Does TRT reverse/improve sexual symptoms for most men with High Range SHBG / Lower Free T?

[ResearchIt]

The more I read about the situation of the healthy active person with normal labs and normal Total T, but higher range SHBG and lower Free T, it seems the only real solution that fixes the numbers is TRT.

For all the other solutions that supposedly help (boron, nettle, more carbs, etc), the body's effort to maintain a lower Free T target overrides whatever is tried. That is my experience anyway with the many tests and labs I have done. I can lower my SHBG a bit (from say 57 to 49), but, if I do, my Total T goes down along with it and my Free T stays about the same.

For most people in this situation who decide to do TRT, aside from fixing the numbers, does TRT fix/improve the following symptoms?

Loss of morning erections
Diminished libido
Weaker erections
Reduced sensitivity

Thanks!

 

[Vince]

The more I read about the situation of the healthy active person with normal labs and normal Total T, but higher range SHBG and lower Free T, it seems the only real solution that fixes the numbers is TRT.

For all the other solutions that supposedly help (boron, nettle, more carbs, etc), the body's effort to maintain a lower Free T target overrides whatever is tried. That is my experience anyway with the many tests and labs I have done. I can lower my SHBG a bit (from say 57 to 49), but, if I do, my Total T goes down along with it and my Free T stays about the same.

For most people in this situation who decide to do TRT, aside from fixing the numbers, does TRT fix/improve the following symptoms?

Loss of morning erections
Diminished libido
Weaker erections
Reduced sensitivity

Thanks!

As you probably read, magnesium improves free testosterone. Have you ever had your magnesium levels checked? Do you supplement with magnesium? I've read long time ago. The number one supplement people should take is magnesium.

 

[Vince]

1 Mineral for Everything: Magnesium

Magnesium is a common element that has many functions in the human body, from energy production to providing bone density. It is also necessary for cardiovascular health. In fact, this simple mineral has been shown in a German study to dramatically reduce both cardiovascular disease mortality...

www.excelmale.com

 

[Vince]

The Interplay between Magnesium and Testosterone in Modulating Physical Function in Men

The role of nutritional status as key factor of successful aging is very well recognized. Among the different mechanisms by which nutrients may exert their beneficial effects is the modulation of the hormonal anabolic milieu, which is significantly reduced with aging. Undernutrition and anabolic...

www.hindawi.com

 

[Dudley]

I am only a bit more than 1 month in to low-dose TRT, but I am the type of person you are asking about: high SHBG, in-range total T, low out-of-range free T repeatedly, before any therapy, trying Clomid, and trying Natesto. Now that I am on T cream I am experiencing my first real improvement in libido and erection. My recent blood work, both peak and trough, shows my total T in the middle of the normal range, my SHBG still a little high but closer to the normal range, and my free T in the low-middle end of the normal range. So I feel better, my symptoms are significantly better, and my blood work looks closer to normal.

 

[Cataceous]

...
For all the other solutions that supposedly help (boron, nettle, more carbs, etc), the body's effort to maintain a lower Free T target overrides whatever is tried. That is my experience anyway with the many tests and labs I have done. I can lower my SHBG a bit (from say 57 to 49), but, if I do, my Total T goes down along with it and my Free T stays about the same.
...

In accordance with this I think it's reasonable to argue that high SHBG can be disregarded in the context of hypogonadism. In practice SHBG has little influence on free testosterone, at least when it's not low. Free testosterone is likely controlled by the production rate in normal men or by the dose rate in men on TRT. Consider the analogy of a stream flowing into a reservoir. The inflow represent testosterone production. The outflow represents metabolism of free testosterone. The reservoir itself represents SHBG. It's clear that at equilibrium the size of the reservoir has no effect on the outflow; once the reservoir is full the outflow matches the inflow, regardless.

If you take a normal guy and suddenly increase his SHBG from 30 nMol/L to 100 nMol/L then what happens? There's a period of time during which the extra SHBG is absorbing testosterone, reducing free levels temporarily. But once saturation is achieved—the reservoir is full—then free testosterone returns to baseline. As you note, the body is regulating to attain its desired level of free testosterone. In secondary hypogonadism that regulation is broken, independent of SHBG.

In seeking treatment with incidental elevated SHBG, the main problem is having doctors who either don't know that free testosterone is the most important parameter, or who think that total testosterone is always an acceptable proxy. I encountered this firsthand, initially seeing a urologist who insisted that my total testosterone in the 300s ng/dL was normal. I then saw an endocrinologist who found that calculated free testosterone was low and initiated treatment.

 

[ResearchIt]

As you probably read, magnesium improves free testosterone. Have you ever had your magnesium levels checked? Do you supplement with magnesium? I've read long time ago. The number one supplement people should take is magnesium.

