Low SHBG and Estradiol

[falconberg]

I've been on TRT since May 2016. I'm currently on a three-month break to reassess some things and am trying to educate myself so that I can hopefully have better results if I have to get back on (which is looking increasingly likely).

I have low SHBG (currently around 18 NMOL/L, but as low as 11 NMOL/L when I am on active TRT). I understand that low SHBG means that I am binding up less of my total testosterone, leaving more free testosterone available for use. That would seem like a good thing at first blush, but (if I understand correctly) it creates a situation where I end up with too much free testosterone, which my body essentially eliminates through the urine before it can use it, followed by a dip in testosterone once I have excreted most of the exogenous testosterone that I injected. If I am misunderstanding that, please correct me.

Here's my question: Given that SHBG binds to testosterone with higher affinity than to estrogen, I am wondering if the poor success I have had with TRT is really an estradiol issue. Could it be that the limited SHBG that I do have is all being used to bind up to all of the exogenous testosterone that I am introducing, leaving no SHBG left to buffer the estradiol (both natural and converted from exogenous testosterone) running through my system?

I hope I am explaining my question correctly, but please let me know if I can clarify. I appreciate any advice. It was posts on this forum that first alerted me to the low SHBG profile and the ways that others are addressing it (more frequent doses, etc.).

 

[Systemlord]

I think I understand your question and I'll skip to the part that would give the the best results possible.

Low SHBG men that have problems with estrogen need to keep levels very steady and at the appropriate levels to minimize estrogen conversion, daily protocol are what works best.

I have tried 20mg EOD and still have estrogen sides, but not on 7mg daily which got me within 79 ng/dL and estrogen <30 minus 23 versus the previous protocol.

You are correct in that by having low SHBG you lose the natural buffer to bind up estrogen, but remember you can't convert testosterone to estrogen if you don't have aromatase enzymes in fat tissues.

 

[Vince Carter]

You’re correct in your understanding but to the point of fat cells and aromatase thats a general rhing but im not fat and i convert ALOT of Estrogen to which im very sensitive. Tupically the low shbg guy has a lot of free t and a similarly high level of free estrogen. Testing estradiol, free, along with the lc/ms/ms can be a real eye opener.

 

[Cataceous]

... I understand that low SHBG means that I am binding up less of my total testosterone, leaving more free testosterone available for use. That would seem like a good thing at first blush, but (if I understand correctly) it creates a situation where I end up with too much free testosterone, which my body essentially eliminates through the urine before it can use it, followed by a dip in testosterone once I have excreted most of the exogenous testosterone that I injected. If I am misunderstanding that, please correct me.

Here's my question: Given that SHBG binds to testosterone with higher affinity than to estrogen, I am wondering if the poor success I have had with TRT is really an estradiol issue. Could it be that the limited SHBG that I do have is all being used to bind up to all of the exogenous testosterone that I am introducing, leaving no SHBG left to buffer the estradiol (both natural and converted from exogenous testosterone) running through my system?
...

On TRT the excretion rate of testosterone is controlled by the slow absorption rate. You can't eliminate it faster than you take it in. SHBG has minimal if any effect on the apparent serum half-life of testosterone. However, lower SHBG does result in proportionally lower total testosterone for the same input (dose).

But with regard to your question, I think the general idea is right: with low SHBG, estradiol is likely one of the most significant problems, if not the most. As SHBG goes lower, the ratio of free estradiol to free testosterone goes up. As Vince says, you can confirm via testing, or you can use the free estradiol calculator, which has shown pretty good agreement with the rather expensive free estradiol test.

 

[falconberg]

As Vince says, you can confirm via testing, or you can use the free estradiol calculator, which has shown pretty good agreement with the rather expensive free estradiol test.

Thanks for the helpful tool reference. I hadn't seen that before. Any idea what the reference range is for total estradiol? The discussion that you links to mentions "0.2.....1.5" but I don't see a reference to that in the calculator or the supporting materials. Is that just coming from the reference published when people get their direct estradiol measured?

 

[Cataceous]

Thanks for the helpful tool reference. I hadn't seen that before. Any idea what the reference range is for total estradiol? The discussion that you links to mentions "0.2.....1.5" but I don't see a reference to that in the calculator or the supporting materials. Is that just coming from the reference published when people get their direct estradiol measured?

The reference range of 0.2-1.5 does come from the lab tests, and because the calculation seems to give similar results it's probably reasonable to apply the same reference range.

 

[madman]

I think I understand your question and I'll skip to the part that would give the the best results possible.

Low SHBG men that have problems with estrogen need to keep levels very steady and at the appropriate levels to minimize estrogen conversion, daily protocol are what works best.

I have tried 20mg EOD and still have estrogen sides, but not on 7mg daily which got me within 79 ng/dL and estrogen <30 minus 23 versus the previous protocol.

