Calculate free testosterone with TruT by FPT

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Cataceous

Super Moderator
The idea of SHBG as a sponge that sucks up large amounts of testosterone and leaves your free T low doesn't seem to be how it really works. The way I understand it, high SHBG makes your meager production (revealed by the free T) look like it's normal or even high when it isn't. The SHBG is basically extending the half-life of the testosterone you've produced and the relationship seems to me alot like ferritin and iron.
An SHBG sponge analogy is compatible with your other points. I've used a similar reservoir analogy. Think of testosterone as like water being dripped onto the sponge. The important feature is that the sponge saturates, at which point it doesn't interfere with the "flow" of free testosterone—free testosterone being driven exclusively by endogenous production or exogenous dosing. If you double the size of the sponge then the flow is temporarily impaired until the sponge is again saturated. Then free testosterone flows the same as before. A larger sponge means more total testosterone is held, but at steady state this is independent of the flow of free testosterone.
 
Defy Medical TRT clinic doctor

FunkOdyssey

Well-Known Member
An SHBG sponge analogy is compatible with your other points. I've used a similar reservoir analogy. Think of testosterone as like water being dripped onto the sponge. The important feature is that the sponge saturates, at which point it doesn't interfere with the "flow" of free testosterone—free testosterone being driven exclusively by endogenous production or exogenous dosing. If you double the size of the sponge then the flow is temporarily impaired until the sponge is again saturated. Then free testosterone flows the same as before. A larger sponge means more total testosterone is held, but at steady state this is independent of the flow of free testosterone.

This is gold. There is so much misunderstanding around SHBG, it cries out for good analogies. Reddit is full of guys that think they just need to knock down their SHBG somehow to double their free T and don't realize all they're likely to accomplish is a reduction of their total T.
 

readalot

Member
This is gold. There is so much misunderstanding around SHBG, it cries out for good analogies. Reddit is full of guys that think they just need to knock down their SHBG somehow to double their free T and don't realize all they're likely to accomplish is a reduction of their total T.
Fun experiment to try with oxandrolone that confirms above with some liberties taken.


 

readalot

Member

 

arseniol

New Member
Thanks again @Cataceous for this meaningful sponge analogy. I agree with @Funkodyssey this helps a lot to have a better picture of the whole mechanism.

According to the literature I found, the half-life of SHBG-trapped T is longer, but not terribly much, which means that the sponge is actually also a sink (or a sponge in which T disappears)

half-life of free T: 18 minutes
half-life of SHBG-bound T : 32 minutes


what is your opinion?
 

madman

Super Moderator
METHODS AND SYSTEMS FOR THE DIAGNOSIS AND TREATMENT OF SEX HORMONE DISORDERS


Screenshot (15503).png







 

rb79

New Member
1658765900351.png

thanks @madman for all this insightful material.

I wanted to put the eugonadic limit as defined by Vermeulen (total T lower than 11 nmol/L or free T lower than 0.225 nmol/L) with it's formula and show on the same graph the Tru-T median ± 1SD.

we see that Vermeulen is much more sensitive than Tru-T.. are we overestimating the effect of SHBG with Vermeulen and similar formulas?
 
Last edited:

arsenio7

New Member
This is gold. There is so much misunderstanding around SHBG, it cries out for good analogies. Reddit is full of guys that think they just need to knock down their SHBG somehow to double their free T and don't realize all they're likely to accomplish is a reduction of their total T.
Hi FunkOdyssey,

I fully agree with you, there is a lot of misunderstanding around SHBG. The sponge analogy is a very good one and shows SHBG from a totally different angle.

Nevertheless, I still think that this sponge consumes a small part of the T (small since the half-life of SHBG-bound-T is longer than free-T). in my mind, SHBG still destroys a part of T, but at small scale.
 

madman

Super Moderator
Phase IIB: Development of TruT Algorithm for Commercialization in Androgen Disorders (2022)

Screenshot (18627).png



TruTTM (v2.0) algorithm

ABSTRACT

Background:
Measurement of free testosterone (T) concentrations is indicated in the diagnosis of androgen disorders, including hypogonadism in men; hirsutism, polycystic ovary syndrome (PCOS), and androgenic alopecia in women; pubertal disorders in boys and management of gender-affirming hormone therapies for transgender and gender diverse (TGD) persons. This Phase IIB proposal aims to continue the development of the TruTTM algorithm by validating it in common conditions characterized by altered estradiol (E2), T, and SHBG concentrations and incorporating the interaction of E2 with T for wider commercial adoption in women in whom E2 levels vary greatly across the menstrual cycle and in TGD population.

