Not so complex mathematical evidence for why Low Shbg men should inject more often.

[JRos895]

It seems like some users don’t buy into the notion that low shbg is cause to inject more often.

But the math is relatively simple:
take two men: Man A has a FT percentage of 2% and Man B has a FT percentage of 3%. If both take 100mg of T a week, and each has a TT peak of 1000 and trough of 500, then Man A will have a FT peak of 20 and FT trough of 10, whereas Man A will have a FT peak of 30 and a FT trough of 15.

The difference in Man A’s peak and trough is 10 and the difference in Man B’s peak and trough is 15. True, both have the same FT peak-trough of 2. But in terms of evaluating symptoms, it’s better (I believe) to judge peak-trough differences in absolute difference vs relative percentage differences. One would likely feel little difference between an FT of 1 versus an FT of 2. One would likely feel a large difference between an FT of 10 and an FT of 20. In both cases, the peak-ratio is 2, but obviously the latter case is a more significant difference.

Therefore, men with low SHBG are more likely to feel more significant differences between their peaks and troughs at a given dose.

Why isn’t this more universally accepted? Or am I missing something?

 

[tareload]

Since @Cataceous has shared the theory multiple times, I'll let him do the honors with the blow by blow. Short answer the two men don't have the same TT on 100 mg/week of T. At SS, they'll have roughly the same free T if they're PK parameters are similar. So now invert your problem so that fT is fixed and fT % varies at either 2 or 3%. What is TT in each case?

TT will snap to its SS value based on dynamic equilibrium set by SHBG and fT.

Full credit to @Cataceous for his excellent treatment of this subject.

Which one matters...fT or TT or both? If you figure that out let the Endos know. No one knows quite yet.

 

[JRos895]

It seems like TT should be the X variable and FT should be the Y variable, no?

You’re TT would depend on how the ester releases the testosterone, right? How could your FT levels influence how quickly the ester releases the testosterone?

Also, your answer seems to imply that higher SHBG men don’t need higher doses of testosterone. Do you believe that?

 

[ERO]

Also, with low SHBG guys, the problem is not how to get steady levels (Inject daily or use cream) the problem is we often feel nothing at all from TRT. Being on TRT still feels like Low T for most of us.

 

[tareload]

It seems like TT should be the X variable and FT should be the Y variable, no?

You’re TT would depend on how the ester releases the testosterone, right? How could your FT levels influence how quickly the ester releases the testosterone?

Also, your answer seems to imply that higher SHBG men don’t need higher doses of testosterone. Do you believe that?

The injected ester is cleaved to release free T, not Total T. Your body then takes that fT and it gets metabolized into downstream products as well some of it reacts with SHBG (as well as albumin) to form bound and weakly bound T. TT = fT + SHBG-bound T + albumin-bound T. SHBG-bound T is a reservoir for fT. Here's some reading...

Blatant reproduction of @Cataceous 's post (with full attribution though ):

800mg Test Cyp a Week, Total Test Is Only 1406!

Adding this (I’ve put on here in a few places) here as this is the most succint description of the confounding of SHBG vs injection frequency requirement I’ve found (attribution to cataceous on ExcelMale): The issue with this study is that they are basing MCR on total T rather than free T...

forums.t-nation.com

800mg Test Cyp a Week, Total Test Is Only 1406!

TLDR: doesn’t matter. More details that are of probably little help but may interest some. Thought about your question which was reason for delay in responding and trying to answer as succinctly as possible based on the constructive feedback I’ve received recently. I FAILED! If your goal...

forums.t-nation.com

ripped the text out of this post:
=====
TLDR: doesn’t matter.

More details that are of probably little help but may interest some.

Thought about your question which was reason for delay in responding and trying to answer as succinctly as possible based on the constructive feedback I’ve received recently. I FAILED! If your goal with respect to question is to maximize muscle growth then my short answer is I don’t think it matters. Area under the curve (how much your body processes) will be proportional to dose so whether you do cyp or prop doesn’t matter.

Guys who have low SHBG need to inject more frequently?
SHBG is related (correlated) to but doesn’t appear to drive (causation) clearance rate. There’s a whole bunch of stuff that determines how your body clears fT, SHBG is not one of them. Your body eliminates based on free T not Total T. TT is set by your SHBG and free T via dynamic equilibrium (chemical kinetics). Guys typically look at their TT and get confused as hell when trying to understand clearance rate. This is where this idea that guys who have lower SHBG need to inject more frequently came from. For the same fT a low SHBG guy will read a lower TT so he thinks he isn’t getting the same bang for his buck even though his fT is the same as the higher SHBG guy. In addition, I’ll argue that WE don’t understand the value of keeping supra T (TT and fT) levels constant with respect to positive vs negative side effects.

