Tru T calculator - what is the range?

jmzwy · Jul 18, 2019

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 previous threads that a 16-31 range was mentioned, but could not locate anywhere on the Tru T site that this was in fact the case. Thanks, james

Vince Carter · Jul 18, 2019

Tru T won't have a range...a lab range is not what some one/Dr/Scientist determined to be good, a lab range is merely a sample of the population that that lab tests. Hence you have different ranges from Quest, LabCorp, and so on. Tru T is just a calculator.

madman · Jul 18, 2019

jmzwy said:
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 previous threads that a 16-31 range was mentioned, but could not locate anywhere on the Tru T site that this was in fact the case. Thanks, james

"Based on the new data on the distribution of free testosterone levels in healthy men the target range of free testosterone has been determined to be 164 to 314 pg/ml (mean+/−1SD)"

.....which would convert to 16-31 ng/dl

*highlighted in blue- refer to the new Multi-step Dynamic Binding Model with Complex Allostery (TruT calculated)

In one aspect, described herein is a computer implemented method for determining a need for adjustment of a dose of testosterone administered to an individual with hypogonadism, androgen deficiency syndrome, or any other condition for which testosterone therapy is indicated, comprising: on a device having one or more processors and a memory storing one or more programs for execution by the one or more processors, the one or more programs including instructions for: a) receiving data from determining the concentration of free testosterone in an individual receiving testosterone therapy at a first dose, wherein the concentration of free testosterone is determined by measuring i) a total SHBG concentration, ii) a total testosterone concentration, and iii) a total albumin concentration in a biological sample obtained from an individual, to determine free testosterone concentration from the individual; b) attributing at least two distinct interconverting microstates of an unliganded SHBG dimer having a first monomer and a second monomer by applying the New Multi-Step Dynamic Binding Model with Complex Allostery to the data of step a); c) calculating the free testosterone concentration in the individual using the New Multi-step Dynamic Binding Model with Complex Allostery encompassing readjustment of a first equilibria between the microstates upon binding of a first testosterone molecule to the first monomer and an allosteric interaction between two binding sites of the SHBG dimer and; d) sending a signal for providing a second (adjusted) dose of testosterone that is higher than the first dose when the free testosterone concentration is below the lower end of the target therapeutic range (e.g. 164 pg/ml); and e) sending a signal for providing a second (adjusted) dose of testosterone that is lower than the first dose when the free testosterone concentration is above the upper end of the target therapeutic range (e.g. 314 pg/ml). In some embodiments, the system can further comprise the step of receiving data of the first dose of testosterone administered to the individual.

Formulas described herein relate to a model of testosterone and SHBG binding in which two distinct interconverting microstates of an unliganded SHBG dimer having a first monomer and a second monomer. SHBG exists as one of two dimerized forms or microstates (see, e.g., FIG. 3), each of which can bind to a first testosterone molecule with a different affinity. These two microstates of SHBG can interconvert. The new Multi-step Dynamic Binding Model with Complex Allostery described herein is a model of the interaction between testosterone and SHBG which accounts for both a first equilibria between the microstates upon binding of a first testosterone molecule to the first monomer and an allosteric interaction between two binding sites of the SHBG dimer.

Using the methods, assays, and systems described herein, the optimal range of free testosterone concentrations that should be targeted in hypogonadal men receiving testosterone replacement therapy have also been determined. The treatment of hypogonadism with testosterone is currently suboptimal. The analyses of clinical trials data described herein demonstrate that a large fraction of hypogonadal men treated with testosterone therapy have testosterone levels in the subtherapeutic range.

The current Endocrine Society guidelines suggest the use of total testosterone levels to guide therapy, which as discussed above, do not provide an accurate assessment of the androgen status. The free testosterone concentrations, determined the new method described herein, can provide accurate assessment of the adequacy of testosterone therapy in hypogonadal men. Based on the new data on the distribution of free testosterone levels in healthy men the target range of free testosterone has been determined to be 164 to 314 pg/ml (mean+/−1SD). If the on-treatment free testosterone concentrations determined using the methods described herein are outside this range, the dose of testosterone should be adjusted using the methods described herein to achieve testosterone levels in the target therapeutic range to maximize benefits and reduce the risks. Furthermore, the initial dose of testosterone therapy can be determined using the methods, assays, and/or systems described herein, e.g. the dosimeter methods described herein.

