TRT dosing help

[Goddar]

Many guys here pushing higher doses have never even tried doses that are physiological, so they have no idea if these doses would be better or worse than where they are now. My question to you is, have you tried doses in the 50-80 mg TC/week range? These lower doses should be split into at least two injections per week, or else use Xyosted—to avoid overly low troughs.

There are risks in dosing at 140 mg TC/week indefinitely. This is much more testosterone than any healthy male would make naturally. Even if lipids and HCT are ok for now, your crashed SHBG is telling you that this much androgen exposure is highly unnatural. Animal and human data suggest that cumulative cardiotoxicity is possible.

If you had no other options for feeling good then perhaps you could justify the uncertain risks in high doses. But it's important to first spend substantial time with serum levels closer to what you'd have naturally in good health. As @madman suggests, until your SHBG recovers you must use free testosterone to monitor your status; total testosterone will be misleadingly low.

Can you post some studies of it please ?

 

[Cataceous]

Can you post some studies of it please ?

I'm in part relying on research done by @readalot, in his threads titled "What is TRT and what is not TRT?". The one on ExcelMale seems to be missing. The one on T-Nation says it has moved, and I don't have an account there to see if it really is still accessible to members.

In any case, some of this relies on studies of animals given larger doses, who develop problems in shorter time frames. But there is still evidence that cumulative exposure contributes to the effects. While we can't say definitively that a particular individual taking 140 mg TC/week for 20 years is going to damage his heart, there are grounds to believe that in a large group facing such long-term exposure the risk signal would achieve statistical significance.

I asked the grok AI to come up with some of the research:

Animal studies support time- and dose-dependent cardiac toxicity from supra-physiological testosterone, while human data (especially from anabolic-androgenic steroid/AAS use as a high-exposure analog, plus some TRT observations) indicate that cumulative/integrated exposure can contribute to cardiovascular risks, though medium-term TRT at physiological targets appears non-inferior for major adverse cardiac events (MACE) in trials.

Animal (rodent) evidence on high-dose and duration/cumulative effects

These studies typically use doses that elevate circulating testosterone well above physiological ranges (often in the range of tens of mg/kg weekly equivalents) and show initial adaptive changes that transition to maladaptive pathology with prolonged exposure:

• Pirompol et al. (2016) administered testosterone (5–20 mg/kg) for 4, 8, or 12 weeks in rats. Short-term (4 weeks) exposure produced physiological concentric hypertrophy with maintained or improved contractile activation and α-MHC upregulation. Longer exposure (8–12 weeks) shifted to pathological hypertrophy with myocardial collagen deposition, suppressed myofilament activation, and (at 12 weeks) eccentric remodeling plus reduced ERK1/2 and mTOR signaling. The authors concluded that the pathological outcome depended more on duration of exposure than on the specific supra-physiological dose.
• Wadthaisong et al. (2019) treated rats with high-dose testosterone (10 mg/kg three times weekly) for 4 or 12 weeks. Four weeks increased ventricular wall thickness, ejection fraction, and myocyte contractile parameters (including calcium dynamics and myofilament force). Twelve weeks reversed this: depressed pump function, myocyte contractility, and myofilament function, consistent with maladaptive remodeling (building on their prior work showing fibrosis).
• Related work (e.g., high-dose testosterone enanthate or propionate models) has demonstrated myocardial hypertrophy, ultrastructural damage, fibrosis, and caspase-3–positive apoptosis, supporting direct cardiotoxic effects at elevated androgen exposure.

These findings align with the idea that higher doses accelerate toxicity on shorter timescales, while more modest supra-physiological exposure over longer periods can produce cumulative integrated effects via sustained androgen receptor activation, oxidative stress, hypertrophy signaling, and remodeling.

Human data relevant to cumulative/long-term exposure and cardiotoxicity concerns

Direct long-term randomized data specifically on high-dose injectable TRT (e.g., sustained 140 mg/week testosterone cypionate, which often produces supra-physiological peaks/troughs and suppressed SHBG relative to natural production of roughly 3–10 mg/day) are limited. Evidence draws from AAS cohorts (higher and more sustained exposure), observational TRT data, and medium-term RCTs:

• Baggish et al. (2017) studied experienced weightlifters with ≥2 years cumulative lifetime AAS use vs. non-users. AAS users had higher coronary artery plaque volume; lifetime duration of AAS use was strongly associated with atherosclerotic burden (roughly 0.60 SD-unit increase in plaque-volume rank per 10-year increase in cumulative duration, adjusted). Current users also showed reduced LV systolic/diastolic function. This supports a cumulative-exposure relationship for coronary pathology.
• Subsequent AAS studies reinforce this: cumulative lifetime duration correlates with coronary non-calcified plaques, positive calcium scores (stronger associations beyond ~3–5+ years), left-ventricular hypertrophy, reduced ejection fraction, and biventricular dysfunction. Effects can persist in former users, though some structural/functional changes show partial reversibility after cessation. Mechanisms discussed include oxidative stress, apoptosis, adverse lipids, prothrombotic shifts, hypertension, and direct myocardial effects.
• For TRT itself, the TRAVERSE trial (NEJM 2023; gel titrated toward mid-normal levels in hypogonadal men at high CV risk; mean treatment ~22 months, follow-up ~33 months) found non-inferiority for MACE vs. placebo. Secondary signals included numerically higher atrial fibrillation, acute kidney injury, and pulmonary embolism. Many reviews and meta-analyses of shorter-to-medium-term RCTs report no clear MACE increase at physiological replacement doses, but consistently note the paucity of long-term (multi-year to decade) data.
• Observational/real-world data are mixed and confounded. Some long-term exposure analyses report higher MACE risk with prolonged testosterone therapy; off-label use (without clear hypogonadism evidence) has been linked to higher long-term CV event and mortality rates vs. use in the setting of hypogonadism. Pharmacovigilance and older meta-analyses have flagged signals for MI/cardiomyopathy in certain contexts. Low SHBG (common with higher androgen exposure) has been associated in cohort data with higher MI incidence in some analyses, though overall relationships are complex and not uniformly causal.

Caveats and context: 140 mg/week cypionate exceeds average natural production and can suppress SHBG while producing fluctuating supra-physiological levels depending on injection frequency and individual pharmacokinetics—conditions closer to the animal high-dose models and AAS cohorts than to tightly controlled physiological gel replacement in TRAVERSE. Individual susceptibility (pre-existing CV risk, hematocrit response, lipids, genetics) matters. RCTs reassure on medium-term MACE at physiological targets in indicated patients, but do not fully address indefinite high-end dosing or very long cumulative exposure. Animal duration-dependent transitions from adaptive to pathological hypertrophy, plus human AAS cumulative plaque/cardiomyopathy associations, provide a mechanistic and observational basis for caution regarding long-term elevated androgen exposure.These references (especially the Pirompol/Wadthaisong rodent series on time-dependent pathology and Baggish on cumulative AAS atherosclerosis) are among the more directly relevant supporting the concerns you described. Clinical decisions should involve monitoring (HCT, lipids, blood pressure, symptoms, imaging if indicated) and individualized risk-benefit assessment with a physician.

 

[Goddar]

I'm in part relying on research done by @readalot, in his threads titled "What is TRT and what is not TRT?". The one on ExcelMale seems to be missing. The one on T-Nation says it has moved, and I don't have an account there to see if it really is still accessible to members.

In any case, some of this relies on studies of animals given larger doses, who develop problems in shorter time frames. But there is still evidence that cumulative exposure contributes to the effects. While we can't say definitively that a particular individual taking 140 mg TC/week for 20 years is going to damage his heart, there are grounds to believe that in a large group facing such long-term exposure the risk signal would achieve statistical significance.