Hence, for 250 mg/week of TC (mild cycle for many based on their metabolic clearance rate of free T), do we need to inject ED or once weekly if our SHBG is 10?

Remember, elimination is driven by free T not Total T. If you really want to know your elimination kinetics it will take some work as I’ve discussed a few times how you can measure AUC and determine how your body processes T. Still seems trial and error to me and related to age, liver activity, lymphatic activity, where you inject, blah blah.

Example:
So what’s the goal? Gainz or something else?
Given SHBG of 10.
Given 250 mg/week of TC.

Better to inject every day and keep constant TT (constant free T) at say 1500 ng/dL (55 ng/dL) or inject once weekly and have peak TT (fT) at 2000 ng/dL (77 ng/dL) and trough TT (fT) at 1000 ng/dL (36 nd/dL)?

Good question that I can’t answer for an individual. Running your body at constant and HIGH TT(fT) levels continuously seems like a bad idea from health perspective. From GAINZ perspective, I have no clue. What drives GAINZ, fT or TT and what’s their individual contributions? No one knows as far as I can tell. Others thoughts or feedback?

Homework: do this same example for a guy with an SHBG of 30 nmol/L and compute the TT / fT levels for ED vs weekly injections? What does this tell you?

=====

SHBG Upregulation

May be of interest. See plot linked therein. Big difference between endogenous T production with an intact HPTGA vs using exogenous T where one uncouples negative feedback loop between T/E2 and hypothalamus/pituitary. With endogenous T production there is typically strong correlation between...

forums.t-nation.com

Test Dosage vs Levels for Cycle Recommendation

See first two pages of review article above. Bioavailable (“free” + “weakly bound”) T assay is a very standard result that attempts to measure non-SHBG bound testosterone by precipitating SHBG bound fraction using ammonium sulfate method...

forums.t-nation.com

So although the calculators and math treatment of TT and fT are usually using TT as independent variable ("x-variable") and fT as the dependent variable ("y-variable"), physiologically its the opposite. I surmise because TT numbers very easy to measure historically after introduction of RIA method in late 60s / early 70s (so there's plenty of data out there). We are still waiting for accurate fT numbers (??).

I feel fortunate @madman will let us know as soon as active researchers in the field solve the free hormone hypothesis challenge and figure out how to measure fT accurately and reproducibly between labs (harmonization program that's ongoing). I'm pulling for you @madman.

 

[Cataceous]

It seems like TT should be the X variable and FT should be the Y variable, no?

You’re TT would depend on how the ester releases the testosterone, right? How could your FT levels influence how quickly the ester releases the testosterone?

Also, your answer seems to imply that higher SHBG men don’t need higher doses of testosterone. Do you believe that?

Perhaps we make the concept less clear by thinking about discrete doses instead of continuous flows: we give ourselves an injection; we apply a dose of cream, etc. But these still translate to fairly continuous flows of testosterone into circulation. Consider an analogy in which the body is represented as a bathtub with an open drain, into which we're pouring water, which represents testosterone. Total water in the tub is like total testosterone in the body. At steady state the flow out of the tub matches the flow in. The key assumption is that the flow rate out of the tub, governed in this model by the drain size and the water depth, corresponds to the metabolism and excretion of testosterone governed by a proportionality to free testosterone. Now what happens if we increase the drain size, which is equivalent to lowering SHBG? Initially the flow rate out of the drain increases, but over time the water level lowers and the flow decreases to again match the flow rate into the tub. Therefore lowering SHBG while keeping dose and underlying metabolism constant results in lower total testosterone and the same free testosterone. The tub analogy isn't perfect, but I think it's close enough to give us a feel for what's happening.

On your specific points: In this theory, TRT dosing drives the total rate of metabolism and excretion, which in turn forces free testosterone to the required level for the rate of use to equal rate of input. This makes total testosterone a dependent variable, just as the water level in the tub analogy can be controlled by the flow rate into the tub. And it is true that men with higher SHBG do not need more testosterone, at least to achieve identical free testosterone to their twins with lower SHBG.

