Shbg/free t?

[Charliebizz]

I have a weird question I do t know if I'm going to be able to word it right. But I'm curious why free testosterone is so import if shbg transports androgens to the cellular targets. This paragraph is from a study on pub med. I can be completely off on my interpretation.

classical hormones, sex steroids or their immediate precursors are produced in steroidogenic cells of the gonads, adrenal glands, and placenta, and they are transported in the blood to their target tissues by several steroid-binding proteins [9]. The most abundant plasma protein, albumin, binds all classes of steroids nonspecifically and with low affinity and functions as a reservoir that enhances the solubility of lipophilic molecules and prolongs their biological half-life [10]. By contrast, a plasma glycoprotein, known as sex hormone-binding globulin (SHBG), binds biologically active androgens and estrogens specifically, with an affinity four to five orders of magnitude greater than that of albumin, and is found in the blood of all classes of vertebrates with the exception of birds [9]. Because of its very high ligand-binding affinity, plasma SHBG is the major plasma transport protein for biologically active androgens and estrogens [11], and changes in the blood levels of SHBG influence their plasma distribution and access to target tissues and cells [12].

Would this mean that total t actual mattered more for low shbg guys. Like for me my tt is around 500-600 but my ft is over the top of the range on the quest test 35-155 pg/ml
But I do not get many benefits from trt.

So is shbg the most important protein for driving t into the cells? Or is something else? Or in layman's terms is free t just floating around and gets picked up by androgen receptors lol. I've always had trouble understanding why free hormones are labeled as the " gold standard " of testing.

 

[Cataceous]

SHBG should still be viewed primarily as a buffer or reservoir. Free testosterone remains the dominant driver of testosterone utilization: Yes, it is "floating around"—after dissociating from albumin or SHBG—and then being "picked up by androgen receptors". The transport mechanism involving SHBG and the megalin receptor is interesting, and apparently important for normal development[R]. But I've seen nothing so far to suggest that this pathway is large in a relative sense:

There is considerable indirect and direct evidence in support of the free hormone hypothesis. Thus, in population studies, it is almost always the non-SHBG-bound fraction of testosterone or estradiol that has been most strongly associated with muscle mass, strength, and bone mineral density (BMD) (4). The non-SHBG-bound estradiol concentration has generally been the most robust predictor of BMD in men, with total estradiol and total or non-SHBG-bound testosterone usually showing weaker associations (reviewed in Ref. 5). Because SHBG concentrations more than double over life in men (3), this has led to the plausible hypothesis that the age-related increase in SHBG levels, by limiting the availability of sex steroids, contributes to the observed decline in bone mass in aging men (5).​

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There is also considerable direct evidence in favor of the free hormone hypothesis (summarized in Ref. 6). Thus, animal as well as in vitro studies have found that SHBG limits access of testosterone to some target tissues such as brain, liver, salivary gland, lymph node, and prostate (6, 7). SHBG also limits the bioavailability of estradiol, particularly in the brain and testis (6, 8, 9), although this effect may be less pronounced in other tissues such as the liver (6).​

...​

... The free hormone hypothesis, which has withstood the test of time, is likely still correct, at least under conditions of declining free hormone levels. On the other hand, the parallel pathway involving SHBG-mediated entry of sex steroids into cells may become more evident in the setting of sex steroid sufficiency. In the end, these apparent contradictory findings reflect the fact that biological processes rarely have absolute truths; it is only our artificial constructs of those truths that tend to be absolute.​

[R]​

Here's a more recent reference looking at the issue:

... In this review, I will examine four hormone groups—vitamin D metabolites (especially 25OHD), thyroid hormones (especially thyroxine [T4]), sex steroids (especially testosterone), and glucocorticoids (especially cortisol)—that are bound to various degrees to their respective binding proteins—vitamin D-binding protein (DBP), thyroid-binding globulin (TBG), sex hormone-binding globulin (SHBG), and cortisol-binding globulin (CBG)—for which a strong case can be made that measurement of the free hormone level provides a better assessment of hormonal status than the measurement of total hormonal levels under conditions in which the binding proteins are affected in levels or affinities for the hormones to which they bind. I will discuss the rationale for this argument based on the free hormone hypothesis, discuss potential exceptions to the free hormone hypothesis, and review functions of the binding proteins that may be independent of their transport role. ...​

[R]​

 

[Charliebizz]

My only reason for questioning it is out of the low shbg guys the ones that seem to be doing good are actually on higher doses. I could be wrong. But seems like most are close to 20mg daily.

