TRT to Supraphysiological Levels for Body Building

[tareload]

Of course that's taking some liberties (cherry picking the blue and red data points but FWIW.

Ok, update to post #93 above.

I took all the rodent studies with testosterone and combined with the PK modeling of this paper. Doing so allows me to take the calculated weekly mean HEDs in post 93 (graph reproduced below)

and convert to an estimated serum TT level (I calculated 2.5th percentile, 50th percentile, and 97.5th percentile based on this figure) using the intensive sampling data for mg/week dosing vs serum TT levels:

Simple linear regression of the intensive sample data above (quick estimate eyeballing the graphs - can refine later):

After the conversion, now I can plot mean human serum TT level (average over 7 day period) vs duration for the rodent toxicity studies and then fit the regression lines using percentiles mentioned above (see below):

The area between the dashed lines represents the toxicity envelope predicted from the rodent studies I've looked at thus far. Obviously a work in progress. The data labels are y-values (duration in years) for the data points. Also plotted are the human data from the HIV studies we discussed above (I only used the 50th percentile regression line to convert these data from mg/week to ng/dl). Ideally, I should plot a density ellipse or set of lines for the 2.5th / 97.5th percentile as well like I did for the rodent data conversions.

EDIT: Included the density ellipse with 2.5/97.5th percentile estimates on serum TT for the human HIV studies as well:

The log-log plot really shows how short term those studies were in comparison to the region where the empirical HED transform model suggests a human male would start running in trouble. Also, note the two yellow shaded data points which are entirely made up by me to simulate the point that chronic use of "physiologic" TRT is relatively non-toxic. Even if we omit those points there's still quite a bit of real estate between the blue HED transform data and the red Human HIV study data.

You can pick a serum TT level on the x-axis and then find the upper and lower limits on the y-axis that correspond to the toxicity curves. Try it out for serum TT levels of 1000, 2000, and 5000 ng/dl? What range of durations do you find? You could compare those numbers against anecdotal data from the bodybuilding world, your own personal experience, etc.

@DS3, @Cataceous , @madman , @Nelson Vergel , @Dr Justin Saya MD, @bixt, @Wilson7, all others: would value your thoughts, critique, review. Propagating all the error involved in this analysis I would easily hand-wave the treatment as-is possesses much greater than +100/-50% error. Nevertheless, an interesting qualitative if not quantitative picture emerges. Perhaps this type of graph is already somewhere in the literature? Please share if so as I didn't mean to reinvent the wheel.

EDIT:
Added in an additional handful of influential studies in human males by Bhasin 1996 and 2001, Matsumoto 1988:

I'll try to find any other longer term rodent studies but as of now we've still got the unknown region between the rodent HED transform data and the human data. Also, I didn't see any echos or other heart surveillance in the green data.

 

[Nelson Vergel]

@readalot Did you make those graphs yourself?

 

[tareload]

@readalot Did you make those graphs yourself?

Yes except the ones explicitly mentioned from literature. A little project as I hadn't ever found an analysis where all the lit data was placed on one graph. We could also add user data and experiences.

 

[Phil Goodman]

@readalot I certainly appreciate the time and effort you’re putting in to compiling all of this data in an organized manner. Really busy with life this week but from skimming over it, it appears well done. I hope to dive into it more in-depth by the end of the week, and will be interested to see whatever other data you add to the mix.


I guess the first critique off the top of my mind since you asked for input, would be with regards to how you translated rodent years into human years. Not saying it is inaccurate, just curious about the conversion. And with rodent metabolism being so high it may be possible that it would affect their heart more, and more quickly. Again not saying that’s the case, just something I was curious about.

I’d also like to get your thoughts on one aspect…the rather large differences in what levels are achieved by different people on similar doses. Do you think the TT and FT levels are more indicative of what types of impact will be seen, or would it be more closely tied to dose?