I asked the grok AI to come up with some of the research:

Animal studies support time- and dose-dependent cardiac toxicity from supra-physiological testosterone, while human data (especially from anabolic-androgenic steroid/AAS use as a high-exposure analog, plus some TRT observations) indicate that cumulative/integrated exposure can contribute to cardiovascular risks, though medium-term TRT at physiological targets appears non-inferior for major adverse cardiac events (MACE) in trials.

Animal (rodent) evidence on high-dose and duration/cumulative effects

These studies typically use doses that elevate circulating testosterone well above physiological ranges (often in the range of tens of mg/kg weekly equivalents) and show initial adaptive changes that transition to maladaptive pathology with prolonged exposure:

• Pirompol et al. (2016) administered testosterone (5–20 mg/kg) for 4, 8, or 12 weeks in rats. Short-term (4 weeks) exposure produced physiological concentric hypertrophy with maintained or improved contractile activation and α-MHC upregulation. Longer exposure (8–12 weeks) shifted to pathological hypertrophy with myocardial collagen deposition, suppressed myofilament activation, and (at 12 weeks) eccentric remodeling plus reduced ERK1/2 and mTOR signaling. The authors concluded that the pathological outcome depended more on duration of exposure than on the specific supra-physiological dose.
• Wadthaisong et al. (2019) treated rats with high-dose testosterone (10 mg/kg three times weekly) for 4 or 12 weeks. Four weeks increased ventricular wall thickness, ejection fraction, and myocyte contractile parameters (including calcium dynamics and myofilament force). Twelve weeks reversed this: depressed pump function, myocyte contractility, and myofilament function, consistent with maladaptive remodeling (building on their prior work showing fibrosis).
• Related work (e.g., high-dose testosterone enanthate or propionate models) has demonstrated myocardial hypertrophy, ultrastructural damage, fibrosis, and caspase-3–positive apoptosis, supporting direct cardiotoxic effects at elevated androgen exposure.

These findings align with the idea that higher doses accelerate toxicity on shorter timescales, while more modest supra-physiological exposure over longer periods can produce cumulative integrated effects via sustained androgen receptor activation, oxidative stress, hypertrophy signaling, and remodeling.

Human data relevant to cumulative/long-term exposure and cardiotoxicity concerns

Direct long-term randomized data specifically on high-dose injectable TRT (e.g., sustained 140 mg/week testosterone cypionate, which often produces supra-physiological peaks/troughs and suppressed SHBG relative to natural production of roughly 3–10 mg/day) are limited. Evidence draws from AAS cohorts (higher and more sustained exposure), observational TRT data, and medium-term RCTs:

• Baggish et al. (2017) studied experienced weightlifters with ≥2 years cumulative lifetime AAS use vs. non-users. AAS users had higher coronary artery plaque volume; lifetime duration of AAS use was strongly associated with atherosclerotic burden (roughly 0.60 SD-unit increase in plaque-volume rank per 10-year increase in cumulative duration, adjusted). Current users also showed reduced LV systolic/diastolic function. This supports a cumulative-exposure relationship for coronary pathology.
• Subsequent AAS studies reinforce this: cumulative lifetime duration correlates with coronary non-calcified plaques, positive calcium scores (stronger associations beyond ~3–5+ years), left-ventricular hypertrophy, reduced ejection fraction, and biventricular dysfunction. Effects can persist in former users, though some structural/functional changes show partial reversibility after cessation. Mechanisms discussed include oxidative stress, apoptosis, adverse lipids, prothrombotic shifts, hypertension, and direct myocardial effects.
• For TRT itself, the TRAVERSE trial (NEJM 2023; gel titrated toward mid-normal levels in hypogonadal men at high CV risk; mean treatment ~22 months, follow-up ~33 months) found non-inferiority for MACE vs. placebo. Secondary signals included numerically higher atrial fibrillation, acute kidney injury, and pulmonary embolism. Many reviews and meta-analyses of shorter-to-medium-term RCTs report no clear MACE increase at physiological replacement doses, but consistently note the paucity of long-term (multi-year to decade) data.
• Observational/real-world data are mixed and confounded. Some long-term exposure analyses report higher MACE risk with prolonged testosterone therapy; off-label use (without clear hypogonadism evidence) has been linked to higher long-term CV event and mortality rates vs. use in the setting of hypogonadism. Pharmacovigilance and older meta-analyses have flagged signals for MI/cardiomyopathy in certain contexts. Low SHBG (common with higher androgen exposure) has been associated in cohort data with higher MI incidence in some analyses, though overall relationships are complex and not uniformly causal.

Caveats and context: 140 mg/week cypionate exceeds average natural production and can suppress SHBG while producing fluctuating supra-physiological levels depending on injection frequency and individual pharmacokinetics—conditions closer to the animal high-dose models and AAS cohorts than to tightly controlled physiological gel replacement in TRAVERSE. Individual susceptibility (pre-existing CV risk, hematocrit response, lipids, genetics) matters. RCTs reassure on medium-term MACE at physiological targets in indicated patients, but do not fully address indefinite high-end dosing or very long cumulative exposure. Animal duration-dependent transitions from adaptive to pathological hypertrophy, plus human AAS cumulative plaque/cardiomyopathy associations, provide a mechanistic and observational basis for caution regarding long-term elevated androgen exposure.These references (especially the Pirompol/Wadthaisong rodent series on time-dependent pathology and Baggish on cumulative AAS atherosclerosis) are among the more directly relevant supporting the concerns you described. Clinical decisions should involve monitoring (HCT, lipids, blood pressure, symptoms, imaging if indicated) and individualized risk-benefit assessment with a physician.

Thanks for reply!

I think you are mixing different things. The doses in rats are much higher than 140mg in mens and others studies are related to persons who use aas and probably other compounds.
If your hct, lipids, bp and other parameters are ok, I don’t know why stand in 1000-1200 of total test could be q problem, specially if you use microdose avoiding peaks

 

[Phil Goodman]

Thanks for reply!

I think you are mixing different things. The doses in rats are much higher than 140mg in mens and others studies are related to persons who use aas and probably other compounds.
If your hct, lipids, bp and other parameters are ok, I don’t know why stand in 1000-1200 of total test could be q problem, specially if you use microdose avoiding peaks

The studies don’t exist, or else he would’ve shared them. His argument comes down to “it’s more than a person would make naturally”. That’s basically the extent of it Is he right?? Maybe, but one would think that the data would support it at this point if that were the case. No need to rely on rodent studies involving crazy high doses and steroids studies in humans.

Also, he is basing the “natural limit” on a poisoned population. We know that levels of men in the 1940’s, 1950’s, and 1960’s were significantly higher than what we see today. This is due in large part to the unending bombardment of harmful chemicals we experience in the form of endocrine disrupting chemicals and other toxins. So saying a person in 2026 wouldn’t make that much testosterone naturally is technically accurate, but that doesn’t mean the “natural” state of males today is what would provide the best outcome. Pushing levels up higher can quite possibly result in better outcomes (and studies support this claim). That doesn’t mean start blasting and cruising, but it does mean that it’s quite possible more benefits can be seen at levels that a male today wouldn’t “naturally” produce. With the huge caveat that all other health markers indicate good health, which you already pointed out.

 

[Cataceous]

Thanks for reply!

I think you are mixing different things. The doses in rats are much higher than 140mg in mens and others studies are related to persons who use aas and probably other compounds.
If your hct, lipids, bp and other parameters are ok, I don’t know why stand in 1000-1200 of total test could be q problem, specially if you use microdose avoiding peaks

Hardly different things. Just indirect evidence, since it would be considered unethical to expose individuals to the risks of long-term supraphysiological dosing for research purposes. Admittedly there are plenty of voluntary guinea pigs out there, and I expect that eventually observational data will also point to the heightened risk of excessive cumulative androgen exposure.

