SHBG cause or consequence of hypogonadism?

[FunkOdyssey]

I'm young healthy and not obese yet only at 10 ng/dl. Total T is over 1000 though

It's easy to get mixed up but you're supposed to inject testosterone, not SHBG.

 

[tareload]

25 ng/dL would land between the 97.5 - 99th percentile among young, healthy, non-obese men in the FHS Gen 3 reference sample. It's basically the tippity-top of the physiological range. Hoping to check out what that feels like in the near future.

View attachment 24461
Reference Ranges for Testosterone in Men Generated Using Liquid Chromatography Tandem Mass Spectrometry in a Community-Based Sample of Healthy Nonobese Young Men in the Framingham Heart Study and Applied to Three Geographically Distinct Cohorts

Looking forward to hearing your report back!

If I had to go back I think I maybe would have just stayed at 5 or 6 ng/dl fT. This TRT slippery slope is quite the journey. Once you open that door it is hard to close it.

hCG mono worked about the best for me if going by performance down below. Obviously if you want the bigger gains you gotta hit the T.

 

[FunkOdyssey]

Looking forward to hearing your report back!

If I had to go back I think I maybe would have just stayed at 5 or 6 ng/dl fT. This TRT slippery slope is quite the journey. Once you open that door it is hard to close it.

No one can rain on a parade like you can! I was thinking of introducing my wife to HRT also and then I read this post of yours on t-nation and am having second thoughts now. Lol

TRT Causes Men to Cheat?

“Ask your your doctor if Leuprorelin is right for him.”

forums.t-nation.com

 

[savefoxes]

It's easy to get mixed up but you're supposed to inject testosterone, not SHBG.

I wasn't injecting anything so that was my natutal state. I was at 1200 total T 65 SHBG when I felt better

 

[savefoxes]

Looking forward to hearing your report back!

If I had to go back I think I maybe would have just stayed at 5 or 6 ng/dl fT. This TRT slippery slope is quite the journey. Once you open that door it is hard to close it.

hCG mono worked about the best for me if going by performance down below. Obviously if you want the bigger gains you gotta hit the T.

You would have developed health issues and died young with that level

 

[FunkOdyssey]

You would have developed health issues and died young with that level

Good point, and we can also assume it would have dropped further with time. If you're at 6 ng/dL free in your 30's or 40's, where would you be in your 50's, 60's, 70's? May as well start now I think.

 

[tareload]

You would have developed health issues and died young with that level

Haha. I almost died young at somewhere in the 40-60 range ng/dl for a couple of weeks. Full disclosure I am typically a member of very small groups so results not typical.

Ya never know. But to your point 10-20 ng/dl probably a good reasonable plan.

You got any tips for the races or stock picks?

 

[tareload]

No one can rain on a parade like you can! I was thinking of introducing my wife to HRT also and then I read this post of yours on t-nation and am having second thoughts now. Lol

TRT Causes Men to Cheat?

“Ask your your doctor if Leuprorelin is right for him.”

forums.t-nation.com

That was for more entertainment. I think the substrate has to be there beforehand which is why there is another good thread on here about selecting the right mate.

I don't like to share other's experience on here but I am aware of a few ladies on HRT (T cream). 800 ng/dl peak but down under 100 ng/dl in a few hours. Pulsing twice daily. Never had a problem like in the article. Life changing actually. So there you go, I made up for the rain. That reminds me I have a very nice PK profile for labially applied T cream with rate constant analysis. Maybe I will post that up.

 

[Dicky]

There's no need for higher testosterone production. Think of production as equaling free testosterone. At steady state the amount of SHBG is basically irrelevant. Someone recently suggested a sponge analogy: SHBG is likened to a sponge, with testosterone being the water. Testosterone—water—is dripped onto the sponge. This represents production. When the sponge is saturated the testosterone drips off the bottom of the sponge—this represents free testosterone being used. At steady state the flow of testosterone leaving the sponge equals the production entering the sponge. You can double the size of the sponge—the amount of SHBG—which temporarily reduces the flow, but the sponge soon saturates again so that outflow again equals inflow. A larger sponge means more total testosterone is contained within the sponge. But that testosterone within the sponge isn't doing much of anything, and so is largely irrelevant. For the sake of simplicity this ignores the possible benefits in having testosterone buffered this way.

A little more detail on the transient effect: Think of the body as regulating production to attain its desired outflow. If you could instantly enlarge the sponge—increase SHBG—then the body detects the reduced outflow and increases production. But the sponge soon saturates and outflow even goes too high, leading to reduced production. There could even be damped oscillations. But over time the flow rates return to where they started.


As illustrated in the above analogy, once the SHBG is "saturated" by the flow of testosterone the amount of SHBG and total testosterone doesn't much matter.