jmzwy · Jul 18, 2019

Thanks. So one follow-up question: are using Labcorp ranges not only futile but potentially dangerous? I'm a 27 on labcorp but 46 on Tru T. No wonder I was getting side effects (hematocrit, acne, and high estrogen) before reducing my dose. Has Defy Medical commented on this? Of course labs are just labs and subjective symptoms/how-you-feel are equally if not more important. Just seems like a drastic difference for Defy to be using Labcorp as a guideline.

madman · Jul 18, 2019

jmzwy said:
Thanks. So one follow-up question: are using Labcorp ranges not only futile but potentially dangerous? I'm a 27 on labcorp but 46 on Tru T. No wonder I was getting side effects (hematocrit, acne, and high estrogen) before reducing my dose. Has Defy Medical commented on this? Of course labs are just labs and subjective symptoms/how-you-feel are equally if not more important. Just seems like a drastic difference for Defy to be using Labcorp as a guideline.

Dangerous.....highly doubtful as even if ones FT is above the reference range.....very rare one would have extremely high supra-physiological FT levels using trt doses 100-200 mg/week.....and even than highly doubtful steroid doses of T as in 300-600 mg/week would cause any serious issues in the short term.

Most men will do well having FT at trough in the 30 ng/dl range (top end) and some may need/choose to run higher levels in the 30-50 ng/dL range (in some cases well over the top end).....but even than it would not be dangerous.....if anything many would not need a FT trough of 50---->50+ng/dl to benefit from testosterone replacement therapy.

If one truly feels better running higher FT levels and blood markers are healthy than do what is best for you!

The direct immunoassay is inaccurate and has been shown to underestimate FT levels when compared to the gold standard testing method Equilibrium Dialysis.

If you truly want to know where your FT levels sit you would need to use the most accurate testing methods such as the gold standard Equilibrium Dialysis or Ultrafiltration (next best) or simply use the newer calculated TruT method as the model is based on the newer understanding of SHBG:T binding.

Results using the newer Tru T calculated method have been shown to be on par with results obtained by the gold standard Equilibrium Dialysis.

jmzwy · Jul 18, 2019

Thank you madman. That helps.

fifty · Jul 18, 2019

I say this regularly. I don't know why people are hell bent on getting LCMS Estradiol but continue to get ECLIA Total Testosterone and RIA Direct Free T. Why? To save $50 yet chase your tail for years on end?

My levels were 1500+ and my doc upped my weekly dose...all because Direct Free T is highly dubious.

madman · Jul 18, 2019

fifty said:
I say this regularly. I don't know why people are hell bent on getting LCMS Estradiol but continue to get ECLIA Total Testosterone and RIA Direct Free T. Why? To save $50 yet chase your tail for years on end?

My levels were 1500+ and my doc upped my weekly dose...all because Direct Free T is highly dubious.

LOL.....I think many are in denial that their FT levels are really much higher than they think.....they work hard at that.....consistently using piss poor testing assays to only convince/reassure themselves that their FT levels are not that high!

Vince Carter · Jul 19, 2019

fifty said:
I say this regularly. I don't know why people are hell bent on getting LCMS Estradiol but continue to get ECLIA Total Testosterone and RIA Direct Free T. Why? To save $50 yet chase your tail for years on end?

My levels were 1500+ and my doc upped my weekly dose...all because Direct Free T is highly dubious.

Most everyone is at the mercy of what the lab tech enters or the nurse of Dr enters...those screens have multiple tests that come up when they type in "Testosterone". Unless you're buying specific tests off of discounted labs which takes out all of the discretionary inputs by the lab tech, you have some point of being at the mercy of whomever enters it in to the system.
I know for a fact when I go in to Quest with "testosterone, total", I can later read the order that was input by the tech and I can see the ECLIA method was entered. I question them about it being wrong and the reply has always been "I enter what I can and I don't interpret what isn't specifically written or the Dr's intent". So guys can be in a corner in a lot of instances to what testing they receive vs the intended tests.

