What is TRT and What is NOT TRT

readalot

Active Member
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!

An interlaboratory study of the pharmacokinetics of testosterone following intramuscular administration to Thoroughbred horses

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Cataceous

Well-Known Member
... 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.
...
So people know what we're talking about I'll insert my earlier criticism of the MCR definition in this same study. I think it shows where SHBG fits in, and I also think SHBG is pretty independent of true MCR. I've noted before that with SHBG varying from low 40s nMol/L to low 20s, my free testosterone appeared to stay linear with dose.

The issue with this study is that they are basing MCR on total T rather than free T. The standard equation used is:
Production_rate = MCR * Hormone_concentration
But as I argued above, the proportionality applies to free testosterone, not total. So the equation should be:
Production_rate = MCR * Hormone_concentration = MCR * FT = MCR * f(SHBG, T)
The reason it might appear to work anyway is because at constant SHBG, free T is nearly proportional to total T. So you get:
Production_rate = MCR * f(SHBG, T) ~= MCR * f1(SHBG) * T = MCRx * T
The problem is that their measured clearance rate, MCRx, is actually dependent on both the underlying metabolism (MCR) and SHBG.

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.
I think what you're seeing is the difference in true metabolism between the young and old groups. Free testosterone in the older guys is forced higher to overcome their slower metabolisms, because they still have to eliminate testosterone at the same rate as the younger guys—with all on the same fixed doses of testosterone.
 

readalot

Active Member
So people know what we're talking about I'll insert my earlier criticism of the MCR definition in this same study. I think it shows where SHBG fits in, and I also think SHBG is pretty independent of true MCR. I've noted before that with SHBG varying from low 40s nMol/L to low 20s, my free testosterone appeared to stay linear with dose.

The issue with this study is that they are basing MCR on total T rather than free T. The standard equation used is:
Production_rate = MCR * Hormone_concentration
But as I argued above, the proportionality applies to free testosterone, not total. So the equation should be:
Production_rate = MCR * Hormone_concentration = MCR * FT = MCR * f(SHBG, T)
The reason it might appear to work anyway is because at constant SHBG, free T is nearly proportional to total T. So you get:
Production_rate = MCR * f(SHBG, T) ~= MCR * f1(SHBG) * T = MCRx * T
The problem is that their measured clearance rate, MCRx, is actually dependent on both the underlying metabolism (MCR) and SHBG.


I think what you're seeing is the difference in true metabolism between the young and old groups. Free testosterone in the older guys is forced higher to overcome their slower metabolisms, because they still have to eliminate testosterone at the same rate as the younger guys—with all on the same fixed doses of testosterone.
Said metabolism being the determining factor in absorption of the medication, which drives the apparent elimination kinetics based on the flip flop kinetics of test ester injection. Beautiful. Great summary!!
 

3percent

New Member
What benefits do you see when adding progesterone? what type do you take? i've seen men on trt take 100mg micronized progesterone



thanks
 
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Cataceous

Well-Known Member
What benefits do you see when adding progesterone? what type do you take? ...
The tangible effects are improved mood and sleep. I'm using the Susten brand injectable from AllDayChemist. I dilute it to 20 mg/mL because of the sub-milligram doses. When my current supply is used up I plan to have Defy prescribe it, and I'll buy it at a local pharmacy.
 

3percent

New Member
Thanks for the reply. I've been told that nandrolone and 100mg Micronized Progesterone is good. Have you tried it? please post any experiences or your opinion here

 

antelopers

Active Member
Great thread @readalot and great info as always @Cataceous ... question for you guys. If you're injecting a long ester like enanthate, and test at your tough and your level is say 900, then you go home and inject, how much lower could your levels be dipping before the testosterone starts to rise in the bloodstream? Is the effect in essence instant, or is there a delay?
 

Cataceous

Well-Known Member
Great thread @readalot and great info as always @Cataceous ... question for you guys. If you're injecting a long ester like enanthate, and test at your tough and your level is say 900, then you go home and inject, how much lower could your levels be dipping before the testosterone starts to rise in the bloodstream? Is the effect in essence instant, or is there a delay?
Under these circumstances the reduction in levels is going to be pretty trivial. Assuming a 5-day half-life, the reduction for each additional hour is exp(-ln(2) * 1 / (5 * 24)) = 0.9942, meaning a loss of 0.6% per hour. So starting from 900 ng/dL, after one hour it drops to 895, after two hours to 890, after three hours to 885, etc. After you inject your levels begin rising within the hour, so the true trough is going to occur shortly after that injection.
 