I don't know if you will know the answer to my question but I'm going to ask anyway. It wasn't so long ago that it was conventional wisdom that SHBG regulated Free T. More SHBG = less Free T for any given dose of exogenous testosterone. Now the current thinking is that SHBG is not that relevant to Free T (in a steady state situation). What happened along the way to change from the conventional wisdom to the new "sponge model" way of thinking about SHBG and Free T? Was there some research published or was this more of an independent thinker kind of realization?

 

[tareload]

independent thinker

Cataceous

Now the current thinking is that SHBG is not that relevant to Free T (in a steady state situation). What happened along the way to change from the conventional wisdom to the new "sponge model"

The current thinking I see almost all the time is still the conventional wisdom you referenced above. I've only seen the sponge model when you dig deep into the mechanistic literature (and it is buried in there) or by reading original thinkers like cataceous. This forum is really something.

Chapter 12 - Hypothalamo-Pituitary Unit, Testis, and Male Accessory Organs

Read this chapter. Chapter 12 - Hypothalamo-Pituitary Unit, Testis, and Male Accessory Organs https://www.sciencedirect.com/science/article/pii/B9780323479127000123?via%3Dihub From https://www.sciencedirect.com/book/9780323479127/yen-and-jaffes-reproductive-endocrinology

www.excelmale.com

Credit to @Weasel who makes a great observation. Probably more like 99%.

 

[Dicky]

Cataceous


The current thinking I see almost all the time is still the conventional wisdom you referenced above. I've only seen the sponge model when you dig deep into the mechanistic literature (and it is buried in there) or by reading original thinkers like cataceous. This forum is really something.

Chapter 12 - Hypothalamo-Pituitary Unit, Testis, and Male Accessory Organs

Read this chapter. Chapter 12 - Hypothalamo-Pituitary Unit, Testis, and Male Accessory Organs https://www.sciencedirect.com/science/article/pii/B9780323479127000123?via%3Dihub From https://www.sciencedirect.com/book/9780323479127/yen-and-jaffes-reproductive-endocrinology

www.excelmale.com

Credit to @Weasel who makes a great observation. Probably more like 99%.

Amen to that. It is very impressive to see this kind of out of the box thinking. The conventional thinking is one of the cornerstone ideas in TRT. That if you have high SHBG you are going to need a higher dose of testosterone to overcome the SHBG in order to achieve a therapeutic level of free T. This new way of thinking about SHBG seems like a big deal to me.

 

[FunkOdyssey]

Amen to that. It is very impressive to see this kind of out of the box thinking. The conventional thinking is one of the cornerstone ideas in TRT. That if you have high SHBG you are going to need a higher dose of testosterone to overcome the SHBG in order to achieve a therapeutic level of free T. This new way of thinking about SHBG seems like a big deal to me.

Yes. When I started grappling with this topic, the conventional SHBG story seemed obviously wrong to me but I didn't have the Cataceous-level understanding to back up my skepticism. I posted my thoughts and questions about SHBG, free T, and testosterone production on a popular TRT ******** group named after a YouTube channel, and the response from the moderator / TRT clinic owner was "no, this is all wrong". When I asked why it was wrong, he said he was giving a talk on the subject in Florida and I could attend the conference if I wanted to hear him speak about it.

I'm glad I made it over here before I wasted $1,000+ on travel and conference tickets.

 

[Cataceous]

... What happened along the way to change from the conventional wisdom to the new "sponge model" way of thinking about SHBG and Free T? Was there some research published or was this more of an independent thinker kind of realization?

For me it was the realization that conventional wisdom is incompatible with a couple very basic assumptions. Here's one of the posts where I lay out the reasoning.

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.​

...
The current thinking I see almost all the time is still the conventional wisdom you referenced above. I've only seen the sponge model when you dig deep into the mechanistic literature (and it is buried in there) or by reading original thinkers like cataceous. This forum is really something.
...

Just in the last year you referenced a paper that mentioned this hypothesis in plain language. I'm sure I saved it, but I have so many I'll have trouble identifying it. In any case, while I arrived at the idea independently, it's not as though I'm the only one who found it to be a logical progression.

 

[Cataceous]

I'm not sure if this is the paper, but it still has lots of good stuff:

A Reappraisal of Testosterone’s Binding in Circulation: Physiological and Clinical Implications

This appraisal of the dynamics of testosterone binding to proteins and of the free hormone hypothesis offers guidance for the application of free testoster

academic.oup.com

If the free hormone hypothesis is correct, an increase in SHBG concentrations would transiently decrease free testosterone concentrations, which would trigger the feedback and feed-forward mechanisms within the hypothalamic-pituitary-testicular axis to stimulate luteinizing hormone (LH) and testosterone production until free testosterone levels were restored.​

...

Some men with HIV may have markedly elevated SHBG levels (162), leading to high-normal or high total testosterone levels, even though free testosterone levels in a significant fraction of men with HIV were low normal or even low in the face of elevated total testosterone levels (163–165), leading many HIV experts to recommend measurement of free testosterone levels in the evaluation of hypogonadism in this population (166).​

...