xqfq · Nov 15, 2019

madman said:
"Based on the new data on the distribution of free testosterone levels in healthy men the target range of free testosterone has been determined to be 164 to 314 pg/ml (mean+/−1SD)"

.....which would convert to 16-31 ng/dl

What’s the source for this quote (study, paper etc). I can’t find it anywhere.

arseniol · Jul 19, 2022

madman said:
*highlighted in blue- refer to the new Multi-step Dynamic Binding Model with Complex Allostery (TruT calculated)

Are the "Multi-step Dynamic Binding Model with Complex Allostery" (also named FTz) and Tru-T really the same, or does Tru-T come with some new fixes?

arseniol · Jul 19, 2022

xqfq said:
What’s the source for this quote (study, paper etc). I can’t find it anywhere.

late answer, these numbers are actually available in the patent WO2014138026A1 - Methods and systems for the diagnosis and treatment of androgen disorders - Google Patents

Jerajera · Jul 19, 2022

madman said:
Most men will do well having FT at trough in the 30 ng/dl range (top end) and some may need/choose to run higher levels in the 30-50 ng/dL range (in some cases well over the top end).....but even than it would not be dangerous.....if anything many would not need a FT trough of 50---->50+ng/dl to benefit from testosterone replacement therapy

Do you still feel this way? I've seen mostly your recent posts and it seems you typically advocate against running high levels, so I'm kind of surprised at the above

madman · Jul 20, 2022

arseniol said:
Are the "Multi-step Dynamic Binding Model with Complex Allostery" (also named FTz) and Tru-T really the same, or does Tru-T come with some new fixes?

Yes.

Three heavyweights in the field behind the invention of TruT™

Ravi Jasuja, Shalender Bhasin, and Mikhail N Zakharov.

Shalender Bhasin

*using our ensemble allostery model we have turned that into an algorithm (cFTZ)

TruT™algorithm (cFTZ): device (calculator/data processing module) which computes FT using the algorithm.

*Our patent-protected, novel TruT™ companion diagnostic framework provides an accurate determination of free testosterone concentrations

U.S. 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

[0006] In one aspect, described herein is a computer-implemented method for an assay, comprising: on a device having one or more processors and a memory storing one or more programs for execution by the one or more processors, the one or more programs including instructions for:

a) receiving data from measuring i) a total SHBG concentration, ii) a total testosterone concentration, and iii) a total albumin concentration in a biological sample obtained from an individual, to determine free testosterone concentration from the individual; b) attributing at least two distinct interconverting microstates of an unliganded SHBG dimer having a first monomer and a second monomer, and c) calculating the free testosterone concentration in the individual using the New Multi-Step Dynamic Binding Model with Complex Allostery encompassing readjustment of a first equilibria between the microstates upon binding of a first testosterone molecule to the first monomer and an allosteric interaction between two binding sites of the SHBG dimer.

[0018] In one aspect, described herein is a method for determining a need for adjustment of a dose of testosterone administered to an individual comprising a) determining the concentration of free testosterone in an individual receiving testosterone therapy at a first dose, wherein the concentration of free testosterone is determined by b) measuring i) a total SHBG concentration, ii) a total testosterone concentration, and iii) a total albumin concentration in a biological sample obtained from an individual, to determine free testosterone concentration from the individual; c) attributing at least two distinct interconverting microstates of an unliganded SHBG dimer having a first monomer and a second monomer by applying the New Multi-Step Dynamic Binding Model with Complex Allostery to the data of steps a) and b); d) calculating the free testosterone concentration in the individual using the New Multi-step Dynamic Binding Model with Complex Allostery encompassing readjustment of a first equilibria between the microstates upon binding of a first testosterone molecule to the first monomer and an allosteric interaction between two binding sites of the SHBG dimer; e) providing a second dose of testosterone that is higher than the first dose when the free testosterone concentration is below the lower end of the target therapeutic range (e.g.164 pg/ml); and f) providing a second dose of testosterone that is lower than the first dose when the free testosterone concentration is above the upper end of the target therapeutic range (314 pg/ml).