There are other parameters that need to be "ok" before you can express confidence that TT of 1,000-1,200 ng/dL is safe for a particular individual. We don't even know all of the parameters. The burden of proof that having double one's healthy natural level is safe for the long-term is strictly on those making the claim. Furthermore, there is zero evidence that having supraphysiological testosterone is better for overall health. On the contrary, side effects are commonplace with higher levels.

The studies don’t exist, or else he would’ve shared them. His argument comes down to “it’s more than a person would make naturally”.

Since you can't refute it you simply ignore the evidence that points to cumulative exposure also being a factor. The research is still against you with respect to unnaturally high dosing. Correlations are almost uniformly towards greater mortality risks.

...Also, he is basing the “natural limit” on a poisoned population. We know that levels of men in the 1940’s, 1950’s, and 1960’s were significantly higher than what we see today.

I challenge you to show that comparable reference ranges have changed significantly due to populational declines. Much of the decline in testosterone is due to a less healthy population that would still be excluded from healthy reference ranges. Additionally, the gradual switch to LC-MS/MS testing from immunoassays is itself lowering reference ranges due to cross reactivity of immunoassays. "The Endocrine Society’s 2018 guideline used a lower limit of ~264 ng/dL (9.2 nmol/L) based on CDC-standardized assays in healthy non-obese young men—explicitly tied to improved assay accuracy/standardization rather than population decline."

 

[Phil Goodman]

Been having issues with the website throwing errors when I try to respond, so l try to keep this simplified to see if I have better luck.

Hardly different things. Just indirect evidence, since it would be considered unethical to expose individuals to the risks of long-term supraphysiological dosing for research purposes. Admittedly there are plenty of voluntary guinea pigs out there, and I expect that eventually observational data will also point to the heightened risk of excessive cumulative androgen exposure.

Just wanting to get clarification here.

Are you saying there is hardly any difference between a guy taking 140 mg/week and a guy running extremely high doses? In the first study you provided which used 3 different doses, the rats saw levels 7-17 times higher than the natural control group. Are you saying there is hardly any difference between using 140 mg/week and driving your levels up to 17 times higher than they’d be naturally?Are you suggesting there is hardly any difference between using 140 mg/week and abusing steroids?

There are other parameters that need to be "ok" before you can express confidence that TT of 1,000-1,200 ng/dL is safe for a particular individual. We don't even know all of the parameters. The burden of proof that having double one's healthy natural level is safe for the long-term is strictly on those making the claim. Furthermore, there is zero evidence that having supraphysiological testosterone is better for overall health. On the contrary, side effects are commonplace with higher levels.

What would you consider “long term”?

The burden of proof is on you as well. And when asked for evidence you just asked AI to give you something…. And it produced rodent studies using absurd doses and articles on steroid abuse. Neither of which is even remotely relevant to your claim.

Since you can't refute it you simply ignore the evidence that points to cumulative exposure also being a factor. The research is still against you with respect to unnaturally high dosing. Correlations are almost uniformly towards greater mortality risks.

I’m not ignoring it. I agree with the evidence that driving levels to 10x + natural levels is harmful. I agree that abusing steroids is harmful. But again, that isn’t really relevant to the current discussion.

I challenge you to show that comparable reference ranges have changed significantly due to populational declines. Much of the decline in testosterone is due to a less healthy population that would still be excluded from healthy reference ranges. Additionally, the gradual switch to LC-MS/MS testing from immunoassays is itself lowering reference ranges due to cross reactivity of immunoassays. "The Endocrine Society’s 2018 guideline used a lower limit of ~264 ng/dL (9.2 nmol/L) based on CDC-standardized assays in healthy non-obese young men—explicitly tied to improved assay accuracy/standardization rather than population decline."

I didn’t say ranges, I said levels. And levels have been declining for decades. The general consensus is that we’ve averaged around a 1% drop every year for decades. I’m surprised you are unaware of this. And it isn’t just attributed to obesity or other factors. Endocrine disrupting chemicals along with other environmental factors likely play a huge role, as well as other factors beyond just the general health of the subject. If you are basing your value for what a healthy male “produces naturally” you are using a poisoned subject that produces substantially less than his peers 50 years ago.

 

[Goddar]

Been having issues with the website throwing errors when I try to respond, so l try to keep this simplified to see if I have better luck.




Just wanting to get clarification here.

Are you saying there is hardly any difference between a guy taking 140 mg/week and a guy running absurdly high doses? Are you saying there is hardly and difference between using 140 mg/week and abusing steroids?


What would you consider “long term”?

The burden of proof is on you as well. And when asked for evidence you just asked AI to give you something produced rodent studies using absurd doses and articles on steroid abuse. Neither of which is even remotely relevant to your claim.


I’m not ignoring it. I agree with the evidence that using hundreds of mgs of testosterone per week is harmful. I agree that abusing steroids is harmful. But again, that isn’t really relevant to the current discussion.

I didn’t say ranges, I said levels. And levels have been declining for decades. The general consensus is that we’ve averaged around a 1% drop every year for decades. I’m surprised you are unaware of this. And it isn’t just attributed
to obesity or other factors. Endocrine disrupting chemicals along with other environmental factors likely play a huge role, as well as other factors beyond just the general health of the subject. If you are basing your value for what a healthy male “produces naturally” you are using a poisoned subject that produces substantially less than his peers 50 years ago.

I agree with you, levels that 25 years ago have considered as normal ranges now are out of it. Of course blasting steroids is harmful. But i don’t understand why being in the top (1000-1200 ) can harm you, specially when everything is under control ( heart test, bp, lipids, etc)

 

[Cataceous]

Are you saying there is hardly any difference between a guy taking 140 mg/week and a guy running extremely high doses? In the first study you provided which used 3 different doses, the rats saw levels 7-17 times higher than the natural control group. Are you saying there is hardly any difference between using 140 mg/week and driving your levels up to 17 times higher than they’d be naturally?Are you suggesting there is hardly any difference between using 140 mg/week and abusing steroids?

This regards integrated exposure, essentially the product of the doses and time periods involved. That is, with respect to certain risks, taking a large dose for a period may in some ways be comparable to taking a smaller dose for a much longer period. The exact relationships and factors in individual susceptibility are not elucidated yet. However, the animal research points to this being a real phenomenon.

For illustration only, suppose that for a particular individual it is safe to take 70 mg of TC indefinitely. If a particular risk happened to increase linearly with integrated exposure above the safe dose rate then we could find the equivalent to some relatively acute abuse. Suppose the acute abuse is 500 mg TC/week for one year. How long would it take at 140 mg/week to attain the same risk? Answer: (500 - 70 mg) / (140 - 70 mg) * 1 year = 6.1 years

The actual relationships are likely to be much more complicated, but the point is that the general pattern appears to exist.

What would you consider “long term”?

The burden of proof is on you as well. And when asked for evidence you just asked AI to give you something…. And it produced rodent studies using absurd doses and articles on steroid abuse. Neither of which is even remotely relevant to your claim.

Read it again if you really think it's not relevant: "Short-term (4 weeks) exposure produced physiological concentric hypertrophy with maintained or improved contractile activation and α-MHC upregulation. Longer exposure (8–12 weeks) shifted to pathological hypertrophy with myocardial collagen deposition, suppressed myofilament activation, and (at 12 weeks) eccentric remodeling plus reduced ERK1/2 and mTOR signaling. The authors concluded that the pathological outcome depended more on duration of exposure than on the specific supra-physiological dose."

I didn’t say ranges, I said levels. And levels have been declining for decades. The general consensus is that we’ve averaged around a 1% drop every year for decades. I’m surprised you are unaware of this. And it isn’t just attributed to obesity or other factors. Endocrine disrupting chemicals along with other environmental factors likely play a huge role, as well as other factors beyond just the general health of the subject. If you are basing your value for what a healthy male “produces naturally” you are using a poisoned subject that produces substantially less than his peers 50 years ago.

