Improving Diagnostic Accuracy and Treatment Decisions in Men with Hypogonadism
- Thread starter madman
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madman
Super Moderator
24:05-26:45
@Nelson Vergel
The Partitioning of Circulating Sex Hormones Among the Plasma Binding Proteins
@Nelson Vergel
The Partitioning of Circulating Sex Hormones Among the Plasma Binding Proteins
madman
Super Moderator
27:04-29:32
@Nelson Vergel
* most hospital labs will offer you a crappy tracer analog method for Free Testosterone
* Direct Measurement/Calculated FT (cFT)
Methods for Assessing Free Testosterone Levels
@Nelson Vergel
* most hospital labs will offer you a crappy tracer analog method for Free Testosterone
* Direct Measurement/Calculated FT (cFT)
Methods for Assessing Free Testosterone Levels
madman
Super Moderator
29:33-31:33
@Nelson Vergel
*cFTV/cFTZ (EAM/TruT)
* most of the linear equations underestimate free testosterone concentrations
A Dynamic Multi-Step Ensemble with Allostery Model (EAM) of Testosterones's Binding to SHBG
@Nelson Vergel
*cFTV/cFTZ (EAM/TruT)
* most of the linear equations underestimate free testosterone concentrations
A Dynamic Multi-Step Ensemble with Allostery Model (EAM) of Testosterones's Binding to SHBG
madman
Super Moderator
31:34-37:00
@Nelson Vergel
* Its an incredibly beautiful design by nature
* so this allostery between the monomers is a very powerful mechanism to regulate bioavailability depending on the concentration of the ligand and the binding protein
www.excelmale.com
Estradiol Binding to SHBG Involves Inter-Monomeric Allostery and Partitioning of Monomers in Distinct Conformational and Energetic States
@Nelson Vergel
* Its an incredibly beautiful design by nature
* so this allostery between the monomers is a very powerful mechanism to regulate bioavailability depending on the concentration of the ligand and the binding protein
The Dynamics of Allosteric Binding of Estradiol to SHBG
Estradiol induces Allosteric Coupling and Partitioning of Sex Hormone Binding Globulin Monomers Among Conformational States Ravi Jasuja, Daniel Spencer, Abhilash Jayaraj, Liming Peng, Meenakshi Krishna, Brian Lawney, Priyank Patel, B. Jayaram, Kelly M. Thayer, David L. Beveridge, Shalender...
www.excelmale.com
Estradiol Binding to SHBG Involves Inter-Monomeric Allostery and Partitioning of Monomers in Distinct Conformational and Energetic States
madman
Super Moderator
Improving Diagnostic Accuracy and Treatment Decisions in Men with Hypogonadism (2022)
Shalender Bhasin, M.D., Professor of Medicine at Harvard Medical School and Director, Boston Claude D. Pepper Older Americans Independence Center; Director, Brigham Research Assay Core Laboratory; Director, Research Program in Men's Health: Aging and Metabolism; Co-Director, The Center for Transgender Health at Brigham and Women's Hospital, presented "Improving Diagnostic Accuracy and Treatment Decisions in Men with Hypogonadism" at Endocrinology Grand Rounds on March 2, 2022.
@Nelson Vergel
Questions/Comments
58:03-1:14:40
* So I want to thank you for spending your hour with me and for letting me share my thoughts that have been percolating in my head for 35 years
1:02:10-1:05:48
* Equilibrium Dialysis/Ensemble Allostery Model (EAM)
* using our ensemble allostery model we have turned that into an algorithm and it provides a much closer approximation of the Equilibrium Dialysis, especially in the physiologic range and extending slightly into the supra-physiologic range we haven't validated it when people have levels that are very supraphysiologic
* we completely discount estradiol levels, similarly, we discount DHT levels and the same thing as with Albumin, Albumin you know the literature says Albumin binds to testosterone with a micromolar affinity and it is oversimplified and completely incorrect and we had so much difficulty publishing that paper but what we've shown using mnr studies we have shown that there are 9 binding sites for testosterone and these binding sites also bind free fatty acids, a whole variety of things and there's also allosteric interaction so amongst the binding proteins most are multimeric but Albumin is the one that is a monomeric protein but it has 9 binding sites and there is allostery between those binding sites some of them have a quite high binding affinity of testosterone
www.excelmale.com
Shalender Bhasin, M.D., Professor of Medicine at Harvard Medical School and Director, Boston Claude D. Pepper Older Americans Independence Center; Director, Brigham Research Assay Core Laboratory; Director, Research Program in Men's Health: Aging and Metabolism; Co-Director, The Center for Transgender Health at Brigham and Women's Hospital, presented "Improving Diagnostic Accuracy and Treatment Decisions in Men with Hypogonadism" at Endocrinology Grand Rounds on March 2, 2022.
