What is TRT and What is NOT TRT

[gerardo]

Note: I originally posted this over at T-Nation so hope it's ok if I share it here @Nelson Vergel. Had an interesting and lively exchange over there with one of the proponents of the "TOT" protocol (Testosterone Optimization Therapy as it is called). This short summary gives guys a look of levels vs dose/dosing and an approach to potentially avoid major sides when just starting out (Hct, Blood pressure, etc) vs other approaches guys are running into with "TOT/supra-level" protocols.

What is TRT

For the curious minds or folks seeking a better understanding, TRT stands for Testosterone Replacement Therapy. The R stands for replacement, not enhancement, or elevation. Sometimes there seems to be some confusion between the TRT and pharma section.

The human male on average produces about 6 maybe 7 mg a day of testosterone (Testosterone, aging, and the mind - Harvard Health). That’s 42-49 mg of testosterone per week. Testosterone production varies over the course of a day with many studies showing a peak in the morning (say 8 AM) and lull in the evening. Looking deeper:


Hypogonadotropic Hypogonadism (HH) and Gonadotropin Therapy - Endotext - NCBI Bookshelf



View attachment 11615

Usually there’s peaks and valleys multiple times per day in LH levels. A normal male can dip to below 300 ng/dL TT over the course of the day.

So with that out of the way, what’s the distribution of testosterone levels in healthy adult males? Here’s a nice summary of the distribution of testosterone levels in healthy males vs age.


A Validated Age-Related Normative Model for Male Total Testosterone Shows Increasing Variance but No Decline after Age 40 Years

View attachment 11619


To convert the units on the y-axis to the more typical units (ng/dL, at least in US) multiply by 28.84 (testosterone molecular weight = 288.42 g/mol). So not to bore you, the 99 percentile range works out to 173 (1%) to 1000 ng/dL (99%) for a ~20 year old man. Therefore, only true freaks are walking around with peak testosterone levels above 1000 ng/dL. To put that in perspective, the CDC 99% reference for height in men is about 6’4’’. How many guys on here are 6’4’’ and taller?

Notice you can find all the natural T-Nation members up there in the top right corner with TT of about 50 nmol/L or 1442 ng/dL .

Some of you may bristle at this reality so let me be a little more generous and call “physiologic” a range from 300 – 1200 ng/dL since I know how many studs we have visiting this forum. Sound fair?

Ok, so now let’s get to the pharmacokinetics of testosterone ester preparations which a lot of guys are using. The plots below were generated assuming testosterone cypionate which has a realistic first order elimination half life of about 4.5 days (see reference below).


Population Pharmacokinetic/Pharmacodynamic Modeling of Depot Testosterone Cypionate in Healthy Male Subjects


I’m not going to go into the details of apparent/actual metabolic clearance rate of testosterone here as not many people care and only 1 part per million in the world understand it. In case you want more info:

AAS That Don't Increase Total T?

Youtube videos clearly more entertaining than my posts. But remember, the educational value of something typically inversely proportional to the entertainment value. Greg Doucette seems to be the rare exception since he does a decent job with both but you won’t find the above discussion on...

forums.t-nation.com

Just realize it (the apparent metabolic clearance rate) controls the dose vs the serum levels of total testosterone over time. Insert more math here with SHBG, free T, blah blah. Add @Cataceous nice posts.


Here’s the time vs testosterone plot for 70 mg testosterone cypionate (TC) per week (dosing intervals of once per week and twice per week). Wait a few weeks and you reach steady state (skipping the LH suppression piece and decay of endogenous T production that most will find dry). TC has a molecular weight (MW) of 412.605 g/mol. Testosterone has MW of 288.42 g/mol. Hence TC is 69.9% testosterone by weight and 70 mg/week of TC is 49 mg/week of testosterone.


To makes things simple I’ve assumed the absorption is very fast (can revise these with accurate absorption kinetics as well if folks interested) and elimination follows first order kinetics (to simplify things a bit but not too simple).

View attachment 11618



I tuned the ratio of clearance to volume of distribution to fit my peak and trough data. With 70 mg/week (once weekly injection), my peak is about 930 and trough is 330 ng/dL. Confirmed with blood work. If I inject every 3.5 days, peak is 750 and trough is 450 ng/dL. I am comfortably inside the physiologic range (green shading) for either dosing strategy.