 

[DS3]

@readalot is not wrong to infer long term high levels may cause harm

@DS3 is technically not wrong either, by saying there is a lack of evidence to prove this. But this is a bullshit approach. For example, there is zero evidence showing 500mg a Trenbolone a week for 10 years causes harm. Really, not ONE study exists. So would you still take it? Is this lack of evidence "proof" that this stuff not harmful?

@bixt Misrepresentation of my position. My position was questioning at what point (dosage, TT, whatever) does testosterone cause damage long-term. A lack of scientific inquiry does not prove correlation or causality in either direction.

 

[DS3]

Continued...

Reference	AAS type	Rat / mouse dosing (mg/kg/week)	HED ratio	HED (mg/kg/week)	HED (mg/week for 90 kg human)	study duration (weeks)	animal days to human years ratio	equivalent duration (approx. human years)
Tanno 2011	nandrolone	10	6.2	1.6	145	6	16	2.6
Penna 2007	nandrolone	105	6.2	16.9	1524	2	16	0.9
Neves 2013	nandrolone	10	6.2	1.6	145	6	16	2.6
da Silva 2009	nandrolone	10	6.2	1.6	145	3	16	1.3
Carmo 2011	nandrolone	70	12.3	5.7	512	10	9	7.8
Alves 2020	testosterone	70	12.3	5.7	512	4.3	9	3.3
Wadthaisong 2019	testosterone	30	6.2	4.8	435	12	16	5.3

Not exhaustive and as @DS3 states, I have no definitive long term data in humans showing a clear causal relationship between solely high testosterone levels from exogenous abuse and harm. However, the data above are useful and should give one pause, especially given the uncertainty involved in the transfer function.




My observation is that we've got the burden of proof on all of this backwards as usual. That's fine, I've done some heavy lifting for you (haha).

It's not up to me to prove running supra/TOT/TRT+ TT levels over x many years is harmful. Quite the opposite when considering any novel/unproven medical intervention. As much as @DS3 may try to twist my position, it's a very simple one. When considering going down this route, go in with your eyes open and realize the potential risks.

@readalot The burden of proof is, in fact, on the party stating the claim or argument.

 

[DS3]

Updated table from the rodent studies (by no means exhaustive):

Each of these rows is a literature study showing various toxic effects (autonomic dysfunction, cardiac remodeling, etc). Perhaps I'll continue to add to the list. If you come across additional studies, please do share.

Reference	AAS type	Rat / Mouse dosing (mg/kg/week)	HED ratio	HED (mg/kg/week)	HED (mg/week for 90 kg human)	study duration (weeks)	animal days to human years ratio	equivalent duration (approx. human years)
Tanno 2011	nandrolone	10	6.2	1.6	145	6	16	2.6
Neves 2013	nandrolone	10	6.2	1.6	145	6	16	2.6
da Silva 2009	nandrolone	10	6.2	1.6	145	3	16	1.3
Pirompol 2016	testosterone	15	6.2	2.4	218	12.0	16	5.3
Olivares 2014	testosterone	25	6.2	4.0	363	5	16	2.2
Wadthaisong 2019	testosterone	30	6.2	4.8	435	12	16	5.3
Carmo 2011	nandrolone	70	12.3	5.7	512	10	9	7.8
Alves 2020	testosterone	70	12.3	5.7	512	4.3	9	3.3
Karbasi 2017	testosterone	40	6.2	6.5	581	8.7	16	3.8
Cartieri 2021	nandrolone	105	12.3	8.5	768	2.7	9	2.1
Cartieri 2021	testosterone	105	12.3	8.5	768	2.7	9	2.1
El-Gendy 2021	testosterone	60	6.2	9.7	871	8	16	3.5
Argenziano 2016	testosterone	87.5	6.2	14.1	1270	1.0	16	0.4
Penna 2007	nandrolone	105	6.2	16.9	1524	2	16	0.9
Papmitsou 2011	testosterone	175	6.2	28.2	2540	2.9	16	1.3

If you make a plot of duration in human years (y-axis) vs calculated HED for a 90 kg human (x-axis) with these data, you get the following:







View attachment 19473

Not a great coefficient of determination (R2) using both nandrolone and testosterone data with a logarithmic trendline.