Approach: This application follows the FDA’s published “Guidance for Industry: Bioanalytical Method Validation”.

The essential parameters to determine the acceptability of a bioanalytical method include its technical performance (accuracy, precision, sensitivity, selectivity, stability, and matrix effects).

Reference ranges should be determined in appropriate human samples.

The analytical method should be validated for the intended use (e.g., determination in conditions of intended use, such as persons with altered E2 and T levels, women with PCOS, TGD persons, etc.).

In studies through the Phase II, we demonstrated that the method has superior performance characteristics and extended the validation of TruTTM algorithm in conditions characterized by altered SHBG concentrations.

*In the proposed Phase IIB studies, we will generate the v2.0 of TruTTM algorithm by incorporating the dynamics of the E2 induced perturbation in free T levels, validate it in men, women, and TGD populations (Aim 1) and deploy HIPAA-compliant, secure integration of the algorithm into electronic medical records (EMR) workflow

*(Aim 2). Future Directions and Commercialization potential: The phase IIB program will enable the pilot commercial deployment of a HIPAA-compliant (FDA registered) platform for commercializing the TruTTM (v2.0) algorithm embedded into electronic medical record (EMR) for wider clinical adoption.

These studies will improve clinical care and advance our fundamental understanding of dynamic regulation of T bioavailability in diverse populations including unrepresented sexual and gender minorities.









Phase IIB: Development of TruT Algorithm for Commercialization in Androgen Disorders (2022)


Project Start Date: 15 September 2014

Project End Date: 31-August-2024
Screenshot (18628).png

Screenshot (18629).png



Phase II: Research and Commercialization of TruT Algorithm for Free Testosterone (2018)



Phase II: Research and Commercialization of TruT Algorithm for Free Testosterone (2017)


Novel Algorithm for Free Testosterone Determination (2014)







 

madman

Super Moderator
Screenshot (19210).png

1671745684083.png



Endocrine Science

XYone is solving the problems present in the clinical treatment of hormonal disorders such as hypogonadism (Low testosterone condition), Hypothyroidism (Low Thyroxine condition) & other hormonal deficiencies. These typically. have therapeutic solutions that have poor delivery (pharmacokinetics) and almost no personalized or rational dosing. Through our research, we are creating the first-in-class, programmable release, aqueous, nano/microparticle formulation for testosterone and other hormones where we can program the delivery to create solutions which go from the current one size fit all, empirical treatments to personalized, rational dosing regimens.

Our first focus is Testosterone & we are proud to announce that our work is being supported by NIH/SBIR grants and we are partnering with the leading institutions in the world to bring our research to the clinic including Brigham & Women’s Hospital, Mayo Clinic, Center for Disease Control, and Karolinka Institute and others.





Accurate measurement of Androgens

Definitive diagnosis and rational management of androgen disorders currently face a number of challenges.




*Our patent-protected, novel TruT™ companion diagnostic framework provides accurate determination of free testosterone concentrations. This algorithm is based on experimental data demonstrating that testosterone’s binding to SHBG is a multi-step process involving an allosteric interaction between the two binding sites on the SHBG dimer. Estimates of free testosterone derived incorporating the allosteric coupling of SHBG monomers within the dimer provide accurate determination of free testosterone without systematic deviation from values obtained using equilibrium dialysis.

*Ongoing development is focused around continued study and validation in common conditions characterized by altered binding protein concentrations. Further, the incorporation of estradiol interactions will allow for wider adoption in women where estradiol levels vary greatly across the menstrual cycle. Because hyperandrogenism in women is the second most frequent indication for free testosterone determination, understanding the competitive binding and displacement dynamics is important for proper diagnosis in both healthy menstruating women and women with hyperandrogenic disorders, such as PCOS.


Through collaborations and partnerships, the TruT™ platform presents a unique opportunity to aggregate large volumes of data and metadata across diverse populations, ultimately enabling deeper understanding of the basis of androgen disorders and other conditions.

Screenshot (19211).png





Formulation Development

Problems with current androgen/hormonal therapies


Hormonal deficiency supplementation therapies are characterized by absence of improved formulations with optimal PK profiles and patient-friendly dosing. Our first candidate is Testosterone replacement therapy (TRT).

