CDC's Clinical Standardization Programs: Free Testosterone soon to be!
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madman
Super Moderator
28:50-32:38
(29:20-30:05) We are working with different organizations on developing reference intervals that are based on certified assays. So we did already that successfully for testosterone.
We are currently working with some groups (research groups) on free testosterone reference intervals.
(29:20-30:05) We are working with different organizations on developing reference intervals that are based on certified assays. So we did already that successfully for testosterone.
We are currently working with some groups (research groups) on free testosterone reference intervals.
madman
Super Moderator
Measurement of FT in Serum Using ED Coupled With ID-UHPLC-MS/MS
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...
www.excelmale.com
*Measuring FT is technically challenging and shows high variability. The CDC clinical standardization program is developing a high throughput method using the gold-standard equilibrium dialysis (ED) procedure with isotope dilution ultra-high-performance liquid chromatography-tandem mass spectrometry (ID-UHPLC-MS/MS).
jacb
Active Member
Looks like great work madman ....
Any international and clinically accepted TRT reference ranges would be great help for those who are staring out on TRT and being faced with, no treatment whilst above some arbitrary and ridiculously low level. Your work looks like a great deal more than that .... So keep going
Any international and clinically accepted TRT reference ranges would be great help for those who are staring out on TRT and being faced with, no treatment whilst above some arbitrary and ridiculously low level. Your work looks like a great deal more than that .... So keep going
madman
Super Moderator
Microdosing Enanthate
Slightly being defined as past the upper quartile but not double the norm. A TT of 1,200 ng/dL would be considered to be slightly supraphyiological. I will take myself as an example of why treating how a patient feels is as important if not more than maintaining physiological testosterone...
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*Assays that are standardized are designed to provide accurate results, traceable to “true” value-assigned certified reference materials and gold-standard reference methods. Results obtained using standardized methods can be compared across assays, institutions, populations, and past and future test results, thereby improving diagnosis, treatment, and outcomes of patients
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...
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*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
T
tareload
Guest
Let's get that data and run the head to head comparison for models @madman.
Thanks @Nelson Vergel
This will be fun.
jacb
Active Member
Interesting ….. I see that the above report concludes with:
”Reference intervals for free FT levels (normative range 66-309 pg/mL [229-1072 pmol/L] in all men and 120-368 pg/mL [415-1274 pmol/L] in men, 19-to-39 years), measured using a standardized equilibrium dialysis method in healthy nonobese men, provide a rational basis for categorizing FT levels. These intervals require further validation in other populations, in relation to outcomes, and in randomized trials”.
It will be interesting in time to see how this compares with the results of the developing TruTTM algorithm.
For those that maybe catching up with this subject, the About TruT page gives good background as to the need for this algorithm.
Last edited:
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tareload
Guest
jacb
Active Member
Using the Mens hormonal health unit conversion calculator the FT levels shown above convert to:
Normative range 66-309 pg/mL [229-1072 pmol/L] = 7-31 ng/dl
19 to 39 Year age range, 120-368 pg/mL [415-1274 pmol/L] = 12-37 ng/dl
Normative range 66-309 pg/mL [229-1072 pmol/L] = 7-31 ng/dl
19 to 39 Year age range, 120-368 pg/mL [415-1274 pmol/L] = 12-37 ng/dl
madman
Super Moderator
Have already been sitting on the paper.
Unfortunately could not post up as I have not been able to upload images/pdfs.
Would not jump to any conclusions as it will still be a while before you can make any true comparisons.
ED assays need to be standardized.
CDC has been working on this let alone Bhasin and his team is heavily involved!
Let me know when the issues are fixed and I will drop the thread.
madman
Super Moderator
Reference Intervals for Free Testosterone in Adult Men Measured Using a Standardized Equilibrium Dialysis Procedure
Again you heard it here first only at Nelson's ExcelMale! @Nelson Vergel Was going to drop this bomb a few days ago but you let down the curtains early LOL! https://onlinelibrary.wiley.com/doi/abs/10.1111/andr.13310 Reference Intervals for Free Testosterone in Adult Men Measured Using a...
www.excelmale.com
*In healthy nonobese men, 19 years or older, the 2.5th, 10th, 25th, 50th, 75th, 90th and 97.5th percentile values for absolute free testosterone were 66, 91, 116, 141, 190, 240, and 309 pg/mL, respectively (Table 3). To convert standard units (pg/mL) to SI units (pmol/L), please divide the concentrations in pg/mL by 0.2885. In the subset of men, 19 to 39 years, the corresponding 2.5 th, 10th, 25th, 50th, 75th, 90th and 97.5th percentile values for absolute free testosterone were 120, 128, 149, 190, 228, 274, and 368 pg/mL. By convention, the 2.5th percentile of the reference sample defines the lower limit of the reference range and the 97.5th percentile value defines the upper limit (46,47). By this convention, the normal range in the reference sample of men 19 to 39 years is 120 to 368 pg/mL (415 to 1274 pmol/L) and, in all men, the range is 66 to 309 pg/mL [229 to 1072 pmol/L], respectively
*These reference ranges, generated in a reference sample of healthy men, should not be applied to other assays in other laboratories without appropriate cross-calibration of assays. Differences in study populations, time of sample collection, and testosterone assays can contribute to the differences in reference ranges. The adoption of a standardized procedure for measuring free testosterone and cross-calibration of the testosterone assays against an accuracy-based benchmark such as the CDC's HoST program will facilitate the application of these reference ranges across laboratories
madman
Super Moderator
Reference Intervals for Free Testosterone in Adult Men Measured Using a Standardized Equilibrium Dialysis Procedure
Again you heard it here first only at Nelson's ExcelMale! @Nelson Vergel Was going to drop this bomb a few days ago but you let down the curtains early LOL! https://onlinelibrary.wiley.com/doi/abs/10.1111/andr.13310 Reference Intervals for Free Testosterone in Adult Men Measured Using a...