If you just plot the testosterone data you get the following:

View attachment 19474

I didn't curate the data so its interesting that the trendline actually fits as well as it does. Higher HED with less duration indicates toxicity just like lower HED at higher duration. As other studies have suggested its the product of dose and duration (cumulative dose) that may really be the important factor.

In an ideal world you could build an envelope curve showing that to the left of the curve you are ok and to the right of the curve you are in bad territory. The curve itself could represent the transition region. Now obviously not all these points represent the same clinical endpoints but at least the doses and durations seem within the realm of possibility. Given human variation it's probably not realistic for this kind of treatment to be predictive but it is fascinating (if not generally instructive).

EDIT: if you are curious what the regression line (above) predicts for various HEDs:

HED (mg/week for 90 kg man)	duration (human years)
25	8.6
50	7.4
100	6.2
200	5.0
400	3.9
800	2.7
1600	1.5
3200	0.3

What sticks out to me are the HEDs under 100 mg/week. We have plenty of anecdotal data out there and patients on this board and others that have been on 100 mg/week of testosterone for over 10 years+. Hence the intercept of the regression line may indicate the dose response for rodents is much more sensitive than humans or the HED ratios used aren't really applicable. FYI.






Note, if you make 50 mg/week and 100 mg/week essentially non-toxic, you can fit all the data with an exponential 3P or biexponential 4P equation pretty well:

View attachment 19475
Of course that's taking some liberties (cherry picking the blue and red data points but FWIW.

Tremendous effort in this. Despite being on opposite sides of a position, your research is impressive.

Looking at the results and your commentary, one would have to question at what level of testosterone does long-term exposure create toxic effects. For the thought provocation, I thank you.

The results are interesting. The R2 of testosterone alone is decent. However, as you point out, the results indicate that doses of 100 ng per week or less create toxic effects over long-term exposure. Which is perhaps, as noted, a result of rats being more sensitive to testosterone exposure even at lower doses. That is, in fact, the piece that really creates pause and causes one to think: If toxic effects in rats are seen at the equivalent of therapeutic doses for humans, then is that an indication that even doses under 100 mg per week are potentially toxic? Or, is the sensitivity of wistar rats incomparable to humans, leaving the transferability of results to humans highly questionable? (Questionable not in the sense that there is no dose of testosterone that over long-term exposure exerts toxic effects, but rather, is the dosage as low as these studies would indicate?)

 

[LionTamer]

@bixt thanks for the tips on clomid. I might reach out for a consultation with Dr. Saya to ask allll my questions, including his thoughts on clomid. Any other doctors you guys would recommend for me to hit with my battery of questions on TRT, peptides, and other means of (hopefully safe) supplementation? @DS3 @Nelson Vergel

@readalot

I never took a moment to recognize your well-written posts and good grammar. It's clear you are really put in the effort here. I appreciate that.

Thanks for the kind words.

Regarding #1, bloodwork on its own isn't going to pick up morphological changes to your heart, fibrosis of the heart muscle, changes in the hemodynamics of your heart chambers. You'll need regular EKG/echocardiograms to monitor this (you keep omitting these in your responses). I guess you'd also be taking your blood pressure regularly. You don't know from the get go how sensitive your critical muscle is to exogenous androgen use.

How about potential autonomic dysfunction? Will you be tracking HRV (heart rate variability) from baseline accurately to see if there's an issue? HRR (heart rate recovery)? Using a fitbit or some other tracker? There are subtle changes that may happen over time.

I think you've nailed it here. I could get a quarterly EKG and wear a fitbit both before and after I start TRT to measure the changes. Are there any other vital signs or health markers I should monitor, if you had to create a list, in addition to Nelson's protocol?

But I promise you I'm not trying to be obtuse. I understand that what you're stating is that there are unknown unknowns and that these are just examples of those unknown unknowns.

 

[Systemlord]

I did get a phlebotomy yesterday and blood pressure did drop right after, we checked my blood pressure before and after. The blood pressure prior to the blood letting was 139/95 and after 115/66.