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:

View attachment 11621
View attachment 11622

View attachment 11623
Going back and looking at the way free T was measured:
View attachment 11624

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
View attachment 11625
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:

View attachment 11626
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 !

This is frightening. At first glance it looks like older men respond better. But it seems T (total and free) are floating around unused by tissue. I am 50. I am able to get with 20mg TE/d to get outside the range here in Germany it means above 1500ng/dl. Free was above 50. 2018 it was 1320 same daily dose, same esther. Even same supplier. Do you have any idea what exactly changes with age?
 

captain_j

New 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.



This is very interesting. I've been struggling with HCT issues myself, I am to a point now where I probably should be donating blood every 3 months. I can't say for sure, but it seems like once I went to ED injections this got worse. For the past year I've been on two main protocols, one at 200 mg week, and another at 140 mg a week, and have also tried 2x weekly, EOD, and ED. I switched to ED a while back just because I kept reading that if you have low SHBG like me (12 on the scale of 10-50) that you will feel better with EOD or ED injections. But injecting 20 mg daily keeps my free T pretty damn high and that needs to change. It has me curious to try 70 mg twice weekly and see how things end up. It's either that or just drop my daily dose down to something like 14 mg.
 

xqfq

Active Member
...
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.
....

I looked into this figure some time ago and wasn't able to verify it. The statement above is from a column in what is akin to a magazine, not a journal, and doesn't have a source attached to it. Digging into the literature, I was unable to find a study or paper that quantified the amount of testosterone in milligrams released in the average male.

Without further elucidation, I would guess this figure is not a direct measurement of testosterone released in milligrams from the testicles, but is instead an approximation based on serum levels.

If such a figure is an approximation based on serum levels, then using it to reason about the relationship between injected testosterone and serum levels would be potentially unreliable.

As a hypothetical, imagine some men metabolize testosterone much faster than others. Imagine their testicles produce 10mg a day of testosterone. When their serum testosterone is measured at its AM peak, it is 400 ng/dL. If some kind of direct measurement of testicular production of testosterone was used, then the man would be recorded as having 10mg/day of production; if an approximation based on serum levels was used, he might be recorded as having 4mg/day of production. I hope this example makes sense.
 
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Cataceous

Well-Known Member
I looked into this figure some time ago and wasn't able to verify it. ...
Here are a few random studies. These should be fodder for more specific criticism.
 
I looked into this figure some time ago and wasn't able to verify it. The statement above is from a column in what is akin to a magazine, not a journal, and doesn't have a source attached to it. Digging into the literature, I was unable to find a study or paper that quantified the amount of testosterone in milligrams released in the average male.

Without further elucidation, I would guess this figure is not a direct measurement of testosterone released in milligrams from the testicles, but is instead an approximation based on serum levels.

If such a figure is an approximation based on serum levels, then using it to reason about the relationship between injected testosterone and serum levels would be potentially unreliable.

As a hypothetical, imagine some men metabolize testosterone much faster than others. Imagine their testicles produce 10mg a day of testosterone. When their serum testosterone is measured at its AM peak, it is 400 ng/dL. If some kind of direct measurement of testicular production of testosterone was used, then the man would be recorded as having 10mg/day of production; if an approximation based on serum levels was used, he might be recorded as having 4mg/day of production. I hope this example makes sense.
You can read this: Testosterone Metabolic Clearance and Production Rates Determined by Stable Isotope Dilution/Tandem Mass Spectrometry in Normal Men: Influence of Ethnicity and Age
Go to table one, it is PRT in this paper, 9,11mg is high among white young males.
 

xqfq

Active Member

Fascinating. I was wondering how on earth this was calculated. So let me see if I understand what's going on here:

They set up an I.V. infusion of a substance that is a testosterone molecule bound to something else ("trideuterated testosterone"). Then because of known metabolic clearance properties of that "trideuterated testosterone", they use levels of the serum "trideuterated testosterone" levels to then figure out the metabolic clearance of testosterone. They then use the metabolic clearance rate to calculate the production rate. Does that sound right?
 

Cataceous

Well-Known Member
Fascinating. I was wondering how on earth this was calculated. So let me see if I understand what's going on here:

They set up an I.V. infusion of a substance that is a testosterone molecule bound to something else ("trideuterated testosterone"). Then because of known metabolic clearance properties of that "trideuterated testosterone", they use levels of the serum "trideuterated testosterone" levels to then figure out the metabolic clearance of testosterone. They then use the metabolic clearance rate to calculate the production rate. Does that sound right?
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]​
 

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