 

[JRos895]

So what you’re sort of saying is that since TT=FT + bound FT, it wouldnt make sense that the ester is injecting TT because it can’t inject bound FT into your body, right?

Could you still argue that men with low SHBG are more sensitive to Estradiol spikes given their free estradiol?

 

[tareload]

Perhaps we make the concept less clear by thinking about discrete doses instead of continuous flows: we give ourselves an injection; we apply a dose of cream, etc. But these still translate to fairly continuous flows of testosterone into circulation. Consider an analogy in which the body is represented as a bathtub with an open drain, into which we're pouring water, which represents testosterone. Total water in the tub is like total testosterone in the body. At steady state the flow out of the tub matches the flow in. The key assumption is that the flow rate out of the tub, governed in this model by the drain size and the water depth, corresponds to the metabolism and excretion of testosterone governed by a proportionality to free testosterone. Now what happens if we increase the drain size, which is equivalent to lowering SHBG? Initially the flow rate out of the drain increases, but over time the water level lowers and the flow decreases to again match the flow rate into the tub. Therefore lowering SHBG while keeping dose and underlying metabolism constant results in lower total testosterone and the same free testosterone. The tub analogy isn't perfect, but I think it's close enough to give us a feel for what's happening.

On your specific points: In this theory, TRT dosing drives the total rate of metabolism and excretion, which in turn forces free testosterone to the required level for the rate of use to equal rate of input. This makes total testosterone a dependent variable, just as the water level in the tub analogy can be controlled by the flow rate into the tub. And it is true that men with higher SHBG do not need more testosterone, at least to achieve identical free testosterone to their twins with lower SHBG.

Excellent. You can coin this treatment the TRT "delta-epsilon" proof for fT invariance to dose with varying SHBG!

Not really but it sounds good and does invoke the concept of a Limit.

 

[xqfq]

1. Why do women with low SHBG experience hyperandrogenism?
2. Why are medications which increase SHBG used to treat hyperandrogenism? For instance, metformin and oral contraceptives.
3. Why do steroids which bind strongly to SHBG increase free testosterone levels for men on exogenous testosterone? For instance, proviron and DHT.

I wonder if you are assuming that SHBG is itself is constant. Obviously it's not - it is being produced and destroyed in the body somehow.

So if there is less SHBG, there are more free steroids. So SHBG is not a "drain" but more like a sushi boat in a sushi restaurant. The supply of sushi produced is constant, but with less boats available, more sushi is boat-free. It's not the case that every sushi roll on a boat will get eaten - some will be thrown out because they've been left out for too long.

Just my line of thinking, I am not sure either way on this yet.

 

[Cataceous]

1. Why do women with low SHBG experience hyperandrogenism?

Wouldn't hyperandrogenism tend to cause low SHBG? That is, a regulatory dysfunction results in an overly high set point for androgen production, which suppresses SHBG production in the liver. Insufficient aromatization does something similar. "Free testosterone significantly increased and sex hormone binding globulin (SHBG) significantly decreased in women on AIs compared to no AIs..."

2. Why are medications which increase SHBG used to treat hyperandrogenism? For instance, metformin and oral contraceptives.

If you treat the hyperandrogenism then SHBG naturally goes up. Give estrogen and that naturally suppresses testosterone production. Higher estrogen and lower testosterone both tend to increase SHBG.

3. Why do steroids which bind strongly to SHBG increase free testosterone levels for men on exogenous testosterone? For instance, proviron and DHT.

First, is there definitive evidence showing this? If it's a real phenomenon then a possible explanation is that the DHT-based steroid lowers the underlying metabolic rate constant of testosterone. Free testosterone is then driven higher because the total clearance rate of testosterone must be maintained to match the input rate.

I wonder if you are assuming that SHBG is itself is constant. Obviously it's not - it is being produced and destroyed in the body somehow.

So if there is less SHBG, there are more free steroids. So SHBG is not a "drain" but more like a sushi boat in a sushi restaurant. The supply of sushi produced is constant, but with less boats available, more sushi is boat-free. It's not the case that every sushi roll on a boat will get eaten - some will be thrown out because they've been left out for too long.

The constancy of SHBG isn't part of the argument. One of the interesting thought experiments is to ask what happens if you could suddenly change the amount of SHBG. In reality SHBG is relatively stable; the half-life is something like a week. There's also research showing little diurnal variation.