I acknowledged the drop in levels, which is linked in part to poorer health. The EDC/environmental link is still somewhat speculative. The general decline doesn't tell us about individuals. That's where the reference ranges come into play. It's a common forum assertion that this declining production is influencing reference ranges. That is what has not been demonstrated, and remains a further rationalization for inflated dosing.

On the integrated exposure topic, here's a more nuanced statement from ChatGPT:

What the literature supports better is a graded, probably nonlinear cumulative-exposure model. In other words, as androgen exposure rises above the physiologic range, risk likely increases through several pathways at once — LV hypertrophy/remodeling, fibrosis, BP, HDL/LDL changes, thrombosis/viscosity, endothelial dysfunction, and arrhythmogenic effects — and duration matters. Human data from long-term AAS users show that greater cumulative lifetime exposure is associated with more coronary plaque burden, and newer data also link cumulative lifetime exposure to worse LV/RV strain. That argues against a pure “only very high doses matter” threshold model.​

​

At the same time, the data do not let you say that 140 mg/week of testosterone cypionate carries a risk that can be quantitatively “integrated” into the equivalent of a shorter AAS cycle. Those studies are mostly in people with much more extreme exposures, stacking, cycling, and other confounders. So the defensible claim is directional, not quantitative: persistent exposure above physiologic androgen levels may plausibly add risk over time, especially in susceptible people, but we cannot map that risk with a simple mg × years formula.​

 

[Phil Goodman]

This regards integrated exposure, essentially the product of the doses and time periods involved. That is, with respect to certain risks, taking a large dose for a period may in some ways be comparable to taking a smaller dose for a much longer period. The exact relationships and factors in individual susceptibility are not elucidated yet. However, the animal research points to this being a real phenomenon.

For illustration only, suppose that for a particular individual it is safe to take 70 mg of TC indefinitely. If a particular risk happened to increase linearly with integrated exposure above the safe dose rate then we could find the equivalent to some relatively acute abuse. Suppose the acute abuse is 500 mg TC/week for one year. How long would it take at 140 mg/week to attain the same risk? Answer: (500 - 70 mg) / (140 - 70 mg) * 1 year = 6.1 years

The actual relationships are likely to be much more complicated, but the point is that the general pattern appears to exist.

Appear to exist based on what? An animal study where the smallest increase was a 700% rise over natural levels? Studies that looked into steroid abuse? If anything, studies seem to show the opposite. The chances of seeing a health event are generally higher in the first two years of treatment iirc, and once a person gets past that the odds drop.

Plus there are studies which show what happens with exposure over years… and best of all they’re actually in humans.

Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study - PubMed

Physicians' Services Incorporated Foundation and Ajmera Family Chair in Urologic Oncology.

pubmed.ncbi.nlm.nih.gov

More than five years of use… and the group with the highest exposure had best outcomes for cardiac events, prostate cancer diagnosis, and all cause mortality. One would think that if your theory of extended exposure were true, then the highest group would’ve been at the most risk over that timeframe. Turns out it was the opposite. And there are other studies that similarly show testosterone use for 5+ years resulting in positive outcomes.

Read it again if you really think it's not relevant: "Short-term (4 weeks) exposure produced physiological concentric hypertrophy with maintained or improved contractile activation and α-MHC upregulation. Longer exposure (8–12 weeks) shifted to pathological hypertrophy with myocardial collagen deposition, suppressed myofilament activation, and (at 12 weeks) eccentric remodeling plus reduced ERK1/2 and mTOR signaling. The authors concluded that the pathological outcome depended more on duration of exposure than on the specific supra-physiological dose."

You never answered the question of what you consider to be long term.

It isn’t relevant because the SMALLEST dose resulted in t levels being seven times higher than levels seen in the control group. They specifically used insanely high doses and then their claim was “hey guys turns out dose isn’t really that important when it comes to results”. You’re an intelligent person so I’m sure you realize the flaw in their structure, right? If you take three groups all of which are running insanely high levels then it makes sense that the duration of abuse would be more of a factor than the dose… because they’ve made ALL the dose groups extremely high, again with the LOWEST group having levels 700% higher than natural. However, this is no way means that you can apply that to all doses and say the same trend would exist. And as I showed above, we have multi year studies in humans where the highest group had the best outcomes. We have plenty of people on this forum (myself included) who have been on trt for over five years. My health is as good as ever. Many other are in the same boat.

I acknowledged the drop in levels, which is linked in part to poorer health. The EDC/environmental link is still somewhat speculative. The general decline doesn't tell us about individuals. That's where the reference ranges come into play. It's a common forum assertion that this declining production is influencing reference ranges. That is what has not been demonstrated, and remains a further rationalization for inflated dosing.

On the integrated exposure topic, here's a more nuanced statement from ChatGPT:

What the literature supports better is a graded, probably nonlinear cumulative-exposure model. In other words, as androgen exposure rises above the physiologic range, risk likely increases through several pathways at once — LV hypertrophy/remodeling, fibrosis, BP, HDL/LDL changes, thrombosis/viscosity, endothelial dysfunction, and arrhythmogenic effects — and duration matters. Human data from long-term AAS users show that greater cumulative lifetime exposure is associated with more coronary plaque burden, and newer data also link cumulative lifetime exposure to worse LV/RV strain. That argues against a pure “only very high doses matter” threshold model.​

​

At the same time, the data do not let you say that 140 mg/week of testosterone cypionate carries a risk that can be quantitatively “integrated” into the equivalent of a shorter AAS cycle. Those studies are mostly in people with much more extreme exposures, stacking, cycling, and other confounders. So the defensible claim is directional, not quantitative: persistent exposure above physiologic androgen levels may plausibly add risk over time, especially in susceptible people, but we cannot map that risk with a simple mg × years formula.​

The environmental link is not speculative at all.


Even the AI slop you threw out said the only defensible approach would be to say it may plausibly add risk. Sure… you can say it might add risks. But we’re right back where we started when another user asked you for evidence. Of which you have shared nothing relevant to the discussion(and again rodent studies using insanely large doses aren’t relevant).

 

[Goddar]

Appear to exist based on what? An animal study where the smallest increase was a 700% rise over natural levels? Studies that looked into steroid abuse? If anything, studies seem to show the opposite. The chances of seeing a health event are generally higher in the first two years of treatment iirc, and once a person gets past that the odds drop.

Plus there are studies which show what happens with exposure over years… and best of all they’re actually in humans.

Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study - PubMed

Physicians' Services Incorporated Foundation and Ajmera Family Chair in Urologic Oncology.

pubmed.ncbi.nlm.nih.gov

More than five years of use… and the group with the highest exposure had best outcomes for cardiac events, prostate cancer diagnosis, and all cause mortality. One would think that if your theory of extended exposure were true, then the highest group would’ve been at the most risk over that timeframe. Turns out it was the opposite. And there are other studies that similarly show testosterone use for 5+ years resulting in positive outcomes.

You never answered the question of what you consider to be long term.

It isn’t relevant because the SMALLEST dose resulted in t levels being seven times higher than levels seen in the control group. They specifically used insanely high doses and then their claim was “hey guys turns out dose isn’t really that important when it comes to results”. You’re an intelligent person so I’m sure you realize the flaw in their structure, right? If you take three groups all of which are running insanely high levels then it makes sense that the duration of abuse would be more of a factor than the dose… because they’ve made ALL the dose groups extremely high, again with the LOWEST group having levels 700% higher than natural. However, this is no way means that you can apply that to all doses and say the same trend would exist. And as I showed above, we have multi year studies in humans where the highest group had the best outcomes. We have plenty of people on this forum (myself included) who have been on trt for over five years. My health is as good as ever. Many other are in the same boat.

The environmental link is not speculative at all.


