What is TRT and What is NOT TRT

readalot

Active Member
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

In the adult male, LH is secreted in pulses approximately every 2 hours (Fig. 2A) (7). However, considerable variability is observed in LH pulse patterns and there is a wide range of testosterone secretory patterns. Indeed, in 15% of normal men whose hypothalamic-pituitary-gonadal (HPG) axis was examined using frequent blood sampling, serum testosterone levels as low as 3.5 nmol/L were recorded (to convert to ng/dL, multiply by 28.6) following long inter-pulse intervals of LH secretion, although mean testosterone levels remained within the normal range (Fig. 3). This within-patient variation must be considered when interpreting single LH and testosterone measurements obtained during the evaluation of a male with suspected hypogonadism. This variability is particularly important in middle-aged and older men as up to 30% men that are found to have a low testosterone concentration, will have a normal level on repeat testing (8).

1605125562682.png


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

1605125797202.png



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:






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).

1605125768567.png




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):
1605125761367.png


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.


Finally, here’s 120 mg per week of TC (84 mg/week of testosterone).
1605125749852.png


Dosing weekly results in running above range for peak. At twice weekly, my peak is right on the edge.


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.


So when you read on some websites or see on some videos that 75-100 mg per week of TC is not enough for TRT, you need to do the work and determine if that is true for you. Just throwing out dosages is meaningless until you experimentally determine your clearance. Good luck and best wishes with your TRT.


For a good example of starting off on a TRT protocol, see this thread. Warms my heart that some people are getting pointed in the right direction when starting TRT.


Postscript: what’s my point here with all this? I hope to define terms and it’s important to know what a term refers to. There’s no judgement on my part for guys who want to run enhanced, but for the new guy coming here seeking education, he should start at minimum effective dose, start low and go slow. He deserves to understand the basics and I know this site wants to get the best information out to guys who are suffering. However, if you need to keep your trough testosterone level at 1,000 ng/dL on weekly or biweekly injection frequency to alleviate symptoms, the vast odds are your problem is not androgen deficiency. I’d love to hear others thoughts and data supported arguments.
 
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readalot

Active Member
Managing Hct when you are on the fine line between TRT and *pFRT (*pseudo-Function/Feeling Replacement therapy, mild cycle, supra, whatever you want to call it). Go too high it won't matter. But in the very fine gray zone, perhaps more infrequent injections will help if you are using injectable testosterone esters (weekly instead of daily):

Start here and read down. I'd love to hear other's feedback/criticism on the topic.


 
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readalot

Active Member
Nice summary for those that don't care about my math / scientific accuracy /harm minimization when it comes to differentiating TRT vs TOT (aka functional replacement therapy with supra-physiological levels of T to resolve symptoms for a disease/condition that isn't currently clinical defined):

 

Blackhawk

Member
I view the issue partly as one of semantics. Whereas your outlook at quantifying it all is intriguing, to me TRT is finding the lowest effective dose THAT ALLEVIATES SYMPTOMS, and that puts lab levels in reasonable range without provoking the problems of excess.
 

Willyt

Active Member
Appreciate all of the legwork you did. It does seem like most people starting off are prescribed doses that are way too high.

That said, the part that vexes me is that Free Testosterone levels seem to be more indicative of how you feel. Many of us higher SHBG guys need higher dose to bump up that Free T level.
 

Cataceous

Well-Known Member
I like to keep it simple with a couple rules of thumb: If you're injecting enanthate or cypionate once a week then your peak serum testosterone could be around 2.5 to 3 times higher than your trough. With twice-weekly injections the peak is around 50% higher than the trough. Although these are crude estimates they immediately reveal how ridiculous it is to have a trough over 1,000 ng/dL.

Just in the last few days I've talked to a couple guys with such measurements and problems with hematocrit, estradiol, etc.[1][2] But instead of being told to lower their TRT doses they are given AIs and told to donate blood. What are these doctors thinking????