Testosterone replacement therapy (TRT) is indicated for the treatment of androgen deficiency in hypogonadal men. The US Food and Drug Administration (FDA) has approved several testosterone formulations for the treatment of hypogonadism in men, including injectable testosterone esters, transdermal testosterone patches, transdermal testosterone gels and solution, buccal adhesive testosterone tablets, intranasal testosterone, and testosterone pellets & recently oral pills. However, each of these modes of testosterone delivery has significant drawbacks.

A feature common to the currently available delivery methods is the high variability in bioavailable testosterone as patients vary between super- and sub-therapeutic levels. This results in undesirable side effects and high rates of treatment discontinuation. These side effects include large fluctuations in mood and sexual function. In addition, treatment-specific side effects are noted, such as inadvertent contact transfer associated with testosterone gel formulations; women and children are particularly susceptible to the significant side effects of cross-contamination.

Thus, there is an unmet clinical need for improved formulations for testosterone replacement therapy (TRT). The limitations of the currently available testosterone formulations have stimulated tremendous interest in developing long-acting delivery systems that can provide uniform circulating levels of testosterone in the target therapeutic range.





nTc Nano/microparticle Formulation

To address the shortcomings of currently available testosterone formulations, the FPT team is in development of an (nTc) nano/microparticle formulation for sustained, consistent release. This novel next-generation formulation offers the promise of superior pharmacokinetics, uniform delivery of testosterone sustained for four weeks or greater, improved adherence, and treatment outcomes for patients seeking testosterone replacement therapy.

The nTc is a novel proprietary nanoparticle formulation that utilizes FDA-approved biocompatible polymeric materials such as poly (lactic-co-glycolic acid), poly (lactic acid), poly (glycolic acid), poly-l- (glutamic acid), and amphiphilic components. This aqueous formulation eliminates the oil depot-related adverse effects, and as shown in preliminary results, delivers testosterone uniformly without the burst release.




Personalization of Hormonal Treatments

We will be able to combine our research in both diagnostics as well as formulations to personalize the treatment of patients uniquely and precisely. Current clinical practice needs multiple office visits as well as lab visits to empirically titrate the correct dosage for a patient. This process needs to be repeated regularly as patient condition changes over time and is a major contributor towards poor adherence and compliance by patients and resulting in suboptimal clinical outcomes. We plan to develop personalized, finely calibrated dosimeters which will enable physicians to accurately determine the dosage for each individual.
 

readalot

Member
View attachment 27693
View attachment 27694


Endocrine Science

XYone is solving the problems present in the clinical treatment of hormonal disorders such as hypogonadism (Low testosterone condition), Hypothyroidism (Low Thyroxine condition) & other hormonal deficiencies. These typically. have therapeutic solutions that have poor delivery (pharmacokinetics) and almost no personalized or rational dosing. Through our research, we are creating the first-in-class, programmable release, aqueous, nano/microparticle formulation for testosterone and other hormones where we can program the delivery to create solutions which go from the current one size fit all, empirical treatments to personalized, rational dosing regimens.

Our first focus is Testosterone & we are proud to announce that our work is being supported by NIH/SBIR grants and we are partnering with the leading institutions in the world to bring our research to the clinic including Brigham & Women’s Hospital, Mayo Clinic, Center for Disease Control, and Karolinka Institute and others.





Accurate measurement of Androgens

Definitive diagnosis and rational management of androgen disorders currently face a number of challenges.




*Our patent-protected, novel TruT™ companion diagnostic framework provides accurate determination of free testosterone concentrations. This algorithm is based on experimental data demonstrating that testosterone’s binding to SHBG is a multi-step process involving an allosteric interaction between the two binding sites on the SHBG dimer. Estimates of free testosterone derived incorporating the allosteric coupling of SHBG monomers within the dimer provide accurate determination of free testosterone without systematic deviation from values obtained using equilibrium dialysis.

*Ongoing development is focused around continued study and validation in common conditions characterized by altered binding protein concentrations. Further, the incorporation of estradiol interactions will allow for wider adoption in women where estradiol levels vary greatly across the menstrual cycle. Because hyperandrogenism in women is the second most frequent indication for free testosterone determination, understanding the competitive binding and displacement dynamics is important for proper diagnosis in both healthy menstruating women and women with hyperandrogenic disorders, such as PCOS.


Through collaborations and partnerships, the TruT™ platform presents a unique opportunity to aggregate large volumes of data and metadata across diverse populations, ultimately enabling deeper understanding of the basis of androgen disorders and other conditions.