Thank you for the feedback. I had my magnesium checked. It was 2.2 (ref range 1.7 to 2.5) during a time without any supplementation.

 

[ResearchIt]

I am only a bit more than 1 month in to low-dose TRT, but I am the type of person you are asking about: high SHBG, in-range total T, low out-of-range free T repeatedly, before any therapy, trying Clomid, and trying Natesto. Now that I am on T cream I am experiencing my first real improvement in libido and erection. My recent blood work, both peak and trough, shows my total T in the middle of the normal range, my SHBG still a little high but closer to the normal range, and my free T in the low-middle end of the normal range. So I feel better, my symptoms are significantly better, and my blood work looks closer to normal.

That is encouraging to hear that you are feeling better after increasing your Free T.

Did you try Clomid and Natesto already? If so, how did they work for you? I think I am going to try them each over the next few months, Clomid (actually hopefully enclomiphene) first, and then Natesto.

Is T cream considered full TRT? Does it shut down your natural production the same way as injecting? Or is it more like Natesto where it interferes less?

 

[tareload]

In accordance with this I think it's reasonable to argue that high SHBG can be disregarded in the context of hypogonadism. In practice SHBG has little influence on free testosterone, at least when it's not low. Free testosterone is likely controlled by the production rate in normal men or by the dose rate in men on TRT. Consider the analogy of a stream flowing into a reservoir. The inflow represent testosterone production. The outflow represents metabolism of free testosterone. The reservoir itself represents SHBG. It's clear that at equilibrium the size of the reservoir has no effect on the outflow; once the reservoir is full the outflow matches the inflow, regardless.

If you take a normal guy and suddenly increase his SHBG from 30 nMol/L to 100 nMol/L then what happens? There's a period of time during which the extra SHBG is absorbing testosterone, reducing free levels temporarily. But once saturation is achieved—the reservoir is full—then free testosterone returns to baseline. As you note, the body is regulating to attain its desired level of free testosterone. In secondary hypogonadism that regulation is broken, independent of SHBG.

In seeking treatment with incidental elevated SHBG, the main problem is having doctors who either don't know that free testosterone is the most important parameter, or who think that total testosterone is always an acceptable proxy. I encountered this firsthand, initially seeing a urologist who insisted that my total testosterone in the 300s ng/dL was normal. I then saw an endocrinologist who found that calculated free testosterone was low and initiated treatment.

Fun to read again (at least for rodents):

Sex hormone-binding globulin regulation of androgen bioactivity in vivo: validation of the free hormone hypothesis

Sex hormone-binding globulin (SHBG) is the high-affinity binding protein for androgens and estrogens. According to the free hormone hypothesis, SHBG modulates the bioactivity of sex steroids by limiting their diffusion into target tissues. Still, the ...

www.ncbi.nlm.nih.gov

In summary, our detailed examination of the SHBG-Tg model reveals that contrary to the general misconception that SHBG decreases free T concentrations, in vivo it mainly increases total androgen and estrogen concentrations (via hypothalamic-pituitary feedback and prolonged circulating half-life). Nevertheless, SHBG attenuated androgen bioactivity resulting in mild hypogonadal signs in reproductive organs, but no major phenotypic effects on other sexually dimorphic target tissues. These findings offer empirical support for measuring free or bioavailable T in clinical practice, since SHBG can clearly confound interpretations based on circulating total sex steroid concentrations. Although we found no evidence that SHBG has ligand-independent effects in vivo, alternative mechanisms of action beyond the regulation of sex steroid plasma transport may still contribute to effects on certain organs9,10. Finally, our study may assist in the appropriate use of male mouse models for translational biomedical research.

And some additional commentary that gets me thinking about the rodent studies WRT testosterone toxicity:

@DS3

Fun to hypothesize how these data affect the discussion we had on high testosterone in rodents vs males and the toxicity curves. Obviously there is only so much SHBG can do to tie up fT so again it remains to be determined if rodent hearts are more sensitive to fT than humans. FYI.

 

[Dudley]

Yes, I tried Ciomid for several months. It raised my total T lab results but I experienced no change in how I felt and what sex was/ wasn't like. I hear it works for some people, so I wish you good luck. I had no downside trying it, though my estradiol went up I didn't experience any of the mood swing symptoms some people mention. I did have a little weight gain that seemed to be a combination of some water retention and some fat; when I stopped the Clomid, these resolved on their own.

Then, I tried two rounds of Natesto. It did not have measurable impact on my T, nor did it alter what I was experiencing. I found it easy to adhere to the 3x per day, though I know some guys don't like that. I did not find the smell or application bothersome. So no harm in trying, except it is expensive if not covered by your insurance.