Even the AI slop you threw out said the only defensible approach would be to say it may plausibly add risk. Sure… you can say it might add risks. But we’re right back where we started when another user asked you for evidence. Of which you have shared nothing relevant to the discussion(and again rodent studies using insanely large doses aren’t relevant).

Which dose do you use? And which levels of test, ft and estradiol do you have?

 

[Phil Goodman]

Which dose do you use? And which levels of test, ft and estradiol do you have?

Started at 120/week and after a few months added HCG at 1000 ius/week. Have always been between 100-120 mg/week and settled on 750 ius/HCG per week.

I can get the exact numbers when I get home, but my total test is always between 850-1200 and free is between 25-30. Can’t remember estradiol exactly but it’s always at the top of the range or slightly over. Have been this way for 5 plus years, feel good, and all my health markers are as good if not better than ever despite being five years older.

 

[Cataceous]

Appear to exist based on what? An animal study where the smallest increase was a 700% rise over natural levels? Studies that looked into steroid abuse? If anything, studies seem to show the opposite. The chances of seeing a health event are generally higher in the first two years of treatment iirc, and once a person gets past that the odds drop.

Plus there are studies which show what happens with exposure over years… and best of all they’re actually in humans.

Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study - PubMed

Physicians' Services Incorporated Foundation and Ajmera Family Chair in Urologic Oncology.

pubmed.ncbi.nlm.nih.gov

I don't think you looked into this study beyond the abstract. Of course it concerns TRT to presumably physiological levels, which is not even the current focus. There is no quantification of levels or dosing. The tertiles are 1-120 days, 121-510 days and >510 days. So hypogonadal men who use testosterone for less than four months have greater risk than those who use it for more than 1.4 years. Ok, hypogonadism is bad. That was never in dispute.

You never answered the question of what you consider to be long term.

That's because it's not known exactly, and is going to vary among individuals. The point is that there is evidence of increasing risk with longer exposure. I've said all along to those who have already tried physiological dosing extensively and find higher levels to be significantly better that they must weigh the perceived benefits against the real, but unquantified risks.

You can criticize the studies all you like, and are free to take whatever risks you like. But the burden of proof is on you if you're going to claim that non-physiological levels are safe for the long haul. In the absence of any evidence it is irresponsible to encourage others to believe this.

 

[Phil Goodman]

I don't think you looked into this study beyond the abstract. Of course it concerns TRT to presumably physiological levels, which is not even the current focus. There is no quantification of levels or dosing.

If it doesn’t quantify levels or dosing why are just assuming it concerns physiological levels? With your extremely conservative approach to dosing, you would say 75 mg/week is supraphysiological. Yet standard doses for trt are at or above that(sometimes very substantially above that). Either way, you have a set a new record for contradictions on this by IMMEDIATELY contradicting yourself within 2 sentences. You don’t get to squeeze it to support your argument while also acknowledging the data isn’t there to support your argument.

The tertiles are 1-120 days, 121-510 days and >510 days. So hypogonadal men who use testosterone for less than four months have greater risk than those who use it for more than 1.4 years. Ok, hypogonadism is bad. That was never in dispute.

You’re leaving out a very important detail here… the group on trt the longest also saw significantly better outcomes than the group that was on trt for 120-510 days. If your theory about exposure adding up over time to increase risks were true, we would expect the group on it the longest would see poorer outcomes… yet we see the opposite. And “more than 1.4 years” is the worst way to paint that picture… it’s quite likely that a very large percentage of the people who stayed on therapy for a year in a half were in it for the long haul and continued treatment for multiple years up to and including when the follow up was done.

That's because it's not known exactly, and is going to vary among individuals.

You don’t know what you consider long term? It was a simple question… “what do YOU consider long term”. Also, how can it vary among individuals? Or is that just a way for you to once again form your argument in a way that allows you to bob and weave as needed? For example, you could see a guy on trt be healthy for 20 years, then have a health issue at 70 and go “see, it was due to longterm trt use” whereas at 19 years you wouldn’t consider it long term for him.

The point is that there is evidence of increasing risk with longer exposure. I've said all along to those who have already tried physiological dosing extensively and find higher levels to be significantly better that they must weigh the perceived benefits against the real, but unquantified risks.

There is also evidence of decreasing risk with longer exposure. It also involves actual humans on trt instead of steroids or rodents on insanely large doses.

Also, just lmao at “perceived benefits” and “real but unquantified” risks. The benefits are all clear with regards to trt. We already both agree that trt is better than living in a hypogonadal state. You just get caught up on promoting extremely conservative doses and trying to convince everyone that anything above “what a male produces naturally” is introducing additional risks. When asked for the evidence you provide studies that do not support that at all and end up saying “real but unquantified risks” even after AI responding to your own prompting (which we can imagine the way you prompt it by the way you frame discussions here) told you that the only justifiable statement would be to say that the risks MAY PLAUSIBLY exist. They aren’t “real and quantifiable”… but they MIGHT exist.

You can criticize the studies all you like, and are free to take whatever risks you like. But the burden of proof is on you if you're going to claim that non-physiological levels are safe for the long haul. In the absence of any evidence it is irresponsible to encourage others to believe this.

And you still haven’t defined “long term”. What do YOU consider to be long term? Once we can actually start establishing guidelines it will likely help the discussion.


Also, I still find it hilarious that rodents on doses that drive their levels between seven to SEVENTEEN times higher than their natural counterparts counts as obvious evidence in your mind, yet a study that shows the group on trt the longest had the best outcomes is tossed aside while claiming I lack any evidence.



So… what do YOU consider longterm?

 

[Cataceous]

If it doesn’t quantify levels or dosing why are just assuming it concerns physiological levels?

I said "presumably", because outliers on the high side are likely to be balanced on the low side by users of commercial topical formulations. We've seen large TRT trials in which the highest quartile is probably averaging TT in the 400's ng/dL. And it's academic anyway, since the burden of proof is on you to show that these guys are on the equivalent of 140 mg TC/week, which obviously you cannot.

With your extremely conservative approach to dosing,

There's nothing extreme about targeting physiological levels in TRT. I have demonstrated repeatedly that your position is the outlier, though you've continued to soften it as your various claims are refuted, e.g. what medical societies actually recommend.

you would say 75 mg/week is supraphysiological. Yet standard doses for trt are at or above that(sometimes very substantially above that). Either way, you have a set a new record for contradictions on this by IMMEDIATELY contradicting yourself within 2 sentences. You don’t get to squeeze it to support your argument while also acknowledging the data isn’t there to support your argument.

At least make an attempt at coherence. What contradictions are you claiming? A dose of 75 mg TC/week does provide more testosterone than the average healthy young man makes naturally, and therefore puts the average man above what's natural for him. That doesn't automatically make his levels supraphysiological by population standards. But in this thread you're trying to downplay the risk of a dose that's approaching double this.

You’re leaving out a very important detail here… the group on trt the longest also saw significantly better outcomes than the group that was on trt for 120-510 days. If your theory about exposure adding up over time to increase risks were true, we would expect the group on it the longest would see poorer outcomes… yet we see the opposite. And “more than 1.4 years” is the worst way to paint that picture… it’s quite likely that a very large percentage of the people who stayed on therapy for a year in a half were in it for the long haul and continued treatment for multiple years up to and including when the follow up was done.

I see you want to keep twisting in the wind here. You are drawing impossible inferences from this study. It only shows that treating hypogonadism provides benefits. It in no way shows that raising testosterone to supraphysiological levels for a prolonged period is safe.

You don’t know what you consider long term? It was a simple question… “what do YOU consider long term”. Also, how can it vary among individuals?

No need for you to play dumb, but I'll spell out why long-term is not currently definable in this context: There will be some individuals who would be harmed by five years of dosing at 140 mg TC/week. There are probably other individuals who would experience no obvious problems afters 20 years of this protocol. The research at this point only shows that there are statistical risks that increase with dose and exposure.