View attachment 27695





Formulation Development

Problems with current androgen/hormonal therapies


Hormonal deficiency supplementation therapies are characterized by absence of improved formulations with optimal PK profiles and patient-friendly dosing. Our first candidate is Testosterone replacement therapy (TRT).

Testosterone replacement therapy (TRT) is indicated for the treatment of androgen deficiency in hypogonadal men. The US Food and Drug Administration (FDA) has approved several testosterone formulations for the treatment of hypogonadism in men, including injectable testosterone esters, transdermal testosterone patches, transdermal testosterone gels and solution, buccal adhesive testosterone tablets, intranasal testosterone, and testosterone pellets & recently oral pills. However, each of these modes of testosterone delivery has significant drawbacks.

A feature common to the currently available delivery methods is the high variability in bioavailable testosterone as patients vary between super- and sub-therapeutic levels. This results in undesirable side effects and high rates of treatment discontinuation. These side effects include large fluctuations in mood and sexual function. In addition, treatment-specific side effects are noted, such as inadvertent contact transfer associated with testosterone gel formulations; women and children are particularly susceptible to the significant side effects of cross-contamination.

Thus, there is an unmet clinical need for improved formulations for testosterone replacement therapy (TRT). The limitations of the currently available testosterone formulations have stimulated tremendous interest in developing long-acting delivery systems that can provide uniform circulating levels of testosterone in the target therapeutic range.





nTc Nano/microparticle Formulation

To address the shortcomings of currently available testosterone formulations, the FPT team is in development of an (nTc) nano/microparticle formulation for sustained, consistent release. This novel next-generation formulation offers the promise of superior pharmacokinetics, uniform delivery of testosterone sustained for four weeks or greater, improved adherence, and treatment outcomes for patients seeking testosterone replacement therapy.

The nTc is a novel proprietary nanoparticle formulation that utilizes FDA-approved biocompatible polymeric materials such as poly (lactic-co-glycolic acid), poly (lactic acid), poly (glycolic acid), poly-l- (glutamic acid), and amphiphilic components. This aqueous formulation eliminates the oil depot-related adverse effects, and as shown in preliminary results, delivers testosterone uniformly without the burst release.




Personalization of Hormonal Treatments

We will be able to combine our research in both diagnostics as well as formulations to personalize the treatment of patients uniquely and precisely. Current clinical practice needs multiple office visits as well as lab visits to empirically titrate the correct dosage for a patient. This process needs to be repeated regularly as patient condition changes over time and is a major contributor towards poor adherence and compliance by patients and resulting in suboptimal clinical outcomes. We plan to develop personalized, finely calibrated dosimeters which will enable physicians to accurately determine the dosage for each individual.
Doc, where'd my GAINZ go???


Doc will have those instantaneous TT/fT levels popping up on her smart phone.
 

readalot

Member
FUN WITH TT/FT Blood Work Part I (dedicated to @madman for all his efforts posting on this site and to get my steak dinner LOL):

Ok, I know you all have been sitting on the edge of your seats. Head to Head Quest vs Labcorp.

24 hr post injection on TC:TP (4:1) at 60 mg twice weekly (120 mg/week total ester). 6 weeks with this protocol before blood work up from 100 mg/week

Quest (thanks to @Nelson Vergel 's Discounted Labs service):


1674488694307.png

1674488723014.png


Quest TT: 1100 ng/dl (MS)
Quest FT: 24.5 ng/dl (equilibrium dialysis)

calculated FT (Vermeulen):
1674488793028.png


calculated FT (TruT):
1674488874581.png


Using my simple heuristic of taking 10% off the Vermeulen calc FT number:

adj CFTV = 0.9 * 27.1 ng/dl = 24.4 ng/dl
Quest FT = 24.5 ng/dl

Coming up...detailed comparison using Labcorp with an extra twist.
 
Last edited:

readalot

Member
FUN WITH TT/FT Blood Work Part II (dedicated to @madman for all his efforts posting on this site and to get my steak dinner LOL):

Labcorp:

I have outdone myself here as I got blood drawn and had the technician order BOTH:


AND


This allows me to get two different labs to measure TT via LCMS (with claimed CDC HoST status) plus FT by equilibrium dialysis and the direct analog enzyme immunoassay (aka direct FT test).

BEHOLD:
1674489200574.png


1674489290709.png


First, let's use the Esoterix lab as the standard (arbitrary) even though both Labcorp's Esoterix Lab and Burlington Lab have HoST certification:

% difference = (1081-992.6)/1081 *100 = 8.2% difference between the two CDC HoST certified labs.