In reference to needing periods of lower serum testosterone to avoid high HCT via hepcidin suppression you say "All this flies in the face of [the] philosophy to keep your T levels as constant as possible while on TRT. Also why [a] regimen of injections every 2 weeks isn’t quite as nuts as everyone makes it out to be." The idea I've been promoting is to do it the way nature intended: Make daily peaks and troughs with injections of a propionate/cypionate mixture. With this protocol you can actually use physiological dosing, 3-9 mg of testosterone per day, and attain normal levels of testosterone. This complexity may be unnecessary for most, but for those who can't find the balance point between low- and high-T symptoms it is something that should be investigated.
 

UCFguy01

Active Member
I like to keep it simple with a couple rules of thumb: If you're injecting enanthate or cypionate once a week then your peak serum testosterone could be around 2.5 to 3 times higher than your trough. With twice-weekly injections the peak is around 50% higher than the trough. Although these are crude estimates they immediately reveal how ridiculous it is to have a trough over 1,000 ng/dL.

Just in the last few days I've talked to a couple guys with such measurements and problems with hematocrit, estradiol, etc.[1][2] But instead of being told to lower their TRT doses they are given AIs and told to donate blood. What are these doctors thinking????

In reference to needing periods of lower serum testosterone to avoid high HCT via hepcidin suppression you say "All this flies in the face of [the] philosophy to keep your T levels as constant as possible while on TRT. Also why [a] regimen of injections every 2 weeks isn’t quite as nuts as everyone makes it out to be." The idea I've been promoting is to do it the way nature intended: Make daily peaks and troughs with injections of a propionate/cypionate mixture. With this protocol you can actually use physiological dosing, 3-9 mg of testosterone per day, and attain normal levels of testosterone. This complexity may be unnecessary for most, but for those who can't find the balance point between low- and high-T symptoms it is something that should be investigated.

But what if a guy has a peak around 1500 and a trough around 1000 and his hematocrit if fine and his E2 is fine, BP is fine......What's the problem?
 

Cataceous

Well-Known Member
But what if a guy has a peak around 1500 and a trough around 1000 and his hematocrit if fine and his E2 is fine, BP is fine......What's the problem?
Let's add good lipids and sexual function to the list of requirements. Even if all of that is fine then he's still participating in an experiment to determine if other issues will crop up from long-term exposure to high levels—we're assuming high free T too. I'm not suggesting the risks are high, but they're not zero either. What are the proven benefits of supraphysiological testosterone? Aren't they mainly in the realm of body composition and athleticism? If these are really important to the guy then maybe he can justify high levels. But should average guys on TRT be messing around with such levels in the first place? I don't think so. Look at these crazy situations where they get negative symptoms, and then the symptoms are attacked with treatments that cause other negative symptoms. There's no good reason for this.
 

readalot

Active Member
I view the issue partly as one of semantics. Whereas your outlook at quantifying it all is intriguing, to me TRT is finding the lowest effective dose THAT ALLEVIATES SYMPTOMS, and that puts lab levels in reasonable range without provoking the problems of excess.

Wow, thanks for that @Blackhawk, that is one elegantly written sentence. Easier said than done for guys wanting a "free lunch" on the GAINZ. TRT can become a gateway to a bad place so great point that we've constantly got to be honest with ourselves.
 

readalot

Active Member
Appreciate all of the legwork you did. It does seem like most people starting off are prescribed doses that are way too high.

That said, the part that vexes me is that Free Testosterone levels seem to be more indicative of how you feel. Many of us higher SHBG guys need higher dose to bump up that Free T level.

Thank you for the feedback. I've really been thinking about your second part. I realize I just skimmed the surface with TT (as intro material) when state of the art is free T/bio-T (free hormone hypothesis) and it's effect. Do the high SHBG dudes really need more exogenous T than low SHBG guys to hit the same free T level (say 15 ng/dL)? That's what confuses me with this study which I keep coming back to.

Differences in the apparent metabolic clearance rate of testosterone in young and older men with gonadotropin suppression receiving graded doses of testosterone


Look at the total T and free T by dosage group:

1605194616287.png

1605194634394.png


1605194694120.png

Going back and looking at the way free T was measured:
1605194883010.png


Sure will be nice to repeat a study like this once the TT/free T methods are harmonized @madman.