Ok, so how about 160 mg/week (that’s 112 mg of testosterone per week):
View attachment 11617

Once again confirmed with blood work, if I inject once per week my peak is 2150 ng/dL and trough is 766 ng/dL. If I inject every 3.5 days (twice weekly) peak goes to 1700 and trough is 1000 ng/dL. Remember the green shaded region is the range I spotted you as “physiologic”. So at either dosing frequency, I am running supraphysiologic for peak and get back into physiologic for trough.

Considering supraphysiological fluctuations and fluctuations in normal levels, it could be said that the higher the dose of testosterone at supraphysiological levels, the side effects will also be greater. If you have testicular atrophy with doses of T at physiological levels then will you have greater atrophy with supraphysiological levels?

 

[S1W]

Considering supraphysiological fluctuations and fluctuations in normal levels, it could be said that the higher the dose of testosterone at supraphysiological levels, the side effects will also be greater. If you have testicular atrophy with doses of T at physiological levels then will you have greater atrophy with supraphysiological levels?

In my experience, no.

 

[gerardo]

In my experience, no.

In your case, whatever the testosterone dose for TRT do you have, for example, the same level of testicular atrophy and hematocrit levels?

 

[gerardo]

In conclusion, these were results tailored to my volume of distribution and clearance rate. Those two parameters for you will be different. See this paper. Therefore, if you want to run physiologic ranges (which by definition is TRT), you’ll need to map your peak and trough to your dosage and dosing frequency. See for example the exchange here I had with our good friend Danny. He and I have very different clearance. You can see from the plots above that having a trough at 1000 ng/dL when dosing either weekly or biweekly with TC is not TRT and depending on your dosing frequency you may be spending a majority of the time above physiologic range. In my particular case this caused elevation of Hct, higher BP. Upon switching to 70 mg/week of TC and staying in range all of the time, all these issues went away.

I think it happened to me because I have low SHBG 13. As soon as I started my TRT I started with EOD cypionate and then ED. I tried several times but the hematocrit got out of control and the BP went up. I think I have a very high sensitivity to cypionate. I had to go to TRT. Seeing your post I will try to start again by injecting only 20mg of cypionate once a week and I will follow up and make adjustments. I used the Nebido for 1 year. One injection every 3 months. The hematocrit was controlled. 48..49. Did the constant decline of the fog help the hematocrit?

 

[tareload]

I think it happened to me because I have low SHBG 13. As soon as I started my TRT I started with EOD cypionate and then ED. I tried several times but the hematocrit got out of control and the BP went up. I think I have a very high sensitivity to cypionate. I had to go to TRT. Seeing your post I will try to start again by injecting only 20mg of cypionate once a week and I will follow up and make adjustments. I used the fog for 1 year. One injection every 3 months. The hematocrit was controlled. 48..49. Did the constant decline of the fog help the hematocrit?

Hey, not following? What do you mean by "fog" in the above sentence?

Maybe this will help you better understand your Hct excursion vs TRT dose per week?

Study: Injection Frequency, Not Dosage, Indicates Risk of Polycythemia

My comments RE: increasemyt’s thread here. Feeling nostalgic for this big lug and even Danny Some guys just aren’t going to be able to handle >=120 mg/week without significant excursion to Hct. What that elevated Hct may mean long-term is your decision.

forums.t-nation.com

 

[gerardo]

Hey, not following? What do you mean by "fog" in the above sentence?

Maybe this will help you better understand your Hct excursion vs TRT dose per week?

Study: Injection Frequency, Not Dosage, Indicates Risk of Polycythemia

My comments RE: increasemyt’s thread here. Feeling nostalgic for this big lug and even Danny Some guys just aren’t going to be able to handle >=120 mg/week without significant excursion to Hct. What that elevated Hct may mean long-term is your decision.

forums.t-nation.com

I mean the Nebido / aveed

I already read this topic that you sent me. Based on my protocol with Nebido, what suggestion would you give me to restart a new protocol?

20mg of EOD cypionate didn't work for me. I remember that even the eighth day was good. That is, I applied 4 doses of 20mg of cypionate and then I had to stop. So I still have doubts about the dose of cypionate to reach the point of saturation of hepicidin and EPO. Returning to Nebido, I think that instead of starting with 1000 mg, maybe starting with 750 mg and going with the hematocrit, but I would like to try the cypionate.