Esoterix sounds more impressive than Burlington so it has that going for it.

Second, Labcorp FT by equilibrium dialysis = 22.7 ng/dl. Remember Quest FT by ED on same sample was 24.5 ng/dl (see above). So regardless of the different reference ranges both assays have very similar FT result. Labcorp's Esoterix TT by MS and Quest TT by MS are also very close (1081 vs 1103 ng/dl).

Third, what does the Labcorp direct FT test tell us. Using the handy transfer function tool I detailed in another thread:

Adjusted FT (direct) = 27.6 pg/ml * 7 / 10 = 19.3 ng/dl

Quite a bit lower than either Labcorp or Quest's FT by ED but in the ball park.
% difference = (24.5-19.3)/24.5 = 21%

So to summarize, on the same blood sample roughly approximating peak blood levels 24 hours after injection for TC (of course off on the TP part):

  1. TT (Quest MS) = 1103 ng/dl
  2. TT (Labcorp Esoterix LCMS) = 1081 ng/dl
  3. TT (Labcorp Burlington (LCMS) = 993 ng/dl
  4. FT (Quest ED) = 24.5 ng/dl
  5. FT (Labcorp Esoterix ED) = 22.7 ng/dl
  6. FT (adj direct FT EIA) = 19.3 ng/dl
  7. cFTV (Vermeulen) ~ 27.1 ng/dl
  8. adjusted cFTV (90% of CFTV) ~ 24.4 ng/dl
  9. TruT ~ 38.9 ng/dl
A few of takeaways for me:
  • Both Labcorp and Quest agree pretty well on measured FT via ED even through reference ranges are quite different as we discussed before).
  • The adjusted direct FT still gets you in the ballpark although the low price of the FT by ED using @Nelson Vergel's Discounted Labs make it stupid easy to get FT by ED with very low cost.
  • Interlab variability with the two Labcorp HoST sites was ~8% for my blood sample.
  • TruT calculator as it currently exists on the website SUCKS unless Labcorp and Quest are both measuring FT wrong. Neither Quest nor Labcorp line up with the training set TruT claims matches their calculated values. If Labcorp and Quest are both full of sh*t then why are we telling guys to keep ordering these tests LOL?

RIP TruT (CFTZ) v1.0:



See this thread for more information than you probably want. Now you don't have to post the question about which free T calculator to use until Madman posts up the next Phase 2 validation results for TruT.

Now let's see how many likes these posts get. Come on I need the dopamine hits. Congratulations if you made it all the way through both posts.
 
Last edited:

readalot

Member
Prettied up summary table:

1674493712199.png



Test / Calc Name

result (ng/dl)

% difference vs arbitrary standard

TT (Quest MS)

1103​

2.0%​

TT (Labcorp Esoterix LCMS)

1081​

std

TT (Labcorp Burlington (LCMS)

993​

-8.1%​

FT (Quest ED)

24.5​

7.9%​

FT (Labcorp Esoterix ED)

22.7​

std

FT (adj direct FT EIA)

19.3​

-15.0%​

cFTV (Vermeulen)

27.1​

19.4%​

adjusted cFTV (90% of CFTV)

24.4​

7.5%​

TruT

38.9​

71.4%​

 

Cataceous

Super Moderator
...
  1. TruT ~ 38.9 ng/dl
...

For grins, take the Tru-T number of 38.9 ng/dL and do a linear mapping from its healthy normal range of 16-31 ng/dL to the cFTV range I use as healthy and normal, 10-20 ng/dL. I get 25.3 ng/dL, which when multiplied by the 0.9 correction factor yields 22.7 ng/dL, coincidentally a direct hit on the Labcorp FT. I think Tru-T is usable if you compare it to its own reference range and SHBG is not very high or low. Tru-T seems to perform worse than cfTV at more extreme SHBG, and of course the absolute numbers are out there.
 

sammmy

Well-Known Member
Basically the LabCorp and Quest FT by dialysis agree, and the cFTV and Labcorp Direct FT also agree but are a bit higher than the dialysis tests and need a depressing factor less than 1.0. All that for someone with a normal SHBG.

Trying to map the values based on "normal ranges" for each test is pontless - they use different samples that are not representative of the healthy population at all. In order to get such samples they have to sample the healthy population randomly and force the selected participants to do a test. Achieving that is not possible so the "representative" samples vary by the lab and so are the "normal ranges".
 
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