You are correct in that by having low SHBG you lose the natural buffer to bind up estrogen, but remember you can't convert testosterone to estrogen if you don't have aromatase enzymes in fat tissues.

Adipose tissue is not the only source of conversion/aromatization.....brain, liver, kidney, bone, lung, thymus, skin, muscle!

As we know lean individuals can be over aromatizers.




SOURCES OF ESTROGENS IN THE MALE

In the male, the free estrogens, estrone and estradiol, enter the blood both as a result of direct secretion from the testis and extragonadal conversion from androgenic precursors (Fig. 2). In the testes of men, testosterone is converted to estradiol and androstenedione to estrone, releasing estradiol (97.2-892.0 pg/ml) and estrone (30.0-234.8 pg/ml) into spermatic venous blood. The conversion of androstenedione to estrone is the main source of estrone entering the body [38]. Extragonadal conversion or aromatization of androgen provides the other source of estrogen (25%-50%) in the male. The major site of androgen secretion is the testis, although the adrenal cortex also secretes smaller amounts of C,, steroids-dehydroepiandrosterone, androstenedione, and 1 1 /?-hydroxyandrosterone [7]. In many species, aromatase activity has been detected in nonneural and neural tissues, specifically in the hypothalamus and limbic system (Fig. 2). In most areas of the brain, the extent of in vitro aromatization is low-in the range of 1% or less of substrate metabolized. However, the potency of estrogen for biological actions is very high-often 10-100-fold higher than that of the parent androgen. Some actions of androgen on the brain may be carried out via conversion to estrogen at the cellular level.

FIGURE 2. Physiologic sources of estrogen in the male. Gonadal androgens are converted by the enzyme complex aromatase to estrogens. Both androgens and estrogens are released into the general circulation. Androgens may, in addition, be aromatized to estrogens in extragonadal tissues. These estrogens may have local actions prior to their release into the general circulation. The adrenals normally contribute relatively minor amounts of androgens and estrogens to the circulatory pool

 

[Vince Carter]

Thanks for the helpful tool reference. I hadn't seen that before. Any idea what the reference range is for total estradiol? The discussion that you links to mentions "0.2.....1.5" but I don't see a reference to that in the calculator or the supporting materials. Is that just coming from the reference published when people get their direct estradiol measured?

Note reference ranges are a sampling of the population that a lab is testing. The reason that Quest uses a Free E range of <0.45, and this lab uses 0.2 > 1.5. No Dr/Scientist/any one else determined that X is healthy for you.

 

[Cataceous]

Note reference ranges are a sampling of the population that a lab is testing. The reason that Quest uses a Free E range of <0.45, and this lab uses 0.2 > 1.5. No Dr/Scientist/any one else determined that X is healthy for you.

The lab reference ranges are based on nominally healthy subpopulations, not on a random sampling of all those being tested, who are, statistically speaking, somewhat less likely to be normal or healthy.

I'd argue that different labs have different reference ranges more because of variations in their testing methods than because of differences between their normal populations.

 

[falconberg]

On TRT the excretion rate of testosterone is controlled by the slow absorption rate. You can't eliminate it faster than you take it in. SHBG has minimal if any effect on the apparent serum half-life of testosterone. However, lower SHBG does result in proportionally lower total testosterone for the same input (dose).

Can anyone explain the last two sentences to me? If I misunderstood about low SHBG resulting in elimination of excess testosterone before it can be used, then I am still unclear on the mechanism that causes low SHBG to result in lower total testosterone. Based on my admittedly rudimentary understanding, it would seem like low SHBG would be a great thing, because it would require less exogenous testosterone to hit a healthy reference range (i.e., that it would result in proportionately higher free testosterone). That seems to be opposite of what actually happens, though.

 

[Vince Carter]

Can anyone explain the last two sentences to me? If I misunderstood about low SHBG resulting in elimination of excess testosterone before it can be used, then I am still unclear on the mechanism that causes low SHBG to result in lower total testosterone. Based on my admittedly rudimentary understanding, it would seem like low SHBG would be a great thing, because it would require less exogenous testosterone to hit a healthy reference range (i.e., that it would result in proportionately higher free testosterone). That seems to be opposite of what actually happens, though.

Cataceous is on a lonely island with most of what he regurgitates on this forum.

 

[Cataceous]

"... SHBG has minimal if any effect on the apparent serum half-life of testosterone. However, lower SHBG does result in proportionally lower total testosterone for the same input (dose)."

Can anyone explain the last two sentences to me? If I misunderstood about low SHBG resulting in elimination of excess testosterone before it can be used, then I am still unclear on the mechanism that causes low SHBG to result in lower total testosterone. Based on my admittedly rudimentary understanding, it would seem like low SHBG would be a great thing, because it would require less exogenous testosterone to hit a healthy reference range (i.e., that it would result in proportionately higher free testosterone). That seems to be opposite of what actually happens, though.