I tried to spot check some of the TT/free T/SHBG numbers with Vermeulen but they weren't making sense to me so I went back to the previous paper with the tabular data:

Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle
1605195091953.png

For the 600 mg/week group, TT = 3286 ng/dL, free T = 42.3 ng/dL, and SHBG = 38 nmol/L. Plugging the TT and SHBG into Vermeulen equation:

1605195336493.png

Using Tru-T method would only make the gap much, much worse.

Regardless, in this work (with what looks like a reasonable free T assay but may have artifacts) the free T was much higher in the high SHBG dudes than the low SHBG dudes (for the same injected dose) for dosages greater than or equal to 300 mg/week of Test ester. At more reasonable TRT dosages, free T levels across SHBG groups were not statistically different. Looking at the argument @Cataceous has brought up that free T levels should be governed by law of mass action, the data is consistent with that (up to 125 mg/week dosage). For the 300 and 600 mg/week cases (denoted with ** to show significant difference between % free T change from baseline between young/lower SHBG and older/higher SHBG guys), the data is not consistent with law of mass action since free T for same dose is higher for high SHBG guys (see Fig 2B in first paper cited).

In conclusion, this is probably a wild goose chase but goes through my thinking about the issue around whether high SHBG guys need more exogeneous T (to hit a target free T) than a low SHBG guys. Bring on the harmonized free T assays @sammmy !
 

Cataceous

Well-Known Member
Wow, thanks for that @Blackhawk, that is one elegantly written sentence. Easier said than done for guys wanting a "free lunch" on the GAINZ. TRT can become a gateway to a bad place so great point that we've constantly got to be honest with ourselves.
I like your rephrasing over at T-Nation: "If you raise this ([lowest effective dose]) past physiological levels, which cover the very vast vast majority of the human population (non-outliers, not clinically diseased), we do not know what may occur (especially long-term) as there is scant evidence either way of what the outcome might be for you."

There's a fresh reminder in research @madman recently posted. Sky's the limit on estradiol? Maybe not.
A paradoxical decline in semen parameters in men treated with clomiphene citrate
...
Elevated estradiol levels result in vacuolization and increased glycoprotein production impairing Sertoli cell function. It also disturbs communication with germ cells, increases collagen synthesis and fatty degeneration in the testicular connective tissue. All these actions collectively result in the induction of germ cell death (Leavy et al., 2017). Oestradiol also plays a critical role in round spermatid chromatin reorganization during spermiogenesis through its action on Estrogen Receptor Alpha (ERα) present on Sertoli cells (Cacciola et al., 2013). Overexposure to estrogens reduces the expression of ERα on Sertoli cells, impacting this critical action. Moreover, it has been recognized that supraphysiological concentrations of estrogen act as powerful apoptotic triggers that induce germ cell apoptosis (Correia et al., 2015).
 
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Wolverine

Member
I like to keep it simple with a couple rules of thumb: If you're injecting enanthate or cypionate once a week then your peak serum testosterone could be around 2.5 to 3 times higher than your trough. With twice-weekly injections the peak is around 50% higher than the trough. Although these are crude estimates they immediately reveal how ridiculous it is to have a trough over 1,000 ng/dL.

Just in the last few days I've talked to a couple guys with such measurements and problems with hematocrit, estradiol, etc.[1][2] But instead of being told to lower their TRT doses they are given AIs and told to donate blood. What are these doctors thinking????

In reference to needing periods of lower serum testosterone to avoid high HCT via hepcidin suppression you say "All this flies in the face of [the] philosophy to keep your T levels as constant as possible while on TRT. Also why [a] regimen of injections every 2 weeks isn’t quite as nuts as everyone makes it out to be." The idea I've been promoting is to do it the way nature intended: Make daily peaks and troughs with injections of a propionate/cypionate mixture. With this protocol you can actually use physiological dosing, 3-9 mg of testosterone per day, and attain normal levels of testosterone. This complexity may be unnecessary for most, but for those who can't find the balance point between low- and high-T symptoms it is something that should be investigated.
It would be great to trial the propionate/cypionate mixture but most docs won't prescribe that, only cypionate.
 