Or is that just a way for you to once again form your argument in a way that allows you to bob and weave as needed? For example, you could see a guy on trt be healthy for 20 years, then have a health issue at 70 and go “see, it was due to longterm trt use” whereas at 19 years you wouldn’t consider it long term for him.

Do you understand what "statistical risk" means?

There is also evidence of decreasing risk with longer exposure. It also involves actual humans on trt instead of steroids or rodents on insanely large doses.

Cite one study showing this to be true for supraphysiological levels.

You just get caught up on promoting extremely conservative doses and trying to convince everyone that anything above “what a male produces naturally” is introducing additional risks.

In medicine, supraphysiological is the extreme when it comes to treating a deficiency. The medical societies say to target mid-physiological levels. That is sensible and supported by the evidence; it's not "extremely conservative".

When asked for the evidence you provide studies that do not support that at all and end up saying “real but unquantified risks” even after AI responding to your own prompting (which we can imagine the way you prompt it by the way you frame discussions here) told you that the only justifiable statement would be to say that the risks MAY PLAUSIBLY exist. They aren’t “real and quantifiable”… but they MIGHT exist.

I explicitly disclaimed that quantification is currently possible. You ignore the key AI assertion about the literature: "What the literature supports better is a graded, probably nonlinear cumulative-exposure model. In other words, as androgen exposure rises above the physiologic range, risk likely increases through several pathways at once — LV hypertrophy/remodeling, fibrosis, BP, HDL/LDL changes, thrombosis/viscosity, endothelial dysfunction, and arrhythmogenic effects — and duration matters."

Meanwhile, you have nothing to show safety.

Also, I still find it hilarious that rodents on doses that drive their levels between seven to SEVENTEEN times higher than their natural counterparts counts as obvious evidence in your mind, yet a study that shows the group on trt the longest had the best outcomes is tossed aside while claiming I lack any evidence.

Are you familiar with the term "Human Equivalent Dose"? You might look into it. Hint one: The scale factor for rats is 7.3. Hint two: If the OP weighed 70 kg then for him the rat dose in Wadthaisong et al. isn't much more than double the 140 mg/week of testosterone cypionate he's taking.

 

[Phil Goodman]

I said "presumably", because outliers on the high side are likely to be balanced on the low side by users of commercial topical formulations. We've seen large TRT trials in which the highest quartile is probably averaging TT in the 400's ng/dL. And it's academic anyway, since the burden of proof is on you to show that these guys are on the equivalent of 140 mg TC/week, which obviously you cannot.

I didn’t say they are on those doses. I used it as a study to push back against your claim regarding exposure over time. Again, I used a human study with thousands of people over years, and the group with the highest exposure had the best outcome.

Meanwhile when asked for evidence to show that it’s harmful you provided rodent studies which blasted them with crazy doses and others that looked into steroid abuse. Double standards much??


Also, I have not seen any studies where the highest quartile was in the 400 TT range. Since you’ve seen them can you share it with the group? Or did you just make it up.

There's nothing extreme about targeting physiological levels in TRT. I have demonstrated repeatedly that your position is the outlier, though you've continued to soften it as your various claims are refuted, e.g. what medical societies actually recommend.

The levels and doses used in patients are what you would consider extreme and harmful. You are in the minority with regards to what you recommend for dosing purposes. This is not disputed.

At least make an attempt at coherence. What contradictions are you claiming? A dose of 75 mg TC/week does provide more testosterone than the average healthy young man makes naturally, and therefore puts the average man above what's natural for him. That doesn't automatically make his levels supraphysiological by population standards. But in this thread you're trying to downplay the risk of a dose that's approaching double this.

You’re contradicting yourself by saying it doesn’t support a case for higher doses because it “presumably” uses physiological doses (which in your eyes is a rather low weekly dose) while also admitting that it doesn’t state the doses so can’t be used as evidence that long term exposure leads to better outcomes. Also, again, most doctors are prescribing doses that you consider supraphysiological. So this isn’t a study with smaller doses, this is an observational study based on what is occurring in the real-world, and you yourself have said you think in the real world doctors are prescribing doses that are too high more often than not.

I see you want to keep twisting in the wind here. You are drawing impossible inferences from this study. It only shows that treating hypogonadism provides benefits. It in no way shows that raising testosterone to supraphysiological levels for a prolonged period is safe.

Fair enough, it doesn’t show that. Now, are you also ready to admit that steroid studies and rodent studies using crazy doses don’t show that having TT levels of 1,000 with good bloodwork is harmful? If I’m able to admit what my studies do and don’t show I imagine you can do the same, correct?

No need for you to play dumb, but I'll spell out why long-term is not currently definable in this context: There will be some individuals who would be harmed by five years of dosing at 140 mg TC/week. There are probably other individuals who would experience no obvious problems afters 20 years of this protocol. The research at this point only shows that there are statistical risks that increase with dose and exposure.

Whether something is longterm or not isn’t contingent on an outcome. Your wording here is only making me further suspect that you are manipulating terminology so you can bob and weave. You know if you say “five years is long term” then it makes it easier for me to look into studies to meet the criteria, or do a poll on here to ask users what their dose and duration of treatment is. And since you know I’ve had high levels for over five years you certainly wouldn’t use that timeframe since my bloodwork is better now than when I started. I suspect if you do ever decide to define “long term” you’ll just put an extensively long window on the term because it gives you the best chance of having something happen during that time (like say 20-30 years) then you would automatically attribute it to the trt.

Do you understand what "statistical risk" means?



Cite one study showing this to be true for supraphysiological levels.



In medicine, supraphysiological is the extreme when it comes to treating a deficiency. The medical societies say to target mid-physiological levels. That is sensible and supported by the evidence; it's not "extremely conservative".

Tons of studies were done with doses that well exceed what a human produces naturally. There are many that show these doses can be not only safe, but beneficial on numerous fronts. This is abundantly clear and pretty much all users here have seen the studies.

I explicitly disclaimed that quantification is currently possible. You ignore the key AI assertion about the literature: "What the literature supports better is a graded, probably nonlinear cumulative-exposure model. In other words, as androgen exposure rises above the physiologic range, risk likely increases through several pathways at once — LV hypertrophy/remodeling, fibrosis, BP, HDL/LDL changes, thrombosis/viscosity, endothelial dysfunction, and arrhythmogenic effects — and duration matters."

Meanwhile, you have nothing to show safety.

it didn’t say that’s accurate, it said the literature better supports it. Or you could actually push back a little instead of wording your prompt in the most leading way possible then not pushing back at all. I could paste tons and tons of response that push back against what it generated for you, but I’ll try to keep it short:

But that's quite different from saying:

"Once testosterone rises above physiologic range, cardiovascular risk progressively increases through LV hypertrophy, fibrosis, thrombosis, endothelial dysfunction, etc."

The evidence doesn't establish that model.

I would modify the original statement​

Your original wording:

"as androgen exposure rises above the physiologic range, risk likely increases through several pathways at once..."

is too confident, particularly if it is intended to describe TRT/high-dose TRT.

A better evidence-based model would be:

Androgen effects appear to be multidimensional and dose- and exposure-dependent, but the relationship between testosterone concentration and cardiovascular risk is not established as a simple monotonic or nonlinear curve. Some adverse effects—particularly erythrocytosis and blood-pressure elevation—clearly become more likely with greater androgen exposure, while other proposed effects such as LV remodeling, fibrosis, thrombosis and arrhythmia are more strongly supported in the setting of sustained high-dose/supraphysiologic anabolic-androgenic steroid exposure than in conventional TRT. Short-term supraphysiologic testosterone trials have demonstrated substantial anabolic benefits without necessarily producing major cardiovascular events, but they are generally too short to establish long-term safety.

That's a much more defensible statement.