 

[tareload]

Fun to read again (at least for rodents):

Sex hormone-binding globulin regulation of androgen bioactivity in vivo: validation of the free hormone hypothesis

Sex hormone-binding globulin (SHBG) is the high-affinity binding protein for androgens and estrogens. According to the free hormone hypothesis, SHBG modulates the bioactivity of sex steroids by limiting their diffusion into target tissues. Still, the ...

www.ncbi.nlm.nih.gov

View attachment 21699

In summary, our detailed examination of the SHBG-Tg model reveals that contrary to the general misconception that SHBG decreases free T concentrations, in vivo it mainly increases total androgen and estrogen concentrations (via hypothalamic-pituitary feedback and prolonged circulating half-life). Nevertheless, SHBG attenuated androgen bioactivity resulting in mild hypogonadal signs in reproductive organs, but no major phenotypic effects on other sexually dimorphic target tissues. These findings offer empirical support for measuring free or bioavailable T in clinical practice, since SHBG can clearly confound interpretations based on circulating total sex steroid concentrations. Although we found no evidence that SHBG has ligand-independent effects in vivo, alternative mechanisms of action beyond the regulation of sex steroid plasma transport may still contribute to effects on certain organs9,10. Finally, our study may assist in the appropriate use of male mouse models for translational biomedical research.

And some additional commentary that gets me thinking about the rodent studies WRT testosterone toxicity:
View attachment 21700
@DS3

Fun to hypothesize how these data to affect the discussion we had on high testosterone in rodents vs males and the toxicity curves. Obviously there is only so much SHBG can do to tie up fT so again it remains to be determined if rodent hearts are more sensitive to fT than humans. FYI.

 

[ResearchIt]

In accordance with this I think it's reasonable to argue that high SHBG can be disregarded in the context of hypogonadism. In practice SHBG has little influence on free testosterone, at least when it's not low. Free testosterone is likely controlled by the production rate in normal men or by the dose rate in men on TRT. Consider the analogy of a stream flowing into a reservoir. The inflow represent testosterone production. The outflow represents metabolism of free testosterone. The reservoir itself represents SHBG. It's clear that at equilibrium the size of the reservoir has no effect on the outflow; once the reservoir is full the outflow matches the inflow, regardless.

If you take a normal guy and suddenly increase his SHBG from 30 nMol/L to 100 nMol/L then what happens? There's a period of time during which the extra SHBG is absorbing testosterone, reducing free levels temporarily. But once saturation is achieved—the reservoir is full—then free testosterone returns to baseline. As you note, the body is regulating to attain its desired level of free testosterone. In secondary hypogonadism that regulation is broken, independent of SHBG.

In seeking treatment with incidental elevated SHBG, the main problem is having doctors who either don't know that free testosterone is the most important parameter, or who think that total testosterone is always an acceptable proxy. I encountered this firsthand, initially seeing a urologist who insisted that my total testosterone in the 300s ng/dL was normal. I then saw an endocrinologist who found that calculated free testosterone was low and initiated treatment.

Thank you for that explanation, very helpful.

Does SHBG bound testosterone eventually get released from SHBG and become free and usable? If so, how does that happen and what is the name of that process? Or does the body just discard the SHBG bound testosterone and it never becomes free and usable?

 

[ResearchIt]

Fun to read again (at least for rodents):

Sex hormone-binding globulin regulation of androgen bioactivity in vivo: validation of the free hormone hypothesis

Sex hormone-binding globulin (SHBG) is the high-affinity binding protein for androgens and estrogens. According to the free hormone hypothesis, SHBG modulates the bioactivity of sex steroids by limiting their diffusion into target tissues. Still, the ...

www.ncbi.nlm.nih.gov

View attachment 21699

In summary, our detailed examination of the SHBG-Tg model reveals that contrary to the general misconception that SHBG decreases free T concentrations, in vivo it mainly increases total androgen and estrogen concentrations (via hypothalamic-pituitary feedback and prolonged circulating half-life). Nevertheless, SHBG attenuated androgen bioactivity resulting in mild hypogonadal signs in reproductive organs, but no major phenotypic effects on other sexually dimorphic target tissues. These findings offer empirical support for measuring free or bioavailable T in clinical practice, since SHBG can clearly confound interpretations based on circulating total sex steroid concentrations. Although we found no evidence that SHBG has ligand-independent effects in vivo, alternative mechanisms of action beyond the regulation of sex steroid plasma transport may still contribute to effects on certain organs9,10. Finally, our study may assist in the appropriate use of male mouse models for translational biomedical research.

And some additional commentary that gets me thinking about the rodent studies WRT testosterone toxicity:
View attachment 21700
@DS3

Fun to hypothesize how these data to affect the discussion we had on high testosterone in rodents vs males and the toxicity curves. Obviously there is only so much SHBG can do to tie up fT so again it remains to be determined if rodent hearts are more sensitive to fT than humans. FYI.