[0019] In some embodiments of any of the foregoing aspects, the step of attributing can be performed according to Figures 2, 3, 5, and 7. In some embodiments, of any of the foregoing aspects, the step of calculating can be performed according to Figure 7 or Example 5. In some embodiments of any of the foregoing aspects, the individual is a male over the age of 35. In some embodiments of any of the foregoing aspects, the androgen disorder is selected from the group consisting of a testosterone deficiency, an androgen deficiency, a hyperandrogenic disorder, an androgen expressing tumor, and a hypogonadism disorder. In some embodiments of any of the foregoing aspects, the androgen disorder is a hyperandrogenic disorder selected from the group consisting of an acne disorder, a hirsutism disorder, and an androgenic alopecia disorder. In some embodiments of any of the foregoing aspects, the individual has been diagnosed with a disease selected from the group consisting of diabetes, human immunodeficiency virus (HIV), hepatitis B, hepatitis C, hypothyroidism or hyperthyroidism, androgen insensitivity, acromegaly, anorexia, muscular dystrophy, liver disease, cancer cachexia, malnutrition, nephrotic syndrome, and obesity, and other conditions in which SHBG or albumin concentrations are altered. In some embodiments of any of the foregoing aspects, the assay, method, system, or medium can further comprise the step of classifying the individual into categories based on additional clinical symptoms. In some embodiments of any of the foregoing aspects, the assay, method, system, or medium can further comprise the step of using the free testosterone concentration determined using the new Multistep Dynamic Binding Model with Complex Allostery to determine the dose or to individually adjust the dose of a formulation of testosterone for the treatment of a medical disease, taking into account patient's age, body weight and body mass index, medical conditions, including any co-morbid conditions, albumin and SHBG, and/or LH and FSH concentrations, and other patient-specific factors. In some embodiments of any of the foregoing aspects, instead of steps a-c, the data received is a previously calculated concentration of free testosterone.

[0029] Fig. 10 depicts a schematic of the control of testosterone levels.

[0030] Fig. 11 depicts a schematic of an exemplary system of determining free testosterone levels and/or dosages.

[0031] Fig. 12 depicts a device or a computer system 1000 comprising one or more processors 1300 and a memory 1500 storing one or more programs 1600 for execution by the one or more processors 1300.

EXAMPLE 5

[00217] Binding proteins (e.g. SHBG, albumin, orosomucoid, and transcortin) and testosterone (T) dynamically interact in multiple steps to regulate testosterone availability.

[00218] Circulating testosterone is bound mostly to plasma proteins, sex-hormone binding globulin (SHBG), and albumin. There are several states in which the testosterone and binding proteins are distributed. They continually re-partition into a series of states that are in conformational equilibria. The populations of the intermediate states redistribute as the concentrations of testosterone and binding proteins change. In one of its embodiments (as an example), SHBG exists in two distinct states in the solution governed by a unimolecular equilibrium constant. Both states are capable of binding T and upon binding T, they proceed to the corresponding states with one monomer bound to T and the other monomer is unoccupied within the dimer. The binding of first T induces allosteric changes in monomer that is still unoccupied and therefore results in a distinct change in affinity for the second molecule of T for the SHBG dimer. Consistent with the crystal structure of liganded SHBG, Binding of the second molecule to either of the intermediates results in the identical state of fully occupied SHBG dimer.

[00219] In one embodiment, free testosterone is calculated as described below.

[00220] The relative population of the intermediates is closely coupled through the multiple equilibria and dynamically readjust. Accordingly, testosterone's binding to SHBG cannot be described as a simple linear equation of ligand binding equilibrium. Described herein is a multi-species allostery model, e.g., in Lab VIEW framework, that fits the experimental data and permits the development of a set of parameters that accurately described the multiple interactions listed below:

yeg7Byn0b5Aio_5AZLYnQWcvbobDbLslSiUdKTulKahGJo8EZ1JvmwoZ7ZaG-2MH_RupgX56pB3X7zf6cD-BoeglgpuuFkxItiH6Z2wkcvYuEC4WkApK9VhVgVo_wvkj6boEacKAKTJMM0C-53LeM3chA7grkv_2Y8dsjY5cOwg

[00221] Using a set of equilibrium constants derived from the fits to the biophysical data provided in Figs. 5A, 5B, and 5C, an exemplary solution of the series of equations is presented below to calculate free T. The solution below doesn't imply presence of a unique equation rather that distinct equations can be developed to achieve accurate calculation of free T with a model of interaction that involves (and is not limited to) inter-subunit allostery in SHBG, regulation of free T levels by albumin and conformational states of binding proteins (albumin and SHBG).