And I think there's an even more interesting question underneath what you're getting at: if someone on TRT runs total T around 1,000–1,200 ng/dL but has normal hematocrit, BP, ApoB/LDL, etc., is that actually meaningfully more dangerous than maintaining 500–800 ng/dL?

The literature is much weaker on that specific question than people often imply. That's where I'd be cautious about extrapolating either "high T is dangerous" or "high T is completely safe."


So no, there is little to no evidence to support your claim that someone with 1200 and good bloodwork is at higher risk than someone on a lower dose with worse bloodwork.

Are you familiar with the term "Human Equivalent Dose"? You might look into it. Hint one: The scale factor for rats is 7.3. Hint two: If the OP weighed 70 kg then for him the rat dose in Wadthaisong et al. isn't much more than double the 140 mg/week of testosterone cypionate he's taking.

I’m not talking about conversions between the rodents and humans(which we have to do a lot since you seem to love using animal studies while crapping on human studies that you disagree with). I’m talking about how the levels of the dosed rodents compared to their natural counterparts. You could’ve verified that in 3 seconds if you used AI for more than just pumping out stuff you agree with.



Yes. I have now confirmed it against the full paper, rather than relying on the abstract or a secondary source.

For the Pirompol et al. 2016 study, the paper itself reports measured plasma testosterone concentrations for the experimental animals. The study is Supra-physiological dose of testosterone induces pathological cardiac hypertrophy in the Journal of Endocrinology.

The values I gave you in my previous response are indeed from the study's reported measurements:

Group	4 wk	8 wk	12 wk
Sham/control	0.26	0.26	0.28 µg/dL
5 mg/kg	1.65	1.81	1.93 µg/dL
10 mg/kg	3.39	3.57	3.77 µg/dL
20 mg/kg	4.57	4.38	4.30 µg/dL

So these aren't estimates based on the administered dose—they are measured testosterone concentrations in the animals.

And converting those measurements to multiples of the corresponding control is appropriate:

• 5 mg/kg: roughly 6–7× control
• 10 mg/kg: roughly 13–14× control
• 20 mg/kg: roughly 15–18× control

One particularly interesting feature is that doubling the dose from 10 to 20 mg/kg did not double plasma testosterone. At 12 weeks, for example, it went from 3.77 to 4.30 µg/dL. That pharmacokinetic relationship is important when interpreting the authors' conclusion that the cardiac effects were more dependent on duration than dose.

So yes—the 7×, 13×, and ~15–18× figures are based on actual measured testosterone levels in the study subjects, not an assumption that mg/kg dose translates directly into a serum-T multiple.

And I want to explicitly correct my earlier answer: my statement that the paper did not report serum testosterone concentrations was incorrect.



and just to quadruple check, I pushed back one more time, then got this response.


You were right to challenge me. I just re-checked the actual full-text paper, including Table 1, and the numbers are real. I did not make them up.

The full paper explicitly contains this table:

“Table 1 Body and heart weights and plasma testosterone concentrations from sham control (SHAM) and testosterone-treated rats with 5 (T5), 10 (T10), and 20 (T20) mg/kg BW for 4, 8, and 12 weeks.”

So yes, the first piece of “evidence” you produced to support your claim that a dose of 140 per week is harmful even if all bloodwork looks good…. Was a rodent study where they drove the levels up between seven to SEVENTEEN TIMES higher than what was seen in the natural control group. All of this while talking about how relevant it is yet saying studies provided by others don’t constitute any supporting evidence whatsoever. And honestly, your other “evidence” wasn’t any better.



But I know from experience, you are willing to die on the “anything supraphysiological is dangerous” hill so I’m not planning to waste anymore time here. Other posters can read the discussion and decide for themselves what they think about the topic. All I hope is that one day you decide to push back against Madman because that conversation/debate would be absolutely hilarious.

 

[Cataceous]

I didn’t say they are on those doses. I said there are studies which showed the subjects with highest exposure had the best health outcomes.

The single study you cited has no demonstrable relevance to this discussion.

Meanwhile when asked for evidence to show that it’s harmful you provided rodent studies which blasted them with crazy doses and others that looked into steroid abuse. Double standards much??

There is tangible dose- and duration-dependent harm demonstrated in animal models, which when combined with human studies conveys that the risk is there, particularly for susceptible individuals. Meanwhile, in dozens of pages of back-and-forth you've presented nothing to demonstrate the safety or benefit to overall health in dosing to supraphysiological levels.

The levels and doses used in patients are what you would consider extreme and harmful. You are in the minority with regards to what you recommend for dosing purposes. This is not disputed.

Take a look at some large TRT trials. TRAVERSE, for example, only raised TT by 148 ng/dL from baseline. The titration was to 350-750 ng/dL. That's in line with my thinking, or even more conservative. In real life the >100 mg TC/week crowd is in the minority. However, they are overrepresented in the forums, which not coincidentally is where guys suffering from side effects end up.

I didn’t say they are on those doses. I said there are studies which showed the subjects with highest exposure had the best health outcomes.

It shows that the group with the highest exposure had the best outcomes. And again lol at your double standards when it comes to studies.

This is a familiar pattern. You latch onto a study with no relevance and refer to it endlessly. Explain in detail how this study supports the long-term safety of dosing to supraphysiological levels.

Whether something is longterm or not isn’t contingent on an outcome.

It's just like trying to predict life expectancy, except we don't have all of the detailed studies giving us better quantification. Even with studies the results are statistical. With life-expectancy, suppose long-term is the time period after which the person is equally likely to be alive or dead. If you know nothing about the individual except that he or she is currently living, then you crunch some statistics based on current age distributions and predicted longevity for those ages. You'll get an answer that works on average, but its bearing on a particular individual is not great.

Excessive androgen exposure is just a different time-dependent risk factor. You could define long-term as something like the period after which you have reduced your life expectancy by 5%. But there is not enough data to even begin to quantify this, even though the effect is real. It is further confounded by individual differences in susceptibility.

Your wording here is only making me further suspect that you are manipulating terminology so you can bob and weave. You know if you say “five years is long term” then it makes it easier for me to look into studies to meet the criteria, or do a poll on here to ask users what their dose and duration of treatment is.

Even if I said arbitrarily that for a dose of 140 mg TC/week a period of 15 years is long-term, you cannot find any directly applicable study. For now we have to make do with the indirect studies, which point to risks without offering definitive quantification.

And since you know I’ve had high levels for over five years you certainly wouldn’t use that timeframe since my bloodwork is better now than when I started.

I also know that your dosing is well under 140 mg TC/week, so "long-term" for you is statistically longer than someone on 140 mg/week. But I do not know your individual susceptibility to excessive androgen exposure, so I can say you increase your risk by maintaining supraphysiological levels, but not that you personally must suffer negative consequences. With your marginally high doses the risk cannot be that great, and if you knew your results were better than with lower doses then I would not advocate for making changes. But you acknowledge not having tried lower doses.

Tons of studies were done with doses that well exceed what a human produces naturally. There are many that show these doses to be not only safe, but beneficial on numerous fronts. This is abundantly clear and pretty much all users here have seen the studies.

This is a familiar overstatement. Studies show that high doses can be tolerated short-term, although the risk of side effects scales up with dose, negating the very limited benefits when a comparison is made to eugonadal males rather than hypogonadal ones.

...
is too confident, particularly if it is intended to describe TRT/high-dose TRT.

You mislead the AI with the use of the term "TRT". Taking 140 mg TC/week is not "replacement" therapy when virtually nobody can naturally produce that much. The short-term misery caused by such dosing in susceptible individuals is easily demonstrated. The only thing left to quibble about is how much time must pass before certain types of damage become irreversible in some individuals.

And I think there's an even more interesting question underneath what you're getting at: if someone on TRT runs total T around 1,000–1,200 ng/dL but has normal hematocrit, BP, ApoB/LDL, etc., is that actually meaningfully more dangerous than maintaining 500–800 ng/dL?

