What is TRT and What is NOT TRT
- Thread starter tareload
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Yes, and also 600 mcg progesterone.
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.
T
tareload
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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!!
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.
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
www.excelmale.com
Nandrolone + Micronized Progesterone
Hello, Does anyone have any experience with Nandrolone only + Micronized Progesterone? I've been told its really good but want to see others opinions before trying it thanks
www.excelmale.com
@readalot you have given me much to think about regarding the right dose to keep my peak within physiological range. You and @Cataceous should write a book, seriously.
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?
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.
andrepohlann
Member
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?
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.
What Benefits with Different Injection Frequencies?
I’ll posit this has to do with both dose and frequency. If I remember correctly trying to trace back the kinetics of testosterone on hepcidin suppression and to EPO, it’s first order. Once you reach saturation, you can’t make more RBCs. If your dosages are too high then daily frequency ain’t...forums.t-nation.com
What Benefits with Different Injection Frequencies?
See the dose response of testosterone effect on hepcidin followed by saturation after going past roughly 125 mg/week. Older guys more pronounced effect. So once you elevate past the upper limit on testosterone physiologic range, no additional penalty on Hepcidin suppression (i.e. saturation)...
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
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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Here are a few random studies. These should be fodder for more specific criticism.
Plasma Production Rates of Testosterone in Normal Adult Men and Women and in Patients with the Syndrome of Feminizing Testes1
The daily plasma productionrate of testosterone was measured in normal men and women and in 2 patients with the complete form of the syndrome of feminizing
academic.oup.com
Estradiol and testosterone metabolism and production in men with prostatic cancer - PubMed
We recently observed a familial influence on the plasma concentration of sex-steroids and the metabolic clearance in men with prostatic cancer. We have now determined, by isotope dilution techniques, the blood estradiol and testosterone production and clearance rates in men with prostatic cancer...
pubmed.ncbi.nlm.nih.gov
Testosterone metabolic clearance and production rates determined by stable isotope dilution/tandem mass spectrometry in normal men: influence of ethnicity and age - PubMed
The metabolic clearance rate (MCRT) and production rate (PRT) of testosterone (T) were measured using constant infusion of trideuterated (d3) T and quantitating serum d3T by liquid chromatography-tandem mass spectrometry (LC-MS-MS). Serum unlabeled T (d0T) was measured by LC-MS-MS, and serum...
pubmed.ncbi.nlm.nih.gov
Mean Plasma Concentration, Metabolic Clearance and Basal Plasma Production Rates of Testosterone in Normal Young Men and Women Using a Constant Infusion Procedure: Effect of Time of Day and Plasma Concentration on the Metabolic Clearance Rate of Test
Abstract. Plasma specimens were obtained from 2 normal men and 2 normal women at 90-min intervals (16 specimens) during a 24-hr period, pooled and analyzed
academic.oup.com
andrepohlann
Member
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?
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]
T
tareload
Guest
Thought I'd share this well-written paragraph (last updated Oct 2020) attempting to describe state-of-the-art with respect to free hormone hypothesis. Unclear what the utility of "free T" actually is when trying to determine androgen sufficiency:
Androgen Physiology, Pharmacology, Use and Misuse
Transfer of hydrophobic steroids into tissues is presumed to occur passively according to physicochemical partitioning between the hydrophobic protein binding sites on circulating binding proteins, the hydrophilic aqueous extracellular fluid and the lipophilic cellular plasma membranes. According to the free hormone hypothesis (78-80), recently restated and updated (62), the free (non-protein bound) fraction of testosterone is the most biologically active with the loosely protein-bound testosterone constituting a less accessible but mobilizable fraction, with the largest moiety tightly bound to SHBG constituting only an inactive reservoir. The free hormone hypothesis derived from now outdated 1970’s pharmacological theory on the mechanism of drug-drug interactions as due to mutual protein binding displacement; however, this theory is long superseded in molecular pharmacology by well-established physiological mechanisms such as cytochrome P450 enzyme induction, drug transporter activity and cognate mechanisms unrelated to binding to circulating proteins (81). As the free and/or bioavailable fractions would also have enhanced access to sites of testosterone inactivation by degradative metabolism that terminates androgen action, the free fractions may equally be considered the most evanescent and least active so that the net biological significance of the free or bioavailable fractions remains unclear and undermines a theoretical basis for the free hormone hypothesis. Furthermore empirical evidence indicates that, rather than being biologically inert, SHBG participates actively in cellular testosterone uptake via specific SHBG membrane receptors, uptake mechanisms and signaling via G protein and cyclic AMP (82-86). These mechanisms include the megalin receptor, a multi-valent low-density lipoprotein endocytic receptor located on cell surface membranes that can mediate receptor-mediated cellular uptake of SHBG loaded with testosterone by endocytosis (87, 88) and might influence tissue androgen action (89, 90). Consequently, lacking a physiological basis for the free hormone hypothesis (91) and with empirical evidence in its favor scarce and speculative, it is refuted by intensive, prospective clinical evaluation (92). Hence, the biological significance of partitioning circulating testosterone into these derived fractions remains to be firmly established and its clinical application is unknown or possibly misleading. Furthermore, direct measurement of free testosterone requires laborious, manual methods only available in research or specialist pathology laboratories. Where available, they are costly and lack any external quality control programs or validated reference ranges. As a result, calculations purporting to replicate dialysis-based measurements are often substituted for direct measurements. These formulae come in two different formats – equilibrium binding equations requiring assumptions on testosterone binding stoichiometry and arbitrary plug-in binding affinity estimates (Sodergard (93), Vermeulen (94), Zakharov (95)) or assumption-free empirical methods (Ly(96, 97), Nanjee-Wheeler (98)) calibrated directly to dialysis-based laboratory measurements. Direct comparison has proven that empirical equations are more accurate compared with laboratory dialysis-based measurements (95, 96, 99, 100). Furthermore, calculations of free testosterone using any formula do not contribute significant to mortality or morbidity prognosis for older men’s health beyond accurate measurement of serum testosterone by liquid chromatography-mass spectrometry (92).