@Nelson Vergel
Questions/Comments
58:03-1:14:40
* So I want to thank you for spending your hour with me and for letting me share my thoughts that have been percolating in my head for 35 years
1:02:10-1:05:48
* Equilibrium Dialysis/Ensemble Allostery Model (EAM)
* using our ensemble allostery model we have turned that into an algorithm and it provides a much closer approximation of the Equilibrium Dialysis, especially in the physiologic range and extending slightly into the supra-physiologic range we haven't validated it when people have levels that are very supraphysiologic
* we completely discount estradiol levels, similarly, we discount DHT levels and the same thing as with Albumin, Albumin you know the literature says Albumin binds to testosterone with a micromolar affinity and it is oversimplified and completely incorrect and we had so much difficulty publishing that paper but what we've shown using mnr studies we have shown that there are 9 binding sites for testosterone and these binding sites also bind free fatty acids, a whole variety of things and there's also allosteric interaction so amongst the binding proteins most are multimeric but Albumin is the one that is a monomeric protein but it has 9 binding sites and there is allostery between those binding sites some of them have a quite high binding affinity of testosterone
Allosterically coupled multi-site binding of T to human serum albumin
Allosterically coupled multi-site binding of testosterone to human serum albumin Abhilash Jayaraj, Heidi A. Schwanz, Daniel J. Spencer, Shalender Bhasin, James A. Hamilton, B. Jayaram, Anna L. Goldman, Meenakshi Krishna, Maya Krishnan, Aashay Shah, Zhendong Jin, Eileen Krenzel, Sashi N. Nair...
www.excelmale.com
madman
Super Moderator
As I have stated numerous times on the forum!
Patiently waiting on the completion of Phase II for the TruT (cFTZ) Algorithm let alone standardization and harmonized reference ranges for Free testosterone which is in the works as we speak.
Phase II should be coming to an end soon enough.
8 years in 2014-2022.
Ravi let alone Bhasin are confident about the validity/soon-to-be commercialization of the TruT Algorithm.
It's going to happen.
He is already pushing the use of the newer calculated method!
Much going on behind the scenes and more to come.
One of Bhasin's current papers.
www.excelmale.com
*Free testosterone concentration is ideally measured using the equilibrium dialysis method, performed under standardized conditions.1,31 Direct tracer analog methods for measuring free testosterone concentrations are inaccurate, and therefore, their use is not recommended.35 Although several equations to estimate free testosterone concentration from total testosterone, SHBG, and albumin concentrations have been published,36-38 the estimation of free testosterone concentration performed using these equations are predicated upon accurate measurements of total testosterone, SHBG, and albumin concentrations.31,35 Furthermore, equations that are based on a linear model of testosterone’s binding to SHBG assume a fixed binding affinity (approximately 1 nM)31 and ignore the competing presence of other sex steroids, such as dihydrotestosterone and estradiol.
*Recent studies using modern biophysical techniques have suggested that the binding of testosterone and estradiol to an SHBG dimer is a dynamic process that involves allosteric interactions between binding sites on each of the 2 SHBG monomers such that the binding affinities of the 2 sites are not equivalent.36,39 The binding of a ligand to the first monomer influences the conformational and energetic states of both the monomers.39 The estimation of free testosterone concentration based on an ensemble allosteric model provides a close approximation of concentrations measured using equilibrium dialysis36;
*the computations of free testosterone concentrations using the ensemble allostery model can be obtained at TruT Free Testosterone Calculator by FPT. Because of dynamic changes in the binding affinity of SHBG upon ligand binding, depending on the ligand and SHBG concentrations, no equation can accurately estimate free testosterone concentration under all conditions.39
Phase II: Research and Commercialization of TruT Algorithm (Sep.15, 2014-May 31, 2022)
Patiently waiting on the completion of Phase II for the TruT (cFTZ) Algorithm let alone standardization and harmonized reference ranges for Free testosterone which is in the works as we speak.