www.excelmale.com
Critical take-home points:
*Using this standardized equilibrium dialysis method coupled with a HoST-certified LC-MS/MS assay for measuring testosterone in the dialysate, described in detail here to enable its easy replication across laboratories, we report for the first time the distribution of free testosterone levels in a prospectively collected sample of carefully screened healthy men, 19 years or older. The range of free testosterone levels (2.5th to 97.5th percentile values) in healthy nonobese men, 19 years or older, is 66 to 309 pg/mL (229 to 1072 pmol/L), and in a reference sample of nonobese healthy young men, 19 to 39 years, is 120 to 368 pg/mL (415 to 1274 pmol/L). The distribution of free testosterone levels by age group is also reported. These normative data can potentially be applied after appropriate cross-calibration to other laboratories that perform the equilibrium dialysis under similar standardized conditions and use a testosterone assay that is certified by an accuracy-based standardization program such as the Center for Disease Control and Prevention's HoST program. Further studies are needed to determine how these reference intervals apply to the diagnosis of androgen deficiency in clinical populations and in men of different races and ethnicities in different geographic regions
*These reference ranges, generated in a reference sample of healthy men, should not be applied to other assays in other laboratories without appropriate cross-calibration of assays. Differences in study populations, time of sample collection, and testosterone assays can contribute to the differences in reference ranges. The adoption of a standardized procedure for measuring free testosterone and cross-calibration of the testosterone assays against an accuracy-based benchmark such as the CDC's HoST program will facilitate the application of these reference ranges across laboratories
T
tareload
Guest
Agreed. Great progress and quite needed before we ever get back to the model / calculator debates.Reference Intervals for Free Testosterone in Adult Men Measured Using a Standardized Equilibrium Dialysis Procedure
Again you heard it here first only at Nelson's ExcelMale! @Nelson Vergel Was going to drop this bomb a few days ago but you let down the curtains early LOL! https://onlinelibrary.wiley.com/doi/abs/10.1111/andr.13310 Reference Intervals for Free Testosterone in Adult Men Measured Using a...
Critical take-home points:
*Using this standardized equilibrium dialysis method coupled with a HoST-certified LC-MS/MS assay for measuring testosterone in the dialysate, described in detail here to enable its easy replication across laboratories, we report for the first time the distribution of free testosterone levels in a prospectively collected sample of carefully screened healthy men, 19 years or older. The range of free testosterone levels (2.5th to 97.5th percentile values) in healthy nonobese men, 19 years or older, is 66 to 309 pg/mL (229 to 1072 pmol/L), and in a reference sample of nonobese healthy young men, 19 to 39 years, is 120 to 368 pg/mL (415 to 1274 pmol/L). The distribution of free testosterone levels by age group is also reported. These normative data can potentially be applied after appropriate cross-calibration to other laboratories that perform the equilibrium dialysis under similar standardized conditions and use a testosterone assay that is certified by an accuracy-based standardization program such as the Center for Disease Control and Prevention's HoST program. Further studies are needed to determine how these reference intervals apply to the diagnosis of androgen deficiency in clinical populations and in men of different races and ethnicities in different geographic regions
*These reference ranges, generated in a reference sample of healthy men, should not be applied to other assays in other laboratories without appropriate cross-calibration of assays. Differences in study populations, time of sample collection, and testosterone assays can contribute to the differences in reference ranges. The adoption of a standardized procedure for measuring free testosterone and cross-calibration of the testosterone assays against an accuracy-based benchmark such as the CDC's HoST program will facilitate the application of these reference ranges across laboratories
Thanks for sharing this information.
jacb
Active Member
Thanks Madman. I also had issues about uploading pictures etc, any idea what the problem is or when it will be fixed?
Thanks also for pointing out that the “Gold Standard” Equilibrium dialysis FT test assay is in fact not standardised. I thought the test assay was finite and the debate was all about the appropriate reference ranges? There was some reference to a “top down“ test that I didn’t understand?
Previously I think you stated that most guys seemed to do well with FT in the 20/30 ng/dl range. That would seem to be confirmed by the new numbers.
With all this talk about FT levels, I find myself asking, is the end goal with TRT users to ultimately (if the measurement system become routinely available & reliable) to supplement Testosterone and vary the amount (in the case of andropause) taken according to Free T levels?
madman
Super Moderator
I mentioned this numerous times in previous threads way back!
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