Freeing Up Testosterone with Average T Levels and/or Higher SHBG

[tareload]

I have one last question about the idea of the body choosing a Free T level to target, and Free T being the constant in the equation with Total T and SHBG being the variables.

How would TRT be successful in raising Free T then? With the increase in T, wouldn't the body just increase SHBG to counteract the TRT T in order to keep Free T at it's target level if Free T is constant?

Or, with TRT, is so much T added to the body that the body perhaps maxing out it's SHBG isn't enough to keep Free T from rising?

Two separate cases: (1) endogenous production vs (2) exogenous administration of what we should term as free testosterone.

In the former, the serum fT number is under direct control of the HPTA and its feedback system (closed loop control).

In the later at "steady state" you break the control loop and mass of T in equals mass of T out (simplifying here, T eliminated or reacted should be better term). Hence, free T in the latter is set by your T adminstration and free T injected has to equal free T "eliminated".

TT is set by equilibrium between fT and SHBG. This has many implications for the former case. And creates much confusion in the latter case!!!!!

**Disclaimer: I stay perpetually confused. I guess that's perpetual growth. **

 

[tareload]

"If you consider total testosterone as essentially fixed then you're left with comparing this constant to SHBG, which still has a normal distribution."

Poor choice of words on my part, as I was thinking more about mean values for total testosterone that would be acquired at multiple SHBG values if N were large enough. Instead, total testosterone might be considered as a separate random variable, subject to the vagaries of the particular doctors overseeing the TRT, but independent of SHBG. If the doctors were instead targeting free testosterone then I expect total testosterone's correlation with SHBG would return.


I think it's possible the time constants involved in HPTA regulation are long enough that even in more realistic SHBG-manipulation scenarios there would not be a lot of hysteresis. Natesto is a possible proxy, with multiple daily doses not being too suppressive. It's true that in the thought experiment the step change in SHBG production is assumed so that there is no change in equilibrium.

A couple of more realistic scenarios are an injection of SHBG or the administration of a drug that affects SHBG in relative isolation. An injection of SHBG would somewhat imitate a step increase. The SHBG would start sucking up the free hormones, which in a normal HPTA would stimulate additional testosterone production. This would taper off as total testosterone reaches a new value that's consistent with the body's free testosterone set point and the amount of SHBG. I'm not sure what happens with the other complications: Is there a set point for SHBG that reduces production? What is its time constant? How complicated is the function modeling the return of SHBG to baseline?

Still thinking about your words. I think this is the point where we meet and duel it out on the whiteboard . Should we set up an ExcelMale whiteboard event?

Thanks for all your effort on here.

 

[ResearchIt]

Very interesting! Thank you again for the excellent feedback on these questions, it's extremely helpful!

 

[Cataceous]

I have one last question about the idea of the body choosing a Free T level to target, and Free T being the constant in the equation with Total T and SHBG being the variables.

How would TRT be successful in raising Free T then? With the increase in T, wouldn't the body just increase SHBG to counteract the TRT T in order to keep Free T at it's target level if Free T is constant?

Or, with TRT, is so much T added to the body that the body perhaps maxing out it's SHBG isn't enough to keep Free T from rising?

The working hypothesis is that in steady state conditions free testosterone is directly proportional to the production rate of endogenous testosterone, or to the dose rate of exogenous testosterone. Only two primary assumptions are necessary: 1) The rate of testosterone entering the system is matched by the rate of testosterone being metabolized and eliminated. 2) The rate of metabolism and elimination is proportional to the level of free testosterone, following the law of mass action. A secondary assumption is that the underlying rate constant for metabolic clearance is relatively static. There are situations in which this constant changes dramatically, presumably including damage to the liver. But we'd hope these would not be common.

If the hypothesis is correct then it's clear that SHBG has little effect on free testosterone. Also, there are so many factors affecting the production rate of SHBG that it probably could not serve as a viable regulator anyway. And SHBG has a half-life of about a week, so it would be a very slow regulator as well.

Think of SHBG as a reservoir for testosterone. If you have high SHBG then you have a big reservoir, and consequently higher total testosterone as well. With low SHBG your reservoir is small and therefore your total testosterone is relatively low.

 

[Dudley]

Thanks, Cataceous, and would you take that same approach if I end up trying skin cream or gel? Aiming to measure the peak, and assume the trough will be very near my regular baseline?

 

[Cataceous]

Still thinking about your words. I think this is the point where we meet and duel it out on the whiteboard . Should we set up an ExcelMale whiteboard event?
...