Phase II should be coming to an end soon enough.
8 years in 2014-2022.
Ravi let alone Bhasin are confident about the validity/soon-to-be commercialization of the TruT Algorithm.
It's going to happen.
He is already pushing the use of the newer calculated method!
Much going on behind the scenes and more to come.
One of Bhasin's current papers.
Testosterone Deficiency in Men
Optimizing Diagnostic Accuracy and Treatment Decisions in Men With Testosterone Deficiency (2021) Shalender Bhasin, MB, BS *, Noelle Ozimek, MSc Abstract Objective: This narrative review offers a guideline-based approach for optimizing diagnostic evaluation and treatment decision-making in...
www.excelmale.com
*Free testosterone concentration is ideally measured using the equilibrium dialysis method, performed under standardized conditions.1,31 Direct tracer analog methods for measuring free testosterone concentrations are inaccurate, and therefore, their use is not recommended.35 Although several equations to estimate free testosterone concentration from total testosterone, SHBG, and albumin concentrations have been published,36-38 the estimation of free testosterone concentration performed using these equations are predicated upon accurate measurements of total testosterone, SHBG, and albumin concentrations.31,35 Furthermore, equations that are based on a linear model of testosterone’s binding to SHBG assume a fixed binding affinity (approximately 1 nM)31 and ignore the competing presence of other sex steroids, such as dihydrotestosterone and estradiol.
*Recent studies using modern biophysical techniques have suggested that the binding of testosterone and estradiol to an SHBG dimer is a dynamic process that involves allosteric interactions between binding sites on each of the 2 SHBG monomers such that the binding affinities of the 2 sites are not equivalent.36,39 The binding of a ligand to the first monomer influences the conformational and energetic states of both the monomers.39 The estimation of free testosterone concentration based on an ensemble allosteric model provides a close approximation of concentrations measured using equilibrium dialysis36;
*the computations of free testosterone concentrations using the ensemble allostery model can be obtained at TruT Free Testosterone Calculator by FPT. Because of dynamic changes in the binding affinity of SHBG upon ligand binding, depending on the ligand and SHBG concentrations, no equation can accurately estimate free testosterone concentration under all conditions.39
Phase II: Research and Commercialization of TruT Algorithm (Sep.15, 2014-May 31, 2022)
Jed Dorsey
Active Member
Why is it that as soon as I read the phrase ’let alone’ in a post I instantly know it’s MadMan LOL
madman
Super Moderator
CDC STANDARDIZED TOTAL T and ESTRADIOL ASSAYS and soon to be FREE TESTOSTERONE!
Measurement of Free Testosterone in Serum Using Equilibrium Dialysis Coupled With ID-UHPLC-MS/MS: Comparison Between Equilibrium Devices (2021) Hui Zhou, Ph.D., Ashley Ribera, BS, Amonae Dabbs-Brown, BS, Uliana Danilenko, Ph.D., Hubert W. Vesper, Ph.D. Centers for Disease Control and...
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madman
Super Moderator
TruT Free Testosterone Calculator by FPT
Free testosterone calculator by FPT. Improved accuracy of free T calculations.
tru-t.org
The new dynamic model leads to the reconsideration of several dogmas related to testosterone's binding to SHBG and has important physiologic and clinical implications.
*First, the fraction of circulating testosterone that is free is substantially greater (2.9±0.4%) than has been generally assumed (% cFTV 1.5±0.4%).
*Second, percent FT is not significantly related to total testosterone over a wide range of total testosterone concentrations. However, the percent FT declines as SHBG concentrations increase, although it does not decline as precipitously as predicted by Vermeulen's model. Due to the allostery between the two binding sites, SHBG is able to regulate FT levels in a much larger dynamic range.
Key points:
EAM (cFTZ) SHBG: T binding
*Intra-dimer complex allostery suggests that SHBG can regulate FT fraction over a wide range of total testosterone concentrations without getting saturated.
*Indeed, it was found that percent FT calculated using the new model changed very modestly over a wide range of total testosterone concentrations.
*Due to the allostery between the two binding sites, SHBG is able to regulate FT levels in a much larger dynamic range.