 

[xqfq]

I think that's basically it. The testosterone molecules have some extra neutrons. I assume "trideuterated" means that three hydrogen molecules are actually deuterium—see deuterated drug. It's a pretty clever method for labeling; historically you'd label with a radioactive isotope to trace such things. But mass spectrometry is sensitive enough to detect the difference between regular testosterone and the testosterone with extra neutrons. In this way you can dispense with the radioactivity.

If this is correct then the technique mirrors what's done with traditional labeling to determine MCR:

It has been shown that the physiologic concentration of a steroid hormone in the circulation is directly proportional to its production rate; therefore,​

​

PR/C = k​

​

where PR is the production rate of the hormone, C is its concentration in the circulation, and k is the proportionality constant. This constant was named the metabolic clearance rate (MCR).​

​

The MCR of a steroid hormone is defined as the volume of blood that is irreversibly cleared of the steroid per unit of time and is usually expressed in liters per day. It is measured by intravenously infusing the radioactive form (usually tritiated) of the steroid, either as a single dose or as a constant rate over a prolonged period (e.g., 2 hours). The radioactive steroid that is infused should have a high specific activity (radioactivity per unit mass), so that only a minute mass of the steroid is administered and the mass does not contribute significantly to the concentration of the endogenous hormone.​

​

The single injection and constant infusion methods yield equivalent MCR for a particular steroid. In the single- dose method, the changes in the concentration of radioactivity (disintegrations per minute [dpm]) associated with the hormone are measured as a function of time. The concentrations of radioactivity are plotted against time, and the areas under the resulting curves are measured. The MCR is then calculated using the following equation: MCR = dose-injected (dpm) divided by area under the radioactivity concentration–time curve (dpm x h/ml).​

​

Because the injected dose is expressed in dpm and the area under the curve as units of dpm per mL multiplied by hours, then the MCR units will be​

​

dpm ÷ (dpm × h)/mL​

​

which can be converted to liters per day. Similarly, if the labeled hormone is infused at a constant rate, a steady state of the radioactive hormone administered will be reached in blood, usually after 1 or 2 hours. A blood sample is taken at this time, and the MCR is calculated using the following equation: MCR = rate of infusion (dpm/h) divided by the concentration of radioactivity associated with the hormone in blood at steady state (dpm/mL).​

​

Because PR ÷ C = MCR, the production rate of a steroid hormone can be readily determined once its MCR and concentration are known. The concentration of the steroid, C, can be measured by radioimmunoassay, whereas the MCR can be determined as described. ...​

[R]​

While these studies provide an average, they have a very small sample size. While the metabolic clearance rate of this trideuterated testosterone molecule may pretty standard between men, isn't testosterone metabolized into inactive metabolites in different men at very different rates? Wouldn't these metabolites still have the trideuterated form and thus would would show up in these "traces" until they were cleared from the body?

I have read that:

"Approximately 50% of testosterone is metabolized via conjugation into testosterone glucuronide and to a lesser extent testosterone sulfate by glucuronosyltransferases and sulfotransferases, respectively" (Testosterone - Wikipedia)

With respect to these metabolites, I found this study on doping which showed that some men with a certain gene have fairly different rates of metabolism of testosterone: Doping test results dependent on genotype of uridine diphospho-glucuronosyl transferase 2B17, the major enzyme for testosterone glucuronidation - PubMed

I am not sure what to make of this yet. I think it is probably wrong to assume someone is e.g. supraphysiological based on dose of testosterone alone (which I don't see on this forum but do see on others).

 

[Cataceous]

While these studies provide an average, they have a very small sample size. While the metabolic clearance rate of this trideuterated testosterone molecule may pretty standard between men, isn't testosterone metabolized into inactive metabolites in different men at very different rates? Wouldn't these metabolites still have the trideuterated form and thus would would show up in these "traces" until they were cleared from the body?
...

The clearance of the labeled testosterone is supposed to mirror the clearance of endogenous testosterone. At least for the mass spectrometry method of measuring MCR the labeled metabolites don't matter because they are not measured. Perhaps in the radiolabeling method concentrations of these metabolites are assumed to be relatively low compared to the labeled testosterone.

...
I am not sure what to make of this yet. I think it is probably wrong to assume someone is e.g. supraphysiological based on dose of testosterone alone (which I don't see on this forum but do see on others).