Cataceous

Well-Known Member
It would be great to trial the propionate/cypionate mixture but most docs won't prescribe that, only cypionate.
At least there's already a precedent, with Empower and APS both offering blends. Unfortunately these have too little propionate to give a natural daily variation in serum testosterone—according to my tests, anyway. If your doctor will only prescribe cypionate then you're kind of stuck. Even if you have a more progressive doctor who would prescribe a blend he might not be willing to openly endorse the self-compounding needed to get the right ester ratio.
 

Willyt

Active Member
At least there's already a precedent, with Empower and APS both offering blends. Unfortunately these have too little propionate to give a natural daily variation in serum testosterone—according to my tests, anyway. If your doctor will only prescribe cypionate then you're kind of stuck. Even if you have a more progressive doctor who would prescribe a blend he might not be willing to openly endorse the self-compounding needed to get the right ester ratio.
Thanks @Cataceous as always. Can you point me to your protocol and of the ratio you use. I have picked up snippets but don’t know if I have the whole picture.
 

Cataceous

Well-Known Member
...
Regardless, in this work (with what looks like a reasonable free T assay but may have artifacts) the free T was much higher in the high SHBG dudes than the low SHBG dudes (for the same injected dose) for dosages greater than or equal to 300 mg/week of Test ester. At more reasonable TRT dosages, free T levels across SHBG groups were not statistically different. Looking at the argument @Cataceous has brought up that free T levels should be governed by law of mass action, the data is consistent with that (up to 125 mg/week dosage). For the 300 and 600 mg/week cases (denoted with ** to show significant difference between % free T change from baseline between young/lower SHBG and older/higher SHBG guys), the data is not consistent with law of mass action since free T for same dose is higher for high SHBG guys (see Fig 2B in first paper cited).

In conclusion, this is probably a wild goose chase but goes through my thinking about the issue around whether high SHBG guys need more exogeneous T (to hit a target free T) than a low SHBG guys. Bring on the harmonized free T assays @sammmy !
As far as I can tell the study is at least not inconsistent with the points I've been arguing. For starters, the law-of-mass-action proportionality requires a linear relationship between dose and free T. We get that:
Image 11-12-20 at 1.07 PM.jpg

Image 11-12-20 at 1.08 PM.jpg

We know that the absolute metabolic clearances of subjects taking the same doses must be the same, high SHBG or low, young or old. At steady state, if you're taking in X mg per week of testosterone, then that's how much you're getting rid of each week. Call Dk some constant that's proportional to dose. Then:

MCR(young) * fT(young) = Dk = MCR(old) * fT(old)

or:

MCR(young) / MCR(old) = fT(old) / fT(young)

Taking the values from the graphs we get: MCR(young) / MCR(old) = 1.6

The young guys do have much higher metabolic rate constants.

What would be really nice to see is a non-linearity in total T with dose. Unfortunately it doesn't appear possible to illustrate with this dataset. Even among the young guys, the resulting SHBG values are too tightly grouped to show a divergence from the free T behavior. We would need an experiment in which there's a large difference in SHBG values.
 
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Cataceous

Well-Known Member
Thanks @Cataceous as always. Can you point me to your protocol and of the ratio you use. I have picked up snippets but don’t know if I have the whole picture.
Regarding testosterone, what works for me to achieve physiological variation is a 4:3 ratio of enanthate to propionate. Substituting cypionate for enanthate should make little difference. What's uncertain is how my absorption of propionate compares to everyone else's. Ideally guys should be running their own tests to confirm the results.