So my thoughts are maybe because those higher doses are getting the total t up. And maybe that matters more for low shbg guys. Just something I've been thinking about. I'm sure I'm wrong and more to the story like A.I use and such. I may never get away with using that much because I have no desire to mess with A.I.

 

[Cataceous]

You could make an argument for more testosterone being needed based on the statements below, which I've quoted before:

However, new research shows that SHBG bound hormones are not only active, but that SHBG is itself a hormone with extracellular receptors ready to receive it. These receptors have been shown to modulate cAMP, which indirectly alters the sensitivity of the cell to the free hormones that enter it. ​

More importantly, internalized SHBG functions within a cell to promote AR activity. Free hormone entering cells is less active without adequate SHBG also entering the cell, because they are rapidly metabolized and effluxed from the cell the same way that free hormones in serum are rapidly metabolized.​

CW is just plain wrong, and we've known it has been wrong. Yes, free hormones are "available" to enter cells ("bio-available",) but their ability to signal AR activity depends on the availability and uptake of free SHBG in many cell lines. This has been proven in studies: too much SHBG, and too little free hormone enters. Too little SHBG, and hormones won't last within the cell long enough, and cAMP will be attenuated, negating many of the effects of the hormone.
[R]​

Here's an underlying reference:

Sex Hormone Binding Globulin (SHBG) is the major serum carrier of sex hormones. However, growing evidence suggests that SHBG is internalised and plays a role in regulating intracellular hormone action. This study was to determine whether SHBG plays a role in testosterone uptake, metabolism, and action in the androgen sensitive LNCaP prostate cancer cell line. Internalisation of SHBG and testosterone, the effects of SHBG on testosterone uptake, metabolism, regulation of androgen responsive genes, and cell growth were assessed. LNCaP cells internalised SHBG by a testosterone independent process. Testosterone was rapidly taken up and effluxed as testosterone-glucuronide; however this effect was reduced by the presence of SHBG. ...​

[R]​

 

[Charliebizz]

I'm not nearly as articulate as most of you guys. But could we be looking at this wrong for low shbg guys. Could it be maybe we have to focus more on having a higher total t and worry less about free t.

Could our free t be higher because the body is actually not utilizing it? Could that also be why a guy like me my total t drops in blood labs at a much faster rate then my free t. Is that maybe why some men do not get symptom relief with put running way to high levels of free t?

I know this goes against everything we know but I've seen a good amount of low shbg guys do better with higher doses then the lower dose crowd and I know a few higher shbg guys that actually do better with lower then average doses

 

[S1W]

I'm not nearly as articulate as most of you guys. But could we be looking at this wrong for low shbg guys. Could it be maybe we have to focus more on having a higher total t and worry less about free t.

Could our free t be higher because the body is actually not utilizing it? Could that also be why a guy like me my total t drops in blood labs at a much faster rate then my free t. Is that maybe why some men do not get symptom relief with put running way to high levels of free t?

I know this goes against everything we know but I've seen a good amount of low shbg guys do better with higher doses then the lower dose crowd and I know a few higher shbg guys that actually do better with lower then average doses

Good topic and I’m glad that Cataceous chimed in.

I’m also a low SHBG guy (16) that does better at higher levels.

It always seems like toeing a thin line though - if my levels aren’t at a certain threshold, it seems like I lose the benefits of TRT. However, just a hair past that threshold I run into issues with high HCT, etc.

 

[Charliebizz]

Good topic and I’m glad that Cataceous chimed in.

I’m also a low SHBG guy (16) that does better at higher levels.

It always seems like toeing a thin line though - if my levels aren’t at a certain threshold, it seems like I lose the benefits of TRT. However, just a hair past that threshold I run into issues with high HCT, etc.

What is your dose/frequency/ft/tt/e2 levels if you don't mind sharing.

I haven't to day ran into any hct or blood pressure issues even as high as 160mg a week. Over time my blood counts are creeping up. But I still have room to play with. I was also on the low end of normal with my CBC before trt.

It's just something I've been constantly thinking about. I wish I could articulate my thoughts better into paper but I just feel like free t might not be being utilized in low shbg guys that's why it's high in comparison to TT

 

[Cataceous]

I'm not nearly as articulate as most of you guys. But could we be looking at this wrong for low shbg guys. Could it be maybe we have to focus more on having a higher total t and worry less about free t.

Could our free t be higher because the body is actually not utilizing it? Could that also be why a guy like me my total t drops in blood labs at a much faster rate then my free t. Is that maybe why some men do not get symptom relief with put running way to high levels of free t?