T
tareload
Guest
Best you can do at the moment is bracket your calculated fT using Vermeulen and Tru-T if you didn't use LC/MS+ED/UF to measure. For higher SHBG, that range is going to be pretty large.
And if you did use the "correct" fT test, is the result accurate? Stay tuned as @madman had told us.
www.excelmale.com
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forums.t-nation.com
From this post as summary of how the math works out in an "easy" to understand example:
In summary, a poor guy with high SHBG:
Total T = 1077 ng/dL
SHBG = 151 nmol/L
EDIT: as I posted below, if you take the RIA result and multiply by 6.7:
0.72 ng/dL * 6.7 = 4.8 ng/dL which is very close to the range of 5-6 ng/dL I estimated would be shown via equilbrium dialysis. So if you want to convert your free T (via direct RIA) number to what it would be if your physician actually had ordered an appropriate test, then multiply by 7 not 10.
And if you did use the "correct" fT test, is the result accurate? Stay tuned as @madman had told us.
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
Harmonized reference ranges for Total and Free T levels
Accurate Measurement and Harmonized Reference Ranges for Total and Free Testosterone Levels (2022) Ravi Jasuja, Ph.D., Karol M. Pencina, Ph.D., Liming Peng, MSc, Shalender Bhasin, MB, BS* INTRODUCTION A central tenet of endocrinology is that the hormones secreted by the endocrine glands...
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Response from LabCorp About Their Incorrect Unit Usages For Their Free Testosterone - Direct - Test
I've been irked for a year by the apparent incorrect unit usage for the particular Free Testosterone test mentioned above. I periodically reach out to whatever relevant executive I can find. No luck for months until the below correspondence. In brief his explanation doesn't hold up in my view...
www.excelmale.com
Realistic TRT Recomp Progress
It’s great to see people posting actual scientific data and not just the “we say take lots of T and lots of thyroid and you’ll be good as new, prove me wrong… oh, you can’t? See, I’m right” that we hear here a lot. So thanks for that @readalot
forums.t-nation.com
From this post as summary of how the math works out in an "easy" to understand example:
In summary, a poor guy with high SHBG:
Total T = 1077 ng/dL
SHBG = 151 nmol/L
- “Direct” RIA free T comes back = 0.72 ng/dL (0.067% of total T)
- Calculated free T by Vermuelen = 7.57 ng/dL (0.7% of free T)
- Calculated free T by Tru-T = 25.3 ng/dL (2.35% of free T)
- Actual free T as measured by equilibrium dialysis probably 5-6 ng/dL (0.46-56% of free T)
EDIT: as I posted below, if you take the RIA result and multiply by 6.7:
0.72 ng/dL * 6.7 = 4.8 ng/dL which is very close to the range of 5-6 ng/dL I estimated would be shown via equilbrium dialysis. So if you want to convert your free T (via direct RIA) number to what it would be if your physician actually had ordered an appropriate test, then multiply by 7 not 10.
Last edited by a moderator:
madman
Super Moderator
What to Measure: Testosterone or Free Testosterone?
What to Measure: Testosterone or Free Testosterone? (2021) Christina Wang and Ronald Swerdloff 1.1 Why Serum Testosterone Is Necessary for the Diagnosis of Testosterone Deficiency? Low serum testosterone (T) levels in adult men can lead to significant clinical symptoms and signs of...