It may be wrong in borderline cases, but with virtually all natural men making less than 10 mg T per day, when I see guys averaging 15-20 mg per day of exogenous T I don't hesitate to label it an overdose. Of course usually they're also reporting trough testosterone over 1,000 ng/dL and various side effects.

 

[tareload]

Ok, I modified these graphs a little bit to help people understand why the 200 mg/week Test ester protocol right off the bat is seldomly the correct place to start if you want to target even high end of the reference range for TRT/TRT+


The reference I adapted this from paper that used 20-39 year olds:

200 mg/week of Test ester is going to put majority of these young guys above range:

There’s another few references I will eventually use to show plots for the older guys who will run even higher serum TT levels on the same dose as the younger guys (in general). In conclusion as I debated tirelessly with you know who at T-Nation, you can use this plot above to see why large majority of the TRT universe will be dosing somewhere in the 50 to 125 mg/week test ester range (includes both in-network PCPs and what should be happening at cash pay clinics for those who don’t really want TOT but instead true TRT).

EDIT: yes the shape of the Bell curves on the log plot should get skewed more the higher you get on the chart but this is free and you get the idea and I haven’t corrected that issue yet. Hence I left the bell curve off the 500 mg/week vertical operating line.

@Nelson Vergel

 

[bixt]

200 mg/week Test ester

This data was collected at trough with a weekly injection frequency right?

 

[tareload]

This data was collected at trough with a weekly injection frequency right?

Population Pharmacokinetic/Pharmacodynamic Modeling of Depot Testosterone Cypionate in Healthy Male Subjects - PubMed

A randomized, double-blind clinical trial was conducted to investigate long-term abuse effects of testosterone cypionate (TC). Thirty-one healthy men were randomized into a dose group of 100, 250, or 500 mg/wk and received 14 weekly injections of TC. A pharmacokinetic/pharmacodynamic (PK/PD)...

pubmed.ncbi.nlm.nih.gov

Both "intensive" (within the week) and"extensive" (weekly troughs) for weekly injection frequency. I used both data sets to estimate mean serum TT over the week (mean serum level from the 3 point AUC).

 

[tareload]

Here is an example plot:

Either one of these injection frequency options will have the same mean at steady state:

 

[tareload]

And here's the Bhasin studies (confidence intervals a little tighter on these papers):

Older Men Are as Responsive as Young Men to the Anabolic Effects of Graded Doses of Testosterone on the Skeletal Muscle

Although testosterone levels and muscle mass decline with age, many older men have serum testosterone level in the normal range, leading to speculation abo

academic.oup.com

Testosterone dose-response relationships in healthy young men

The ordinate (y-axis) is mean AUC TT level which I calculated as ~1.6*TT(trough) from the papers.

Again, easy to see why older fellas may run into trouble quickly with the T-mill 200 mg/week TC/TE dosing.

@Nelson Vergel please feel free to use these in your wonderful educational materials as you see fit. Might be useful in this form to help educate news guys on dose response.

 

[tareload]

What is TRT and What is NOT TRT

Another item I wanted to check. Here’s a real world provider set from @highpull that we discussed some time ago. I’ve put those data on the graph I shared above to see how they match up. Since almost all the data he shared are trough TT values (I culled the few non-trough values as per...

forums.t-nation.com

A TRT+ provider's data set placed on the plot shared above:



Summary for the 200 mg/week group:

• 70% of patients have mean TT level above 1200 ng/dl
• 87% above 1000 ng/dl
• 96% above 800 ng/dl

Summary for the 160 mg/week group:

• 77% of patients have mean TT level above 1200 ng/dl
• 85% above 1000 ng/dl
• 92% above 800 ng/dl

So as you can see leveraging both (1) clinical trial literature data and (2) generous data provided by a TRT practitioner on T-Nation, doses > 150 mg/week Test Ester result in majority of patients having AUC mean TT level above 1200 ng/dl.

 

[tareload]

@Dr Justin Saya MD

"Quick" questions if you don't mind...haha.

What is the mean weekly dosage of test ester used with your patient population? N=?

Mean with SD would be even better. Is that a fairly normal distribution once normalized for body mass or lean body mass?