For less SHBG to imply more free testosterone you must assume total testosterone is constant. But you cannot make this assumption. It's the rate of testosterone production—or absorption with TRT—that we treat as fairly constant. This implies that the total metabolic clearance rate is also fairly constant to match the input. If we accept that free testosterone is proportionally driving metabolic clearance then SHBG is not affecting free testosterone.

In the water tub analogy SHBG is not the drain, but it inversely controls the size of the drain; the higher the SHBG the smaller the drain.

 

[xqfq]

Wouldn't hyperandrogenism tend to cause low SHBG? That is, a regulatory dysfunction results in an overly high set point for androgen production, which suppresses SHBG production in the liver. Insufficient aromatization does something similar. "Free testosterone significantly increased and sex hormone binding globulin (SHBG) significantly decreased in women on AIs compared to no AIs..."

If you treat the hyperandrogenism then SHBG naturally goes up. Give estrogen and that naturally suppresses testosterone production. Higher estrogen and lower testosterone both tend to increase SHBG.

First, is there definitive evidence showing this? If it's a real phenomenon then a possible explanation is that the DHT-based steroid lowers the underlying metabolic rate constant of testosterone. Free testosterone is then driven higher because the total clearance rate of testosterone must be maintained to match the input rate.

The constancy of SHBG isn't part of the argument. One of the interesting thought experiments is to ask what happens if you could suddenly change the amount of SHBG. In reality SHBG is relatively stable; the half-life is something like a week. There's also research showing little diurnal variation.

For less SHBG to imply more free testosterone you must assume total testosterone is constant. But you cannot make this assumption. It's the rate of testosterone production—or absorption with TRT—that we treat as fairly constant. This implies that the total metabolic clearance rate is also fairly constant to match the input. If we accept that free testosterone is proportionally driving metabolic clearance then SHBG is not affecting free testosterone.

In the water tub analogy SHBG is not the drain, but it inversely controls the size of the drain; the higher the SHBG the smaller the drain.

I am not sure if there are specifically studies on men on exogenous testosterone + an SHBG-lowering-agent.

I may dig further here later, but on my quick dip into research I found this paper describing studies on oral contraceptives in women (screenshot above), which raise SHBG and lower free testosterone. Note that in women, the production of testosterone is also held constant and is, I believe, mostly produced via DHEA from the adrenals.

Looking at the relative binding affinities of the sex hormones (e.g. DHT >> T >> E2) and the changes in SHBG levels between men and women, and before/after puberty, it seems like the body wants to use SHBG to limit androgen (and some estrogen) action.

 

[Cataceous]

... Note that in women, the production of testosterone is also held constant and is, I believe, mostly produced via DHEA from the adrenals.
...

I don't think you can assume constant testosterone. Women also have an HPGA, and "... high levels of luteinizing hormone can also result in the ovary producing excess amounts of testosterone."[R]

...
Looking at the relative binding affinities of the sex hormones (e.g. DHT >> T >> E2) and the changes in SHBG levels between men and women, and before/after puberty, it seems like the body wants to use SHBG to limit androgen (and some estrogen) action.

But the body has more direct methods for regulating the free hormone levels. I view SHBG as primarily for buffering and some signaling.

 

[xqfq]

I don't think you can assume constant testosterone. Women also have an HPGA, and "... high levels of luteinizing hormone can also result in the ovary producing excess amounts of testosterone."[R]

But the body has more direct methods for regulating the free hormone levels. I view SHBG as primarily for buffering and some signaling.

I was able to find some studies where metformin is used in PCOS. Conclusion seems to be it raises SHBG and lowers free androgen levels.

Here is one that's more directly applicable. Danazol, when given to women, lowers SHBG and increases free testosterone levels:

Free testosterone levels during danazol therapy - PubMed

Danazol is a testosterone (T) derivative widely used in the clinical treatment of endometriosis. Its mechanism of action is poorly understood, but is side effects are mainly androgenic. Previously it was demonstrated that danazol can displace T from sex-hormone-binding globulin (SHBG). The...

pubmed.ncbi.nlm.nih.gov

Levels of total T, SHBG, and albumin were measured in 16 women undergoing danazol treatment for endometriosis. Thereafter, free and protein-bound T levels were calculated. A marked rise in free T was found during danazol therapy as compared with pretreatment levels. The data suggest that many of the effects of danazol could be explained by increased levels of free T during treatment.