I know this goes against everything we know but I've seen a good amount of low shbg guys do better with higher doses then the lower dose crowd and I know a few higher shbg guys that actually do better with lower then average doses

I'd still view total testosterone as relatively unimportant. The TRT dose drives free testosterone directly. With low SHBG you may be stuck between opposing problems: You have less efficient utilization of that free testosterone, but pushing levels higher to compensate further skews your ratio of free estradiol to free testosterone.

 

[Charliebizz]

I'd still view total testosterone as relatively unimportant. The TRT dose drives free testosterone directly. With low SHBG you may be stuck between opposing problems: You have less efficient utilization of that free testosterone, but pushing levels higher to compensate further skews your ratio of free estradiol to free testosterone.

I'd still view total testosterone as relatively unimportant. The TRT dose drives free testosterone directly. With low SHBG you may be stuck between opposing problems: You have less efficient utilization of that free testosterone, but pushing levels higher to compensate further skews your ratio of free estradiol to free testosterone.

I'd have to a gree with that. And an a.i is the only thing I have never committed too. Just so worried about adding another variable. And I'm so damn sensitive to minor changes. Like the reaction I have to HCG almost right away (2-250iu shots would lead me to believe it is high e2. But I'm not really sure how fast HCG could mess with e2. I have an a.i on hand but I've only tried one pill over the last 2 years lol.

 

[Cataceous]

I'd have to a gree with that. And an a.i is the only thing I have never committed too. Just so worried about adding another variable. And I'm so damn sensitive to minor changes. Like the reaction I have to HCG almost right away (2-250iu shots would lead me to believe it is high e2. But I'm not really sure how fast HCG could mess with e2. I have an a.i on hand but I've only tried one pill over the last 2 years lol.

AIs tend to be rather blunt instruments. It doesn't surprise me that low-SHBG guys in particular seem to have a hard time finding the right testosterone and AI doses to achieve a good balance. I suspect it would be even worse with hCG use because then the AI has reduced effect on the intratesticular aromatization.

I think this post on E2/T ratios is worth repeating:

One of the problems with low SHBG may be the ratio of free estradiol (fE2) to free testosterone (fT). Without TRT, the normal HPTA uses free estradiol as its primary regulator. With a fixed free estradiol, the lower the SHBG the lower the free testosterone. This means low SHBG provides a built-in propensity towards hypogonadism.​

​

So the symptomatic low-SHBG guy goes on TRT. What happens? Now the exogenous testosterone is directly controlling free testosterone. With a fixed free testosterone, the lower the SHBG the higher the free estradiol. What this means in practice is that the low-SHBG guy starts with a higher fE2/FT ratio than in normal guys, and increasing testosterone via large, infrequent injections pushes the ratio even higher.​

​

If we posit that there is a tolerable normal range for the fE2/fT ratio then it's clearly safer for the low-SHBG guy to avoid large peaks in his serum testosterone and estradiol. This is accomplished with smaller and more frequent injections.​

​

Here are some numbers calculated using the multi-ligand model:​

​

​

In this thought experiment there are two guys on TRT who are identical except for SHBG. They are on the same E5D doses of testosterone cypionate. In the last line of the table the peak fE2/fT ratio of the guy with normal SHBG is chosen as the reference point. The normal guy is operating in a range of 93-100%. The low-SHBG guy starts out at 106% and then climbs to 111%. Suppose symptoms occur at over 109%. In this case daily injections would probably help. But if symptoms occur at a lower figure, such as 107%, then a dose reduction would also be necessary, and this would risk sending free testosterone too low, which might cause other symptoms. It's easy to see why TRT can be a struggle for guys with low SHBG.​

 

[S1W]

What is your dose/frequency/ft/tt/e2 levels if you don't mind sharing.

I haven't to day ran into any hct or blood pressure issues even as high as 160mg a week. Over time my blood counts are creeping up. But I still have room to play with. I was also on the low end of normal with my CBC before trt.

It's just something I've been constantly thinking about. I wish I could articulate my thoughts better into paper but I just feel like free t might not be being utilized in low shbg guys that's why it's high in comparison to TT

I’ve settled on EOD injections. Generally between 34mg EOD (119/wk) to 38mg EOD (133/wk).

Last labs were from 38mg EOD (trough before injection):

SHBG: 16
TT: 875
TruT FT: 31.5
E2 (LC/MS): 72

This was a good protocol for me in terms of symptom resolution - which is something that sometimes gets lost in the weeds.

