie restriction, and nothing else to worry about.
If you're in a similar spot I was, maybe trying a diet without glp-1 is better since we don't have any long term study on it yet, but if you're not: obesity will destroy your body more than any long term side effects can. Please take them if you can afford it.
The only thing I earned beside uncomfort and pain when I lost weight without drugs are internet points on hacker news, and the ability to say 'i did it' (also glp-1 didn't exist, so less long term health issues from obesity). Honestly if I had to redo it, I would take the drug despite a similar situation. Weight loss is hard, and not being able to do it without help is not an indictment on you or your character, but on your situation.
So there appears to be an off-ramp, we just don't know what it is.
calories_in < calories_out seems to be a pretty good formula.
Calorie restriction works up to a certain point, and weirdly the benefits aren't linear, and almost flat for visceral fat(i.e: if you're using 2.6 kcal a day and eating 2.4 kcal, you will loose roughly the same amount of visceral fat than if you only ate 1.8kcal, and slightly more 'external' fat (that one you shouldn't care much if you're only interested in health)).
Calorie expenditure works linearly though, but it's hard to out-exercise your diet, and exercise while obese can be dangerous (my ankles still have to be reinforced despite me being under 24 BMI)
These symptoms will be familiar for anyone who has lost weight dieting and then returned to eating junk food.
You don't say ;-) I lost 50 lbs and have kept it off for the past year while maintaining great BP. But I'm under no illusions GLP-1 medications don't have dangers and cause problems for many. It should be handled on an individual basis like any serious medication.
That said, is someone losing a lot of weight then gaining half of it back worse than them just staying where they were? I don't know the answer to that one.
The trick, of course, is to repeat the process as you asymptotically approach your goal.
Zeno's paradox of mass.
>stop taking weight loss drug
>regain weight
>there is no safe off-ramp for GLP-1
I guess taking weight loss drugs don't really teach healthy eating habits.
The fact it spun of of research on Gila monsters is still crazy to me.
Then, I stopped working out, and gained 15lbs. Exercise: no safe off-ramp for some.
I suspect the manufacturers view this as a feature not a bug. :-) More seriously, I find the article's conclusions to be pretty much what I'd expect. Most medicines aren't permanent cures and obesity results from a variety of factors with lifestyle and diet being major elements.
I was seriously obese for decades and about 9 years ago, hovering on the edge of becoming diabetic and other serious obesity-related health issues (high BP, IBS/GERDS, chronic apnea, etc), I decided I had to do something. GLP-1's weren't available then but none of the other typical approaches, including medically supervised diets worked more than a few months. Doing my own research, I discovered keto (this was before keto became big) and decided to try it. It was hard at first but also remarkably effective. I lost over 100 pounds in 8 months, becoming fit and seeing abs for the first time in my life. As I lost the weight, all the other health issues resolved too. But I knew if I returned to my previous diet and habits, I'd eventually grow obese again. Many people will take GLP-1s, lose weight but then stop and regain the weight because they didn't change their underlying behavior. Just like many people do with dieting, keto or any other intervention. But any intervention that works can be an invaluable for the few willing to understand, use it as a tool and do the work.
I stayed strict keto for 5 years. Long enough to train my body and mind how to be fit and healthy as normal (not a temporary diet). Then I started a rigorous process of gradually transitioning away from strict keto over a period of two years and that's also worked. I still eat a pretty low carb diet averaging less than 100g or less a day and will for life because there is no "Eat whatever junk you want and stay fit", at least for my metabolism. Reading that article, the criticisms of GLP-1s would also apply to keto or just "eat less, move more". If you stop the intervention, the system returns to state. However, for me keto helped me break an insidious pattern driven by habit, metabolism and blood sugar levels. I was then able to adopt new patterns. I suspect GLP-1s could help others in a similar way. Obviously, there is no magic drug that "cures" obesity by making you immune to bad habits and the physics of calories in/calories out.
My wife is back devouring cookies after being on mounjaro for 4 months. Thankfully she lost most weight all by herself so wasn’t totally reliant on the medication. But it’s crazy how noticeable the difference of one’s eating habits when on and off it.
When the treatment is ceased, the benefits go away.
I think that it is quite unsurprising that without the drug a large amount of people revert to their previous behavior and with that will revert to their previous weight.
I think the intuition many people have--which I am not at all defending as correct, but it certainly isn't so obviously wrong that we should scoff at someone for thinking it works this way--is more like "if my weight was stable before I did this intervention, I just need to lose the weight and then my weight will once again be stable after it"; in this mental model, one would assume you only need lots of willpower to lose weight: after, you only will need as much willpower as you already know you have to not gain it back, as it isn't as if you are gaining weight currently.
There's of course a risk that when they stop the drugs that hunger will drive them to re-establish those habits, but now that they have new habits that fight that hunger they are in a much better position to resist it than they were when they'd initially established their eating patterns.
That's literally the implication of these findings.
But one can always hope for a miracle drug that you can take for a bit, then stop, and have its effects last. Now we know that Ozempic is not that drug.