I know that might not be significant, but over 30-40 years... I'm on a beta blocker as well.

The 500 ml of blood was discarded.

 

[bixt]

@LionTamer Turns out that thread with clomid wasnt deleted after all. Enjoy.

"Interesting alternative to t-replacement therapy. I am 35, healthy, regular lifter. Recently I was curious about raising my testosterone to assist my general well being and lifting. I have an endocrinologist who put me on Clomid 25mg every other day. Within 30 days my t went from Total T 687 to 1352, and my free t went from 114 to 258. These numbers are off the charts, and I feel amazing, my libido is crazy!"

Clomid for Testosterone

Interesting alternative to t-replacement therapy. I am 35, healthy, regular lifter. Recently I was curious about raising my testosterone to assist my general well being and lifting. I have an endocrinologist who put me on Clomid 25mg every other day. Within 30 days my t went from Total T 687 to...

www.rooshvforum.com

 

[bixt]

Now, it seems anecdotally when perfectly normal people (who are not low T) take clomid, they get a T boost AND do not experiance the bad effects of clomid.

 

[tareload]

Role of Renin-Angiotensin-Aldosterone System Activation in Promoting Cardiovascular Fibrosis and Stiffness

www.ahajournals.org

Nice review of why too much T may not be a good idea for you.



Other resources that form a nice primer below:

Physiology, Cardiac Output - StatPearls - NCBI Bookshelf

Frank–Starling law - Wikipedia

en.wikipedia.org

 

[tareload]

The results are interesting. The R2 of testosterone alone is decent. However, as you point out, the results indicate that doses of 100 ng per week or less create toxic effects over long-term exposure. Which is perhaps, as noted, a result of rats being more sensitive to testosterone exposure even at lower doses.

Thanks for taking a look and providing your feedback. Regarding your point above, I see where I may have misled people in post #93. In that post I extrapolated the logarithmic regression line for the rodent data back to TRT-type doses and observed the model implied a toxic effect within 10 years:

EDIT: if you are curious what the regression line (above) predicts for various HEDs:

HED (mg/week for 90 kg man)	duration (human years)
25	8.6 (extrapolation)
50	7.4 (extrapolation)
100	6.2 (extrapolation)
200	5.0
400	3.9
800	2.7
1600	1.5
3200	0.3

Extrapolating is a big leap. Afterwards I added two data points to adjust the best fit curve to reflect doses under 100 mg/week were non-toxic for practical purposes (again one has to understand the serum levels at the individual level for each dosage/dosing strategy). Hence the real question is if there are "TRT" dose data for rodents and where they would show up on the curve.



I've found some Test Ester PK data for rodents and I'll review that at some point in this thread in the context of their typical baseline serum levels.

 

[tareload]

Nandrolone for Mood | Feeling much Better..

Also, I haven't read the mouse study, but it occurs to me that in the early days of Low Carb, there was an attempt to show that (I think) olive oil was toxic using FMD as a measure. However I believe Volek subsequently showed that it was a short-term affect which disappeared after several weeks...

www.excelmale.com

Subjects and study design​

Study subjects included 27 healthy volunteers originated from the study population described in more detail elsewhere.14 All participants were males aged 18–50 years, with a body mass index (BMI) range of 18.2–28.7 (median value 24.3) who gave informed consent consistent with the approval of the Ethics Review Board. All subjects underwent a medical examination before enrolment to exclude any possible diseases. The participants were not taking any kind of substance that could interfere with testosterone metabolism and were tested negative for illegal drugs, AAS, HIV and hepatitis B or C. For inclusion it was also required that the subjects did not belong to the Swedish Sports Confederation nor had had a malignancy within the past five years. The participants were given 500 mg testosterone enanthate as a single intramuscular dose (Testoviron®–Depot kindly provided by Schering Nordiska AB, Solna, Sweden) equivalent to 360 mg testosterone. The testosterone dose among AAS abusers varies depending on the purpose of their abuse and which other AAS they co-administrate, but most abusers report testosterone doses corresponding to 500–2000 mg testosterone enanthate/week. For safety reasons, we chose the lower dose in this range. Before administration, a baseline morning urine sample was collected (day 0) and morning urine was further collected on days 1 and 2. The urine samples were collected and kept refrigerated for a maximum of 48 h and then frozen at −20°C. Adverse drug reactions (ADRs) were monitored from the time of screening until day 15 after administration of testosterone. No ADRs were registered and no follow-up was needed. The study was conducted according to the Helsinki declaration and the ICH Harmonized Tripartite Guideline for Good Clinical Practice, and was approved by the Ethic Review Board, Karolinska Institutet.