If you're looking for someone who thinks on his feet, I'm not he. At least with asynchronous communication I don't put my foot in my mouth as often.

Thanks, Cataceous, and would you take that same approach if I end up trying skin cream or gel? Aiming to measure the peak, and assume the trough will be very near my regular baseline?

Some differences here. With transdermal testosterone you'll probably fully suppress your HPTA, meaning your baseline testosterone level has no special significance. Trough testosterone becomes a function of dose and your absorption characteristics. Over time it's useful to measure both peaks and troughs. Faster absorbers can see levels drop too quickly, necessitating a second daily dose. You also want to ensure peaks aren't excessive. Measure DHT as well, because transdermal testosterone is notorious for sending it quite high. Serum peaks occur later compared to nasal gels. I think guys are taking measurements about four hours post-application. Many guys have trouble achieving consistent absorption with lower-concentration formulations, such as Androgel. We see few such complaints with high-concentration compounded products.

 

[tareload]

If you're looking for someone who thinks on his feet, I'm not he. At least with asynchronous communication I don't put my foot in my mouth as often.

No, I meant it as a venue for more dedicated, intense exchange of information and problem solving. I'm with you, not great on my feet.

 

[Cataceous]

Still thinking about your words. ...

I also thought more about my argument that Winters' results could be explained by basic principles rather than by some uncharacterized behavior of SHBG. It's based on the two assumptions: First, that in untreated men free testosterone and SHBG are independent random variables. And second, that in treated men total testosterone is an independent variable because doctors are titrating doses to achieve normal levels. An issue with the first assumption is that there probably is an inverse correlation because androgens reduce SHBG production. But because we're talking about the physiological realm, and many factors affect SHBG, I'd suggest the correlation is weak enough to be neglected. A potential problem with the second assumption is the extent to which dose titration is based on symptom relief as opposed to the level of total testosterone. Symptom relief would correlate more with free testosterone. But arguably most doctors are content to push total testosterone back into the normal range and call it a day.

The possible complications cut both ways: They may weaken the argument a little but they would also seem to demonstrate enough unaddressed complexity to cast doubt on any interpretation of a small retrospective study like this one.

Thoughts?

 

[tareload]

I also thought more about my argument that Winters' results could be explained by basic principles rather than by some uncharacterized behavior of SHBG. It's based on the two assumptions: First, that in untreated men free testosterone and SHBG are independent random variables. And second, that in treated men total testosterone is an independent variable because doctors are titrating doses to achieve normal levels. An issue with the first assumption is that there probably is an inverse correlation because androgens reduce SHBG production. But because we're talking about the physiological realm, and many factors affect SHBG, I'd suggest the correlation is weak enough to be neglected. A potential problem with the second assumption is the extent to which dose titration is based on symptom relief as opposed to the level of total testosterone. Symptom relief would correlate more with free testosterone. But arguably most doctors are content to push total testosterone back into the normal range and call it a day.

The possible complications cut both ways: They may weaken the argument a little but they would also seem to demonstrate enough unaddressed complexity to cast doubt on any interpretation of a small retrospective study like this one.

Thoughts?

Very nice and I would agree. The study is small enough and inconclusive enough that multiple hypotheses could be proposed and these data do not rule these out. Hard to jump to what Winters did with the data in hand.

 

[CanadaJim]

I'm beginning to believe that my "not so great" experience with TRT is because of elevated SHBG. In January 2020 I had blood work done, about three months after I initially started and stopped self prescribed test. My SHBG at that time was 51.8 nmol/l.
Then in December 2020 after starting again (due to the shitty withdrawal) and ultimately stopping, my SHBG was 66.2nmol/l. I had blood work again in March 2021 and my SHBG was still elevated at 53.6. My most recent blood work (March 25th, 22) after stopping injections February 4th indicates high testosterone 29.5 nmol/l (normal reference range is 7.6-24.8). I find it hard to believe that it is still indicating that high after being off for two months. Unfortunately that test didn't include SHBG. I am feeling much better off the test. Libido is still in the basement though which I would love to rectify. I have been taking Boron as I've read it can help lower SHBG. Is there anything else supplement wise that would be helpful?

 

[ResearchIt]

In addition to Boron, Nettle is said to be helpful. Nettle doesn't lower SHBG like Boron can, but instead binds to SHBG which supposedly increases Free T somewhat. I think some people respond well to it, but others don't.