A comprehensive list of markers for excessive androgen exposure is probably an order of magnitude or more long. Many remain undiscovered. How are you going to screen for cardiac fibrosis? For some individuals the difference in TT you mention could be enough to turn some risk factors into reality when enough time passes.

Comment from AI on markers for excessive exposure: "Emerging research continues to identify additional candidates (collagen-turnover markers, specific cytokine profiles, epigenetic changes, long-term remodeling signatures, etc.). Detection methods such as the athlete biological passport concept further illustrate how multi-marker longitudinal profiles are used because no single marker is fully comprehensive."

So no, there is little to no evidence to support your claim that someone with 1200 and good bloodwork is at higher risk than someone on a lower dose with worse bloodwork.

An apples-to-oranges comparison. The individual with worse [standard] blood work has one set of risk factors. The guy with TT at 1,200 ng/dL has risk factors that may only be revealed through esoteric/expensive testing, or which have not yet been identified.

I’m not talking about conversions between the rodents and humans(which we have to do a lot since you seem to love using animal studies while crapping over human studies that you disagree with). I’m talking about how the levels of the doses rodents compared to their natural counterparts. You could’ve verified that in 3 seconds if you used AI for more than just pumping out stuff you agree with.

The studies you cite are usually ok, but even the authors would cringe at the extrapolations you're attempting to make with them.

[detail about serum levels]

I wasn't even disputing those serum numbers. The point is that the Human Equivalent Dose suggests risk to humans at lower per-kilogram doses. Neither metric is going to be a perfect predictor of risk, but the risk is there and scales with dose and time. You have presented no evidence that there is some particular threshold for safety.

But I know from experience, you are willing to die on the “anything supraphysiological is dangerous” hill so I’m not planning to waste anymore time here.

"Dangerous" is a subjective term, which I generally would not use. I simply say there are risks that increase with dose and exposure time. I do not believe they are trivial enough to dismiss, and if symptoms of hypogonadism can be resolved with physiological levels then it is foolish to test the limits unless you have specific goals that outweigh concerns about overall health.

All I hope is that one day you decide to push back against Madman because that conversation/debate would be absolutely hilarious.

Madman and I are more aligned than many seem to think. He repeatedly emphasizes the low-and-slow approach to TRT, as I do. I do not proscribe modestly supraphysiological doses if they produce better results than the lower ones that preceded them. I just ask that people go into it properly informed, recognizing that the risk in this is not zero.

 

[Phil Goodman]

The single study you cited has no demonstrable relevance to this discussion.



There is tangible dose- and duration-dependent harm demonstrated in animal models, which when combined with human studies conveys that the risk is there, particularly for susceptible individuals. Meanwhile, in dozens of pages of back-and-forth you've presented nothing to demonstrate the safety or benefit to overall health in dosing to supraphysiological levels.



Take a look at some large TRT trials. TRAVERSE, for example, only raised TT by 148 ng/dL from baseline. The titration was to 350-750 ng/dL. That's in line with my thinking, or even more conservative. In real life the >100 mg TC/week crowd is in the minority. However, they are overrepresented in the forums, which not coincidentally is where guys suffering from side effects end up.




This is a familiar pattern. You latch onto a study with no relevance and refer to it endlessly. Explain in detail how this study supports the long-term safety of dosing to supraphysiological levels.



It's just like trying to predict life expectancy, except we don't have all of the detailed studies giving us better quantification. Even with studies the results are statistical. With life-expectancy, suppose long-term is the time period after which the person is equally likely to be alive or dead. If you know nothing about the individual except that he or she is currently living, then you crunch some statistics based on current age distributions and predicted longevity for those ages. You'll get an answer that works on average, but its bearing on a particular individual is not great.

Excessive androgen exposure is just a different time-dependent risk factor. You could define long-term as something like the period after which you have reduced your life expectancy by 5%. But there is not enough data to even begin to quantify this, even though the effect is real. It is further confounded by individual differences in susceptibility.



Even if I said arbitrarily that for a dose of 140 mg TC/week a period of 15 years is long-term, you cannot find any directly applicable study. For now we have to make do with the indirect studies, which point to risks without offering definitive quantification.



I also know that your dosing is well under 140 mg TC/week, so "long-term" for you is statistically longer than someone on 140 mg/week. But I do not know your individual susceptibility to excessive androgen exposure, so I can say you increase your risk by maintaining supraphysiological levels, but not that you personally must suffer negative consequences. With your marginally high doses the risk cannot be that great, and if you knew your results were better than with lower doses then I would not advocate for making changes. But you acknowledge not having tried lower doses.



This is a familiar overstatement. Studies show that high doses can be tolerated short-term, although the risk of side effects scales up with dose, negating the very limited benefits when a comparison is made to eugonadal males rather than hypogonadal ones.



You mislead the AI with the use of the term "TRT". Taking 140 mg TC/week is not "replacement" therapy when virtually nobody can naturally produce that much. The short-term misery caused by such dosing in susceptible individuals is easily demonstrated. The only thing left to quibble about is how much time must pass before certain types of damage become irreversible in some individuals.



A comprehensive list of markers for excessive androgen exposure is probably an order of magnitude or more long. Many remain undiscovered. How are you going to screen for cardiac fibrosis? For some individuals the difference in TT you mention could be enough to turn some risk factors into reality when enough time passes.

Comment from AI on markers for excessive exposure: "Emerging research continues to identify additional candidates (collagen-turnover markers, specific cytokine profiles, epigenetic changes, long-term remodeling signatures, etc.). Detection methods such as the athlete biological passport concept further illustrate how multi-marker longitudinal profiles are used because no single marker is fully comprehensive."



An apples-to-oranges comparison. The individual with worse [standard] blood work has one set of risk factors. The guy with TT at 1,200 ng/dL has risk factors that may only be revealed through esoteric/expensive testing, or which have not yet been identified.



The studies you cite are usually ok, but even the authors would cringe at the extrapolations you're attempting to make with them.



I wasn't even disputing those serum numbers. The point is that the Human Equivalent Dose suggests risk to humans at lower per-kilogram doses. Neither metric is going to be a perfect predictor of risk, but the risk is there and scales with dose and time. You have presented no evidence that there is some particular threshold for safety.



"Dangerous" is a subjective term, which I generally would not use. I simply say there are risks that increase with dose and exposure time. I do not believe they are trivial enough to dismiss, and if symptoms of hypogonadism can be resolved with physiological levels then it is foolish to test the limits unless you have specific goals that outweigh concerns about overall health.



Madman and I are more aligned than many seem to think. He repeatedly emphasizes the low-and-slow approach to TRT, as I do. I do not proscribe modestly supraphysiological doses if they produce better results than the lower ones that preceded them. I just ask that people go into it properly informed, recognizing that the risk in this is not zero.

Not gonna go into all of that because it’s a waste of time, but if you’d like a detailed response to it I’ll provide it. A lot to unpack which I could do, but I’ll just say that I’m disappointed you didn’t at least admit that the studies you provided aren’t evidence for what you’re claiming just like I was able to admit the study I provided wasn’t evidence for the 140 mg/week claim even though that was not what I using it to support). Instead you just doubled down insisting it IS evidence for your claim. You also avoided presenting the studies you claim to exist about top quartile seeing ranges around 400. Which I’m assuming is because they don’t exist.


Also, you and madman only align if you completely ignore the fact that his idea of a “low dose” is drastically larger than yours. When he says “low and slow” 100 mg/week is the BOTTOM of his suggestion. It is ABOVE what you would recommend for pretty much anyone.

This is because he follows the evidence of risks and rewards for various doses. So no… you don’t align at all unless you’re completely throwing definitions and dosing recommendations out the window. Yet for some reason you never call him out for guiding new members in that direction.