Patients with undetectable SHBG concentrations serve as unique experiments of nature for examining the free hormone hypothesis. Vos et al. (172) recently identified a brother and sister pair who were homozygous for a missense mutation within the SHBG gene (p.G224R SHBG), resulting in retention of the mutant protein in the endoplasmic reticulum, failure to secrete SHBG, and undetectable serum SHBG levels. As expected with an undetectable SHBG level, the male patient with SHBG deficiency had a very low total testosterone level of 4.8 nmol/L (reported normal range, 10 to 30 nmol/L) but a normal free testosterone level (174 pmol/L; normal range of the assay, 120 to 750 pmol/L). Both siblings had normal gonadal development and function. Furthermore, the LH level in the male was not elevated, and he had normal sexual development and normal secondary sex characteristics with normal spermatogenesis, suggesting that free testosterone concentrations, rather than total testosterone concentrations, regulate sexual development and feedback inhibition of gonadotropins.​

...

Transgenic male mice that hyperexpress human SHBG had markedly elevated serum total testosterone levels that were 10 to 100 times higher than those in wild-type littermates (184). Despite markedly elevated total testosterone levels, free testosterone concentrations and reproductive function in these mice were normal (185), providing further support for the free hormone hypothesis.​

 

[arsenio7]

25 ng/dL would land between the 97.5 - 99th percentile among young, healthy, non-obese men in the FHS Gen 3 reference sample. It's basically the tippity-top of the physiological range. Hoping to check out what that feels like in the near future.

View attachment 24461
Reference Ranges for Testosterone in Men Generated Using Liquid Chromatography Tandem Mass Spectrometry in a Community-Based Sample of Healthy Nonobese Young Men in the Framingham Heart Study and Applied to Three Geographically Distinct Cohorts

This study used the Mazer algorithm to compute free testosterone, which might differ from Vermeulen and the gold standard equilibrium dialysis.
So I order to use this table for a specific case, maybe the same formula should be used.
WDYT?

 

[FunkOdyssey]

This study used the Mazer algorithm to compute free testosterone, which might differ from Vermeulen and the gold standard equilibrium dialysis.
So I order to use this table for a specific case, maybe the same formula should be used.
WDYT?

I agree that would make the most sense. Is there a mazer algorithm calculator out there?

 

[tareload]

I agree that would make the most sense. Is there a mazer algorithm calculator out there?

There's a thread for almost everything on here thanks to @Nelson Vergel / @Cataceous / @madman / @Vince

A novel spreadsheet method for calculating the free testosterone, free DHT, and free estradiol.

Abstract In humans, testosterone (T), dihydrotestosterone (DHT), estradiol (E2), estrone (E1) and cortisol (C) bind to the serum proteins sex hormone-binding globulin (SHBG), albumin (Alb) and corticosteroid-binding globulin (CBG). Equilibrium dialysis is considered to be the "gold standard" for...

www.excelmale.com

A novel spreadsheet method for calculating the free testosterone, free DHT, and free estradiol.

Abstract In humans, testosterone (T), dihydrotestosterone (DHT), estradiol (E2), estrone (E1) and cortisol (C) bind to the serum proteins sex hormone-binding globulin (SHBG), albumin (Alb) and corticosteroid-binding globulin (CBG). Equilibrium dialysis is considered to be the "gold standard" for...

www.excelmale.com

Spreadsheet for Calculating Free T & E2

There's been a lot discussion recently in Excelmale on wanting to test for Free E2 and the relatively high cost of this test. There are online calculators which calculate an estimate of Free T based on Total T, SHBG and Albumin. However there doesn't appear to be an online calculator for...

www.excelmale.com

Spreadsheet for Calculating Free T & E2

There's been a lot discussion recently in Excelmale on wanting to test for Free E2 and the relatively high cost of this test. There are online calculators which calculate an estimate of Free T based on Total T, SHBG and Albumin. However there doesn't appear to be an online calculator for...

www.excelmale.com

 

[Belekas]

Very interesting topic. Following. My SHBG is 64 and FT crashed below range. Anecdotically my pops did a blood test and his SHBG is 51 and FT 2x more and hes 64. I'm turning 40 yet we both lived a very different lifestyles, as many of guys from Eastern Europe back in 80s/90s. So wonder if SHBG is hereditary by any means?

 

[tareload]

This study used the Mazer algorithm to compute free testosterone, which might differ from Vermeulen and the gold standard equilibrium dialysis.

Is there a mazer algorithm calculator out there?

And let's not leave out Sartorius from the fun (very simple empirical formula):

Calculate Free Testosterone with TruT by FPT

[0026] Fig. 7 depicts the thermodynamic Parameters associated with testosterone's binding to SHBG derived from the fit of binding isotherms and ITC data to new model. While this parameter set is not unique, together they consistently describe the binding isotherms, depletion curves and ITC data...

www.excelmale.com

In case you like a calculator that lines up pretty closely with Quest (hat tip to @Cataceous).

Come on fT CDC Host results! @madman, I just can't wait.