Nandrolone for Mood | Feeling much Better..

Also, I haven't read the mouse study, but it occurs to me that in the early days of Low Carb, there was an attempt to show that (I think) olive oil was toxic using FMD as a measure. However I believe Volek subsequently showed that it was a short-term affect which disappeared after several weeks...

www.excelmale.com

 

[tareload]

Nandrolone for Mood | Feeling much Better..

Also, I haven't read the mouse study, but it occurs to me that in the early days of Low Carb, there was an attempt to show that (I think) olive oil was toxic using FMD as a measure. However I believe Volek subsequently showed that it was a short-term affect which disappeared after several weeks...

www.excelmale.com

 

[Deleted member 43589]

The difference between 600ng/dl and 1100ng/dl is going to be tiny if anything, with regards to gains.

You are wasting your time and needlessly shutting down natural production for....nothing.

I agree, the difference you will see from 600 to 1100 is going to be minimal. I just ran mine up to 2103 trying to find my sweet spot and the only real difference is I gained a few pounds and feel pretty good. At my age I need to realistically be down quite a bit. I am at 830 now.

The risk/benefits have to be your decision. Lots of guys have done pretty large mg doses/wk for 12 weeks and then are off the rest of the year and have no problem.

 

[tareload]

I wonder when our favorite Youtubers will get around to reviewing this book chapter (2021):

High Testosterone Levels: Impact on the Heart

Nothing earth shattering but nice review with comprehensive references.

 

[Deleted member 43589]

Nice! You know Readalot, there have been quite a few well known pro bodybuilders come out lately and tell what they really took. Every one of them was taking FAR less that what these internet warriors claim they take without even knowing any of them. Yet these pros are called liars. Some times I am shocked about what is being told you need to take to be competitive. I know a whole lot of guys who do some absolutely huge doses and so far none of them have ever walked onto a Olympia stage. We live in a world of instant gratification and so many want to be at the top of the game tomorrow and are not willing to dedicate themselves to work that has to be done. They honestly believe the more drugs they take the quicker they will get there. STUPID!

 

[tareload]

Nice! You know Readalot, there have been quite a few well known pro bodybuilders come out lately and tell what they really took. Every one of them was taking FAR less that what these internet warriors claim they take without even knowing any of them. Yet these pros are called liars. Some times I am shocked about what is being told you need to take to be competitive. I know a whole lot of guys who do some absolutely huge doses and so far none of them have ever walked onto a Olympia stage. We live in a world of instant gratification and so many want to be at the top of the game tomorrow and are not willing to dedicate themselves to work that has to be done. They honestly believe the more drugs they take the quicker they will get there. STUPID!

see case report from June 2022 in case your are interested. Too bad they didnt do more digging on integral amounts used over 18 year period...


Unfortunately both of us know something of this @BigTex . I hope you are doing well.


A unique case of tachycardia-mediated cardiomyopathy in a patient misusing anabolic steroids

 

[Deleted member 43589]

Interesting that these doctors thought it best to discontinue using anabolic steroids at any dose. I can't imagine how low his T levels went after being on for 18 years, stopping all testosterone and taking spironolactone. The spironolactone must have made his estrogen level hit the roof. I can't understand why cardiologists love putting people on this drug. Seems to me to be a case of doctors who are wanting to make steroid use to be the bad guy. I have had two doctors try to put me on spironolactone and I absolutely refused.