Androgen Physiology, Pharmacology, Use and Misuse
Transfer of hydrophobic steroids into tissues is presumed to occur passively according to physicochemical partitioning between the hydrophobic protein binding sites on circulating binding proteins, the hydrophilic aqueous extracellular fluid and the lipophilic cellular plasma membranes. According to the free hormone hypothesis (78-80), recently restated and updated (62), the free (non-protein bound) fraction of testosterone is the most biologically active with the loosely protein-bound testosterone constituting a less accessible but mobilizable fraction, with the largest moiety tightly bound to SHBG constituting only an inactive reservoir. The free hormone hypothesis derived from now outdated 1970’s pharmacological theory on the mechanism of drug-drug interactions as due to mutual protein binding displacement; however, this theory is long superseded in molecular pharmacology by well-established physiological mechanisms such as cytochrome P450 enzyme induction, drug transporter activity and cognate mechanisms unrelated to binding to circulating proteins (81). As the free and/or bioavailable fractions would also have enhanced access to sites of testosterone inactivation by degradative metabolism that terminates androgen action, the free fractions may equally be considered the most evanescent and least active so that the net biological significance of the free or bioavailable fractions remains unclear and undermines a theoretical basis for the free hormone hypothesis. Furthermore empirical evidence indicates that, rather than being biologically inert, SHBG participates actively in cellular testosterone uptake via specific SHBG membrane receptors, uptake mechanisms and signaling via G protein and cyclic AMP (82-86). These mechanisms include the megalin receptor, a multi-valent low-density lipoprotein endocytic receptor located on cell surface membranes that can mediate receptor-mediated cellular uptake of SHBG loaded with testosterone by endocytosis (87, 88) and might influence tissue androgen action (89, 90). Consequently, lacking a physiological basis for the free hormone hypothesis (91) and with empirical evidence in its favor scarce and speculative, it is refuted by intensive, prospective clinical evaluation (92). Hence, the biological significance of partitioning circulating testosterone into these derived fractions remains to be firmly established and its clinical application is unknown or possibly misleading. Furthermore, direct measurement of free testosterone requires laborious, manual methods only available in research or specialist pathology laboratories. Where available, they are costly and lack any external quality control programs or validated reference ranges. As a result, calculations purporting to replicate dialysis-based measurements are often substituted for direct measurements. These formulae come in two different formats – equilibrium binding equations requiring assumptions on testosterone binding stoichiometry and arbitrary plug-in binding affinity estimates (Sodergard (93), Vermeulen (94), Zakharov (95)) or assumption-free empirical methods (Ly(96, 97), Nanjee-Wheeler (98)) calibrated directly to dialysis-based laboratory measurements. Direct comparison has proven that empirical equations are more accurate compared with laboratory dialysis-based measurements (95, 96, 99, 100). Furthermore, calculations of free testosterone using any formula do not contribute significant to mortality or morbidity prognosis for older men’s health beyond accurate measurement of serum testosterone by liquid chromatography-mass spectrometry (92).
I came across this reference, suggesting independent importance of free testosterone. They used the Vermeulen calculation:
Symptomatic androgen deficiency develops only when both total and free testosterone decline in obese men who may have incident biochemical secondary hypogonadism
Symptomatic androgen deficiency develops only when both total and free testosterone decline in obese men who may have incident biochemical secondary hypogonadism
...
Results: ... [Low total testosterone and low free testosterone], but not [low total testosterone and normal free testosterone], was associated with new/worsened sexual symptoms, including low desire ..., erectile dysfunction ... and infrequent morning erections ... .
Conclusions: These longitudinal data demonstrate the importance of FT in the diagnosis of hypogonadism in obese men with low TT and SHBG. The concurrent fall in TT and FT identifies the minority (27.3%) of men with hypogonadal symptoms, which were not present in the majority developing low TT with normal FT.
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