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?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
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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).
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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):
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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.