I get in vigorous debates with TOT proponents who claim 150-175 mg/week is either the typical or even minimum dosing in the vast TRT/TOT universe. I find that extremely hard to believe given what we know about the dose response distribution with injectable testosterone. Perhaps that is the A4M universe?

Paging Garrison Keillor or are most patients running 1000-1200 ng/dl troughs?

@Nelson Vergel if you have data could you share based on your knowledge and vast experience in this space?.

Thanks so much for considering.

Would be great to build/expand a dose response chart like I've already started on here and over at Tnation with a provider's data set. Any other providers ?

Dr. Keith N...I know you are reading this. Feel free to chime in with your patient distribution as well. I speak cream too so we can build your cream dose response chart as well

 

[tareload]

Target T levels & Defy

Or does it? With performing an actual regression with 60+samples on his data, its hard to say * without performing the regression I see I cant edit posts anymore

www.excelmale.com

 

[Dr Justin Saya MD]

@Dr Justin Saya MD

"Quick" questions if you don't mind...haha.

What is the mean weekly dosage of test ester used with your patient population? N=?

Mean with SD would be even better. Is that a fairly normal distribution once normalized for body mass or lean body mass?

I get in vigorous debates with TOT proponents who claim 150-175 mg/week is either the typical or even minimum dosing in the vast TRT/TOT universe. I find that extremely hard to believe given what we know about the dose response distribution with injectable testosterone. Perhaps that is the A4M universe?

Paging Garrison Keillor or are most patients running 1000-1200 ng/dl troughs?

@Nelson Vergel if you have data could you share based on your knowledge and vast experience in this space?.

Thanks so much for considering.

Would be great to build/expand a dose response chart like I've already started on here and over at Tnation with a provider's data set. Any other providers ?

Dr. Keith N...I know you are reading this. Feel free to chime in with your patient distribution as well. I speak cream too so we can build your cream dose response chart as well

View attachment 21596

Always insightful posts readalot.

The bell curve for our patients lies mostly between 100mg - 180mg weekly, with the mean right around 140mg estimated. Of course there are outliers above and below, but this would account for the majority.

 

[tareload]

Always insightful posts readalot.

The bell curve for our patients lies mostly between 100mg - 180mg weekly, with the mean right around 140mg estimated. Of course there are outliers above and below, but this would account for the majority.

Great to know. Thanks very much for sharing that information. Plugging that info into graphics above would indicate a healthy mix of patients within and above physiologic range at trough (using appropriate multiplier to convert trough to mean with various dosing strategies...E7D, E3.5D, ED, etc.). Does that jive roughly with your patients' responses or would you say that the 2.5 and 97.5 percentiles above are different than what you've seen?

I assume at this point you have seen and treated a 5 figure number of patients with testosterone?

I had spent some time lately trying to flesh out the plot below. But it of course takes the input of folks with significant clinical experience to flesh out the intermediate region, the envelope if you will. Any thoughts on that zone with appropriate error bars?

While i gather that there are plenty of men out there who have run their TT levels at 2000+ ng/dl for years without major or measurable toxicity, i thought it useful to map something out that may be helpful for the more sensitive bottom quartile even. Thank you very much for your time.


More background and info here:

TRT to Supraphysiological Levels for Body Building

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...

www.excelmale.com

BTW: I am going to add @BigTex as his own data point on graph above. He's earned it.

 

[tareload]

Added the Xyosted 2018 sub-Q data set to the prior IM/Sub-Q data. As you can see completely self-consistent.

LINEAR scale ordinate:





LOG scale ordinate:





Goes to show how 50-75 mg/week TC is chemical castration (LMFAO).

And same data against the Bhasin work from 17 years earlier…




Hmmm. Seems like we’ve got a pretty good estimate of dose response with injectable testosterone in both male and FTM patients.

Stupid graphs.

What is TRT and What is NOT TRT

Added the Xyosted 2018 sub-Q data set to the prior IM/Sub-Q data. As you can see completely self-consistent. Thanks for catalyzing this @Andrewgen_Receptors with the SubQ discussion on the other thread. LINEAR scale ordinate: LOG scale ordinate: Goes to show how 50-75 mg/week TC is...

forums.t-nation.com

I better find another hobby. @madman what do you recommend?

 

[Cataceous]

I have to chuckle every time I read this. I'm seeing peak daily TT of 700 ng/dL on 4.4 mg/day, with SHBG ~30 nMol/L. Castration? I think not.