The first point is pretty straightforward. After you inject a testosterone ester there's an oily deposit under the skin or in the muscle. This depot slowly dissolves, releasing the ester, which results in a steady flow of testosterone into circulation. It's this flow rate that determines the apparent half-life of testosterone. There is no obvious way for SHBG to influence this flow of testosterone into circulation.

The confusion arises because of the relationship between free T, total T and SHBG; at a fixed total T, lower SHBG means higher free T. The clearance rate of testosterone is proportional to free T, so you'd infer that lower SHBG means faster excretion. But this is turned around, because under TRT the flow of testosterone is fixed, on average. This means that the excretion rate is also fixed, which implies a constant free T, as long as other metabolic factors don't vary in this time frame—and I do not see claims that they do.

If you accept this premise then total T becomes the dependent variable, determined by SHBG and free T. From this it follows directly that lower SHBG implies lower total testosterone.

There are a couple of known problems with low SHBG. First is that it leads to relatively higher free estradiol. And second, in some locations testosterone is delivered directly by SHBG, so a dearth of SHBG might leave these cells without enough testosterone.

 

[Cataceous]

Cataceous is on a lonely island with most of what he regurgitates on this forum.

Every time I ask you to explain your disagreement you run away.

 

[falconberg]

"The confusion arises because of the relationship between free T, total T and SHBG; at a fixed total T, lower SHBG means higher free T. The clearance rate of testosterone is proportional to free T, so you'd infer that lower SHBG means faster excretion. But this is turned around, because under TRT the flow of testosterone is fixed, on average. This means that the excretion rate is also fixed, which implies a constant free T, as long as other metabolic factors don't vary in this time frame—and I do not see claims that they do.

I'm still not following. Are you saying that it is the *free* testosterone that is fixed? In other words, that total T is the fluctuating number based on the SHBG and free testosterone in the system? If so, I am not saying that you are wrong, but I am not sure how to get there logically since free T is a product of how much total T is bound to SHBG. In other words, SHBG and total T are the precursors needed to determine free T. I don't know how free T can be the constant (which implies that free T and SHBG are the precursors and total T the result of their interaction with each other, if that is what you are saying).

 

[Cataceous]

I'm still not following. Are you saying that it is the *free* testosterone that is fixed? In other words, that total T is the fluctuating number based on the SHBG and free testosterone in the system? If so, I am not saying that you are wrong, but I am not sure how to get there logically since free T is a product of how much total T is bound to SHBG. In other words, SHBG and total T are the precursors needed to determine free T. I don't know how free T can be the constant (which implies that free T and SHBG are the precursors and total T the result of their interaction with each other, if that is what you are saying).

I'm saying that treating total testosterone as the "fluctuating" number (dependent variable) is a simpler way to view things at equilibrium under TRT. This is not worrying about the more complex behavior that happens during transitions, or about actual precursors. This simplification is possible because the metabolism/excretion of testosterone must match the slow trickle entering circulation. This should hold for anyone getting his testosterone at a fairly steady rate.

Mathematically, the simplest model is this:

A_fixed_constant = T_aborption_rate = T_metabolic_clearance_rate = k * free_T

Where k is a metabolic constant. It's also true that:

free_T = f(SHBG, total_T)

But if the metabolic constant k doesn't change then at equilibrium free_T must not change either. Thus if we're examining changes in SHBG then total testosterone must change appropriately to preserve the free_T value.

 

[falconberg]

Cataceous, so you are saying that free testosterone is fixed, not in the f(SHBG, total_T) equation, but another equation that deals with a metabolic constant, which I assume simply represents the way that a person's body processes free testosterone.

You are also assuming that the absorption rate will always equal the metabolic clearance rate (if I understand correctly, because "SHBG has minimal if any effect on the apparent serum half-life of testosterone"), and that both are simply a function of the way that a person's body processes free testosterone.

Am I following your thought?

 

[Cataceous]

Free testosterone can be calculated from total T and SHBG (ignoring albumin). You can turn it around to say that total T can be calculated from free T and SHBG. So in a situation with fairly constant free T, which I'm claiming generally applies to TRT, then you can calculate total T. And furthermore, if only SHBG changes then this means that total T adjusts appropriately to return free T to where it was before the change.

The absorption rate and the metabolic clearance rate must match in any reasonable time frame. If the rates don't match then there's not an equilibrium; testosterone is accumulating or being depleted, and serum values are in flux. But we've required the absorption rate to be constant or slowly changing, while metabolic processes have much faster time constants, on the order of minutes to a couple hours. This means that the absorption rate effectively controls free testosterone, which along with SHBG effectively controls total testosterone.