That's a great article, thank you.

I found this snippet from it interesting as well:

"our recent finding that men with high SHBG but normal total T may still have symptoms and signs consistent with late-onset male hypogonadism"

 

[Dudley]

As for the T cream, my doc believes the low-ish dose I'm on is unlikely to shut down my whole system. It may take me being on this for a few months before we know exactly how my body is reacting to it. At this point, a bit more than 1 month in, I am very happy with the significant incremental changes I am seeing in labs and significant incremental changes I am feeling with libido and erections. But I realize some people have a honeymoon at the start of TRT that subsides later on, so I am trying to enjoy the learning process.

 

[ResearchIt]

Yes, I tried Ciomid for several months. It raised my total T lab results but I experienced no change in how I felt and what sex was/ wasn't like. I hear it works for some people, so I wish you good luck. I had no downside trying it, though my estradiol went up I didn't experience any of the mood swing symptoms some people mention. I did have a little weight gain that seemed to be a combination of some water retention and some fat; when I stopped the Clomid, these resolved on their own.

Then, I tried two rounds of Natesto. It did not have measurable impact on my T, nor did it alter what I was experiencing. I found it easy to adhere to the 3x per day, though I know some guys don't like that. I did not find the smell or application bothersome. So no harm in trying, except it is expensive if not covered by your insurance.

Interesting, I appreciate your experience with both of those approaches. I will post my results with them here as well. No harm trying them it sounds like.

 

[ResearchIt]

As for the T cream, my doc believes the low-ish dose I'm on is unlikely to shut down my whole system. It may take me being on this for a few months before we know exactly how my body is reacting to it. At this point, a bit more than 1 month in, I am very happy with the significant incremental changes I am seeing in labs and significant incremental changes I am feeling with libido and erections. But I realize some people have a honeymoon at the start of TRT that subsides later on, so I am trying to enjoy the learning process.

That's great to hear that your labs and symptoms are both improving. I hope for your sake (and mine) that it's not a honeyman phase and will last I will probably need to follow a similiar course of action.

What type of T cream and what dose were you prescribed?

Do you mind me asking if your nocturnal/morning erections have improved/returned?

 

[Cataceous]

...
Does SHBG bound testosterone eventually get released from SHBG and become free and usable? If so, how does that happen and what is the name of that process? Or does the body just discard the SHBG bound testosterone and it never becomes free and usable?

Short answer: SHBG-bound testosterone eventually gets released at random. The body does not just discard the complex. Long answer: At the molecular, level associations and dissociations occur randomly. But with the huge numbers involved statistics can be used to make predictions about the relative numbers of bound and unbound molecules. The binding of SHBG with testosterone is particularly complex due to allostery.

I've previously used this analogy to equate the process to something relatable: You have a large number of energetic monkeys in a room. They're all running around bumping into each other. Now imagine that the monkeys are wearing vests with Velcro on the outside. Some have the hook side and the rest have the loop side. As the monkeys run around and bump into one another sometimes one with hooks will stick to one with loops. They continue squirming and jumping around together until they break apart. Your variables include the concentrations of the two types of monkeys, their energies, and the stickiness of the Velcro. The latter corresponds to the binding affinities of molecules—the stronger the binding force the longer on average it takes for dissociation to occur after association.

 

[Cataceous]

...
"our recent finding that men with high SHBG but normal total T may still have symptoms and signs consistent with late-onset male hypogonadism"

They're alluding to this study showing that low free testosterone is associated with the negative symptoms, even with normal total testosterone. I don't believe they are implying a causal connection to SHBG.

Conclusions: Low cFT, even in the presence of normal TT, is associated with androgen deficiency-related symptoms. Normal cFT, despite low TT, is not associated with cognate symptoms; therefore, cFT levels should be assessed in men with suspected hypogonadal symptoms.​

 

[Willyt]

As for the T cream, my doc believes the low-ish dose I'm on is unlikely to shut down my whole system. It may take me being on this for a few months before we know exactly how my body is reacting to it. At this point, a bit more than 1 month in, I am very happy with the significant incremental changes I am seeing in labs and significant incremental changes I am feeling with libido and erections. But I realize some people have a honeymoon at the start of TRT that subsides later on, so I am trying to enjoy the learning process.

I thought the same thing when experimenting with low dose cream awhile back until it drove my TT into the ground under 200 at trough along with feeling like crap. It will be interesting to see if your tests show otherwise. It stays in system too long to mimic Natesto-like variations.

 

[Dudley]

Hey Willyt, thanks for telling me about your experience. How long were you on the cream before it started driving down your TT? So far mine has held pretty steady and is in mid to mid-high range of normal.