www.excelmale.com
*The binding of T to SHBG is complex, which results in many different methods that directly measure or calculate free T. Some of these methods do not measure the free fraction of T and some formulae may provide less accurate results [40]
*Recent evidence suggests that the law of mass action formula which is based on the assumption that two T molecules bind to two binding sites on the SHBG with similar binding affinity may be incorrect. And further argues that the binding of T to SHBG may be a multistep, dynamic process with complex allosteric characteristics [65]. Based on this new model, investigators used a new formula to calculate free T in younger men in the Framingham Heart Study and showed that the newly calculated values were similar to those measured by equilibrium dialysis. They further verified that the calculated free T values had clinical diagnostic validity using data from the European Male Aging Study
*Currently, the CDC is developing a harmonized method for free T based on calculated free T using revised formulae. This may bring the measurement of free T to a referable standard in clinical laboratories and common reference intervals that all clinicians can use
*Perhaps the newer formula for calculated free T validated in multiple laboratories [65], will become generally available, correlate with free T by equilibrium dialysis and demonstrate improved correlation with clinical symptoms and therapeutic responsiveness. If all these prove to be true, then this formula to calculate free T may be a justified replacement for free T measurement by the equilibrium dialysis methodology
Phase II: Research and Commercialization of TruT Algorithm for Free Testosterone
Jasuja, Ravi
https://grantome.com/grant/NIH/R44-AG045011-02
The measurement of testosterone (T) levels is central to the diagnosis of androgen disorders, such as hypogonadism in men and polycystic ovary syndrome (PCOS) in women. Circulating T is bound with high affinity to sex hormone-binding globulin (SHBG) and with substantially lower affinity to albumin; only the free fraction is biologically active. Conditions that affect SHBG concentrations, such as aging and obesity, alter total but not free T concentrations; in these conditions, the determination of free T is necessary to obtain an accurate assessment of androgen status. The tracer analog method, the most widely used method for free T, has been shown to be inaccurate. The equilibrium dialysis method, considered the reference method, is technically difficult to implement and standardize, and is not available in most hospital laboratories, leading the Endocrine Society's Expert Panel to conclude that ?? the calculation of free testosterone is the most useful estimate of free testosterone in plasma?? Therefore, there is an unmet need for algorithms that provide accurate estimates of free T that match those derived from equilibrium dialysis. We have designed a novel and accurate TruTTM algorithm for the determination of free T, based on the characterization of testosterone's binding to SHBG using modern biophysical techniques. We have discovered that testosterone's binding to SHBG is a dynamic multistep process that includes allosteric interaction between the two binding sites on an SHBG dimer. Our computational framework incorporates the correct binding parameters derived experimentally in these studies, the non-linear dynamics in T: SHBG association, and allostery
In phase I studies, we demonstrated that the TruTTM algorithm provides accurate free T values that match those obtained using the equilibrium dialysis in healthy and hypogonadal men. We have also shown that the binding parameters that have formed the basis of previous equations (e.g., Vermeulen) are incorrect, and that free T values derived using these equations deviate substantially from free T measured by equilibrium dialysis. The phase I studies have led to the adoption of the TruTTM algorithm at several institutions.
The phase II program will continue the development of the TruTTM algorithm by validating it in common conditions characterized by altered SHBG concentrations, such as obesity and aging (AIM 1), in healthy women across the menstrual cycle, and in women with PCOS (Aim 2). We will generate population-based reference ranges for free T (Aim 3). Phase II also includes plans for the commercialization of the TruTTM algorithm using a HIPAA-compliant infrastructure for its clinical adoption
The phase II program will provide validation of the TruTTM algorithm in the two most common clinical indications for free T measurement? men suspected of hypogonadism and altered SHBG levels, and women with hyperandrogenic disorders. It will also enable the development of a HIPAA-compliant platform that can be embedded into the electronic medical record for wider clinical adoption and for improving clinical care
madman
Super Moderator
METHODS AND SYSTEMS FOR THE DIAGNOSIS AND TREATMENT OF SEX HORMONE DISORDERS
patents.justia.com
patents.justia.com
www.excelmale.com
Ravi Jasuja Inventions, Patents and Patent Applications - Justia Patents Search
USPTO patent applications submitted by and patents granted to Ravi Jasuja
patents.justia.com
US Patent Application for METHODS AND SYSTEMS FOR THE DIAGNOSIS AND TREATMENT OF SEX HORMONE DISORDERS Patent Application (Application #20220206018 issued June 30, 2022) - Justia Patents Search
The technology described herein is directed to the diagnosis and treatment of sex hormone disorders and/or deficiencies, such as estrogen and/or testosterone disorders and/or deficiencies.
patents.justia.com
TruT Free Testosterone Calculator by FPT
Free testosterone calculator by FPT. Improved accuracy of free T calculations.
tru-t.org
Tru T calculator - what is the range?
Labcorp 'normal' range for Free T is 6.8 - 21.5. Obviously, the Tru T calculator produces much different results. For example, on a recent test, my Labcorp Free T was 27.7. The Tru T measure yielded 46. This begs the question, what is the ideal range using the Tru T method. I saw in some...
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