I've experimented with a few different levels using the combination. The highest was 3.7 mg TE and 2.8 mg TP daily. This is about 5 mg pure T per day, equivalent to 50 mg T cypionate per week. I've also gone as low as 2.8 mg TE and 2.1 mg T, which is like 38 mg TC per week. On the higher dose daily peak serum testosterone is around 800 ng/dL. On the lower dose it's in the 500s. Troughs should be roughly 40% lower.
 

readalot

Active Member
As far as I can tell the study is at least is not inconsistent with the points I've been arguing. For starters, the law-of-mass-action proportionality requires a linear relationship between dose and free T. We get that:
View attachment 11634
View attachment 11635
We know that the absolute metabolic clearances of subjects taking the same doses must be the same, high SHBG or low, young or old. At steady state, if you're taking in X mg per week of testosterone, then that's how much you're getting rid of each week. Call Dk some constant that's proportional to dose. Then:

MCR(young) * fT(young) = Dk = MCR(old) * fT(old)

or:

MCR(young) / MCR(old) = fT(old) / fT(young)

Taking the values from the graphs we get: MCR(young) / MCR(old) = 1.6

The young guys do have much higher metabolic rate constants.

What would be really nice to see is a non-linearity in total T with dose. Unfortunately it doesn't appear possible to illustrate with this dataset. Even among the young guys, the resulting SHBG values are too tightly grouped to show a divergence from the free T behavior. We would need an experiment in which there's a large difference in SHBG values.
Thank you very much for correcting my error caused by not plotting the data and playing the relative % increase on the p-values vs absolute numbers and correlation. Excellent work and poor work on my part to try an erroneous shortcut. Now my question is the functional relationship between true MCR and SHBG. Or is there some other parameters that govern MCR that are just correlated with SHBG (causation vs correlation)?

My own experience with oxandrolone tells me that SHBG has nothing to do with it. Then we are back to absorption kinetics of the testosterone ester and the flip flop kinetics: diffusion, lymphatic activity, all the stuff in the nandrolone depot paper @madman posted.

Fun, the SHBG status and age of the volunteers in the study (combined with basing MCR on Total T) can really lead people on a wild goose chase on what's driving what.

Thank you @Cataceous, always appreciate being around people smarter than myself!
 
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readalot

Active Member
As far as I can tell the study is at least is not inconsistent with the points I've been arguing. For starters, the law-of-mass-action proportionality requires a linear relationship between dose and free T. We get that:
View attachment 11634
View attachment 11635
We know that the absolute metabolic clearances of subjects taking the same doses must be the same, high SHBG or low, young or old. At steady state, if you're taking in X mg per week of testosterone, then that's how much you're getting rid of each week. Call Dk some constant that's proportional to dose. Then:

MCR(young) * fT(young) = Dk = MCR(old) * fT(old)

or:

MCR(young) / MCR(old) = fT(old) / fT(young)

Taking the values from the graphs we get: MCR(young) / MCR(old) = 1.6

The young guys do have much higher metabolic rate constants.

What would be really nice to see is a non-linearity in total T with dose. Unfortunately it doesn't appear possible to illustrate with this dataset. Even among the young guys, the resulting SHBG values are too tightly grouped to show a divergence from the free T behavior. We would need an experiment in which there's a large difference in SHBG values.
Unless I am brain dead today, this also shows the higher SHBG guys in this study needed less Test dosage to hit the same free T (say 20 ng/dL), not more.
 

Willyt

Active Member
Regarding testosterone, what works for me to achieve physiological variation is a 4:3 ratio of enanthate to propionate. Substituting cypionate for enanthate should make little difference. What's uncertain is how my absorption of propionate compares to everyone else's. Ideally guys should be running their own tests to confirm the results.

I've experimented with a few different levels using the combination. The highest was 3.7 mg TE and 2.8 mg TP daily. This is about 5 mg pure T per day, equivalent to 50 mg T cypionate per week. I've also gone as low as 2.8 mg TE and 2.1 mg T, which is like 38 mg TC per week. On the higher dose daily peak serum testosterone is around 800 ng/dL. On the lower dose it's in the 500s. Troughs should be roughly 40% lower.
And still on GnRH to maintain upstream?
 

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