What I can find seems to indicates that SHBG helps control sex steroid availability, not just buffers it. Mechanistically, I can imagine this working in a few different ways.

For instance, I can imagine the sex hormones binding to the SHBG, the SBHG then breaking apart / losing the hormones, and then the hormones re-binding to SHBG. So the fact a given hormone might stay bound to SHBG for, let's say, 2 hours, doesn't mean that the hormone is then in a constant state of availability. If it has high binding affinity for SHBG, maybe it could bind SHBG again.

In the situation in which SHBG acts entirely as a buffer, we would have to assume that there would be no re-binding of sex hormones after their disassociation? Particularly if there is "more" of SHBG than the sex hormones available.

I can imagine that any 'excess' sex hormones, for which there is insufficient SHBG available, that SHBG would act only as a buffer. So there is probably a point at which SHBG would become saturated and the model would shift to where SHBG acts almost entirely as a 'buffer'.

 

[Cataceous]

I was able to find some studies where metformin is used in PCOS. Conclusion seems to be it raises SHBG and lowers free androgen levels.
...

Or does it lower androgen levels, which in turn raises SHBG? The amount of androgen reduction seems to be in question. "Metformin has indirect antiandrogenic effects in women with insulin resistance, such as those with PCOS, due to its beneficial effects on insulin sensitivity. It may reduce testosterone levels in such women by as much as 50%. A Cochrane review, though, found that metformin was only slightly effective for decreasing androgen levels in women with PCOS."[R]

...
Here is one that's more directly applicable. Danazol, when given to women, lowers SHBG and increases free testosterone levels:
...

Let's go back to basics. The only thing that matters is whether the overall metabolic clearance rate of testosterone is proportional to free testosterone. This seems likely due to the Law of Mass Action. If you accept this then changing SHBG can have no effect on free testosterone at steady state. I inject 4 mg of testosterone daily. At steady state I must be metabolizing and clearing 4 mg of testosterone daily, no matter what my SHBG. If my clearance rate is proportional to free testosterone then my free testosterone must also be independent of SHBG.

In the case of danazol I can only offer the same speculation as with DHT: the underlying metabolic rate constant for testosterone is driven lower, which in turn forces up free testosterone to ensure that the total production rate continues to match the total clearance rate. Alternatively the production rate is driven up, but this seems less likely.

You need to clarify what you're saying about SHBG binding to and dissociating from hormones. This occurs constantly, but with the huge numbers involved the macroscopic results follow appropriate statistics to yield predictable concentrations and actions.

 

[tareload]

Or does it lower androgen levels, which in turn raises SHBG? The amount of androgen reduction seems to be in question. "Metformin has indirect antiandrogenic effects in women with insulin resistance, such as those with PCOS, due to its beneficial effects on insulin sensitivity. It may reduce testosterone levels in such women by as much as 50%. A Cochrane review, though, found that metformin was only slightly effective for decreasing androgen levels in women with PCOS."[R]

Let's go back to basics. The only thing that matters is whether the overall metabolic clearance rate of testosterone is proportional to free testosterone. This seems likely due to the Law of Mass Action. If you accept this then changing SHBG can have no effect on free testosterone at steady state. I inject 4 mg of testosterone daily. At steady state I must be metabolizing and clearing 4 mg of testosterone daily, no matter what my SHBG. If my clearance rate is proportional to free testosterone then my free testosterone must also be independent of SHBG.

In the case of danazol I can only offer the same speculation as with DHT: the underlying metabolic rate constant for testosterone is driven lower, which in turn forces up free testosterone to ensure that the total production rate continues to match the total clearance rate. Alternatively the production rate is driven up, but this seems less likely.

You need to clarify what you're saying about SHBG binding to and dissociating from hormones. This occurs constantly, but with the huge numbers involved the macroscopic results follow appropriate statistics to yield predictable concentrations and actions.

I guess this is the burden when writing or speaking about complex topics on the internet:

The bullshit asymmetry principle | Statistical Modeling, Causal Inference, and Social Science

Brandolini's law - Wikipedia

en.wikipedia.org

It's why I'll probably only be on this site from now on as I am tired on having to deal with this on T-Nation. Thank you Nelson @Nelson Vergel and all you guys who go the extra mile on here. I appreciate it.

 

[M.J]

What is a low SHBG ? Where do you draw the line ?