What I mean by that is that with all of the trial and error, labs, etc that are part of TRT, it’s important for me to simply step back and say, “Why did I start TRT and does it seem like it’s helping with whatever issue I wanted it to help with?”

For me, this is erectile function. The above protocols work for me. I’ve tried lower dose daily, EOD, E3.5D with less success in terms of system resolution.

I also don’t like AIs. I just don’t feel right on them. I only tried them because my E2 was high on paper. But my E2 has been everywhere between mid 30s and as high as low 80s and I honestly never felt like it was causing me any issues.

Cream (2 clicks AM 1 click PM) has also worked well for me and has been the only TRT method in which I have symptom resolution and picture perfect labs. I just prefer injections for a number of reasons.

Another point of clarification - I may not be a true low SHBG guy. When I started TRT my SHBG was high 20s. Either long-term TRT or running consistently high levels has pushed it down.

 

[Charliebizz]

I’ve settled on EOD injections. Generally between 34mg EOD (119/wk) to 38mg EOD (133/wk).

Last labs were from 38mg EOD (trough before injection):

SHBG: 16
TT: 875
TruT FT: 31.5
E2 (LC/MS): 72

This was a good protocol for me in terms of symptom resolution - which is something that sometimes gets lost in the weeds.

What I mean by that is that with all of the trial and error, labs, etc that are part of TRT, it’s important for me to simply step back and say, “Why did I start TRT and does it seem like it’s helping with whatever issue I wanted it to help with?”

For me, this is erectile function. The above protocols work for me. I’ve tried lower dose daily, EOD, E3.5D with less success in terms of system resolution.

I also don’t like AIs. I just don’t feel right on them. I only tried them because my E2 was high on paper. But my E2 has been everywhere between mid 30s and as high as low 80s and I honestly never felt like it was causing me any issues.

Cream (2 clicks AM 1 click PM) has also worked well for me and has been the only TRT method in which I have symptom resolution and picture perfect labs. I just prefer injections for a number of reasons.

Another point of clarification - I may not be a true low SHBG guy. When I started TRT my SHBG was high 20s. Either long-term TRT or running consistently high levels has pushed it down.

Thanks for the detailed reply. I wasn't a low shbg guy at first when I started my low t journey almost 15 years ago. I tried trt a few times in those years but never even making it a year. Something with test cyp didn't agree withy body. I had all kinds of sides. But my shbg got lower even off trt. So now even off trt it's around 15. I switched to test e and been on trt for about 2 years now. I feel ok but still missing something.

Reading a post on Reddit from a guy who had fantastic results raising shbg with berberine and milk thistle. He says he finally feels all the effects of trt and completely fixed his lipid panel. Mine is skewed just like his. Normal total cholesterol ,high triglycerides and low HDL. I'm super excited to try it. I will report back if it works well for me.

 

[goolapsh]

I’ve settled on EOD injections. Generally between 34mg EOD (119/wk) to 38mg EOD (133/wk).

Last labs were from 38mg EOD (trough before injection):

SHBG: 16
TT: 875
TruT FT: 31.5
E2 (LC/MS): 72

This was a good protocol for me in terms of symptom resolution - which is something that sometimes gets lost in the weeds.

What I mean by that is that with all of the trial and error, labs, etc that are part of TRT, it’s important for me to simply step back and say, “Why did I start TRT and does it seem like it’s helping with whatever issue I wanted it to help with?”

For me, this is erectile function. The above protocols work for me. I’ve tried lower dose daily, EOD, E3.5D with less success in terms of system resolution.

I also don’t like AIs. I just don’t feel right on them. I only tried them because my E2 was high on paper. But my E2 has been everywhere between mid 30s and as high as low 80s and I honestly never felt like it was causing me any issues.

Cream (2 clicks AM 1 click PM) has also worked well for me and has been the only TRT method in which I have symptom resolution and picture perfect labs. I just prefer injections for a number of reasons.

Another point of clarification - I may not be a true low SHBG guy. When I started TRT my SHBG was high 20s. Either long-term TRT or running consistently high levels has pushed it down.

I also have low shbg and it seems scrotal cream was the only method that worked for me. I did eod with cypionate from 100-150 per week with no improvement in libido or erectile function. In fact it gave me ED, which I had never had in my life until I began the shots. That’s when I looked into dht and had below reference range on cypionate. Naturally my dht lies in the middle of the reference range. I see many low shbg guys being poor converters to dht on cypionate for some reason.