 

[Dudley]

If you're looking for someone who thinks on his feet, I'm not he. At least with asynchronous communication I don't put my foot in my mouth as often.


Some differences here. With transdermal testosterone you'll probably fully suppress your HPTA, meaning your baseline testosterone level has no special significance. Trough testosterone becomes a function of dose and your absorption characteristics. Over time it's useful to measure both peaks and troughs. Faster absorbers can see levels drop too quickly, necessitating a second daily dose. You also want to ensure peaks aren't excessive. Measure DHT as well, because transdermal testosterone is notorious for sending it quite high. Serum peaks occur later compared to nasal gels. I think guys are taking measurements about four hours post-application. Many guys have trouble achieving consistent absorption with lower-concentration formulations, such as Androgel. We see few such complaints with high-concentration compounded products.

Thanks, this is super-helpful. I am just beginning cream but it is not totally clear to me what dose of T I am getting. It's from a compounding pharmacy and the label on the dispenser says T20%, 200 MG/GM. My doc has me starting with 4 clicks 1x daily. If you can help me figure out what amounts to in terms of dose, I appreciate it. I have already scheduled blood work for about a month from now, once to get a peak and another to get a trough reading. Thanks for the guidance and advice.

 

[Cataceous]

Thanks, this is super-helpful. I am just beginning cream but it is not totally clear to me what dose of T I am getting. It's from a compounding pharmacy and the label on the dispenser says T20%, 200 MG/GM. My doc has me starting with 4 clicks 1x daily. If you can help me figure out what amounts to in terms of dose, I appreciate it. I have already scheduled blood work for about a month from now, once to get a peak and another to get a trough reading. Thanks for the guidance and advice.

I can't be sure what you have, but often these dispensers are giving 0.25 mL per click. If so then your total daily dose is 200 mg, which is on the high side. If you're absorbing at the nominal rate of 10% then you're getting about three times the testosterone that the average healthy young man makes naturally. If you can confirm the dosing then you might ask your provider if you can drop it to a more reasonable starting amount of 50-100 mg daily.

 

[Dudley]

Thanks for your help with this, Cataceous. He told me he was starting me with a low dose, but didn't specify what that meant. Starting low has been his general approach all along, the least possible intervention. But I will see if he can tell me the numeric dose he's intending that I get, and adjust down if you're right that he has started me on the high side.

 

[CanadaJim]

If you can tolerate Viagra/ Cialis It will lower your estrogen and increase your testosterone levels . Also good levels of magnesium will improve your free testosterone.

This may be a stupid question but would 10mg EOD be the equivalent of a 5mg daily dose? I know mathematically it is the same but does the half life and absorption come into play? Maybe it needs daily administration to obtain consistent levels? Just wondering as I have scored 20mg tabs...easier to cut in half than quarters...

 

[Vince]

This may be a stupid question but would 10mg EOD be the equivalent of a 5mg daily dose? I know mathematically it is the same but does the half life and absorption come into play? Maybe it needs daily administration to obtain consistent levels? Just wondering as I have scored 20mg tabs...easier to cut in half than quarters...

I'm sure 10 every other day will work fine. I like daily better but shouldn't make much of a difference.

 

[Cataceous]

This may be a stupid question but would 10mg EOD be the equivalent of a 5mg daily dose? I know mathematically it is the same but does the half life and absorption come into play? Maybe it needs daily administration to obtain consistent levels? Just wondering as I have scored 20mg tabs...easier to cut in half than quarters...

For most guys the nominal five-day half-life of cypionate means that there's not much difference between daily and EOD dosing at the same average rate. My levels on EOD dosing were consistent enough that there appeared to be little difference in serum testosterone between pre-injection troughs and the days between injections.

However, there are a few reports from guys who appear to have relatively rapid absorption; they measure fairly large swings in serum testosterone in a 24-hour period. Some have repeated these measurements a number of times, making the results harder to dismiss as erroneous.

 

[M.J]

For most guys the nominal five-day half-life of cypionate means that there's not much difference between daily and EOD dosing at the same average rate. My levels on EOD dosing were consistent enough that there appeared to be little difference is serum testosterone between pre-injection troughs and the days between injections.

However, there are a few reports from guys who appear to have relatively rapid absorption; they measure fairly large swings in serum testosterone in a 24-hour period. Some have repeated these measurements a number of times, making the results harder to dismiss as erroneous.

I noticed my levels moves between 22 and 28 on 20mg EOD. (More or less)