[00222] Tf*(4311602270490*T_0-792951348000*S_0+95385510*Alb0-5341588560000)+Tf^2*(916102610798*T_0-210702480309*S_0+153989202*Alb0- 8623204540980)+Tf^3*(18366076550*T_0-22591273900*S_0+32723450*Alb0-1832205221596)+Tf^4*(1539342900*T_0-3079192900*S_0+657100*Alb0-36732153100)+2670794280000 *T_0+Tf^5*( 55000*T_0+110000*S_0+55000*Alb0-3078685800)+110000*Tf^6=0

madman · Jul 20, 2022

What is Optimal Estradiol Range for Libido/Erection

Simply put, if you require a t or E number outside of the range (especially way outside) that you had when you were feeling your best there are likely other things off with your metabolism that are not being examined. Hormones work in synergy with one another. this im sure if your needing trt...

www.excelmale.com

To any of the idiots on this forum or any of those other BUMASS forums shooting off at the mouth about the so-called stupid calculator being FDA registered.

For the last F**KING time the FDA has absolutely nothing to do with the TruT™algorithm (cFTZ) other than registering the device (calculator/data processing module, for clinical use).

madman · Jul 20, 2022

It's coming.

Time to put a nail in the coffin on this FT S**TSHOW!

*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)

*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

*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

* Limitations of using free testosterone by equilibrium dialysis and calculated free testosterone concentrations in practice are the lack of assay standardization, an accuracy-based quality control program, and a harmonized reference range. Until these limitations are addressed, free testosterone by equilibrium dialysis and calculated free testosterone should use reference ranges established by individual laboratories or their specific assay method

THE IMPORTANCE OF ACCURATE HORMONE TESTS

https://www.hormoneassays.org/ Watch our video to learn about the importance of accurate hormone testing. Tests to measure the level of a specific hormone in the body are the third most common diagnostic in medicine today yet some current hormone tests are not sufficiently accurate or...

www.excelmale.com

*but let me show you some additional data which persuade me that no equation can ever be an accurate measure of the free testosterone at all levels of SHBG, testosterone, estradiol, DHT, and albumin under all conditions in men and women

tareload · Jul 20, 2022

madman said:
To any of the idiots on this forum or any of those other BUMASS forums shooting off at the mouth

Guilty ;-) [raises hand]

We need to come clean with the fact we can't build an accurate model until we have accurate data (and agree on what we are trying to measure and agree on what the reference conditions are for the property we are trying to measure).

Once we have the standardized and harmonized reference data let's see those parity plots for cfTV and cfTZ. Will be fun!

Thanks for all your contributions and posts on this and so much more.

tareload · Jul 20, 2022

madman said:
Yes.

Three heavyweights in the field behind the invention of TruT™

Ravi Jasuja, Shalender Bhasin, and Mikhail N Zakharov.

Shalender Bhasin

*using our ensemble allostery model we have turned that into an algorithm (cFTZ)

TruT™algorithm (cFTZ): device (calculator/data processing module) which computes FT using the algorithm.

*Our patent-protected, novel TruT™ companion diagnostic framework provides an accurate determination of free testosterone concentrations

U.S. 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

[0006] In one aspect, described herein is a computer-implemented method for an assay, comprising: on a device having one or more processors and a memory storing one or more programs for execution by the one or more processors, the one or more programs including instructions for:

a) receiving data from measuring i) a total SHBG concentration, ii) a total testosterone concentration, and iii) a total albumin concentration in a biological sample obtained from an individual, to determine free testosterone concentration from the individual; b) attributing at least two distinct interconverting microstates of an unliganded SHBG dimer having a first monomer and a second monomer, and c) calculating the free testosterone concentration in the individual using the New Multi-Step Dynamic Binding Model with Complex Allostery encompassing readjustment of a first equilibria between the microstates upon binding of a first testosterone molecule to the first monomer and an allosteric interaction between two binding sites of the SHBG dimer.

[0018] In one aspect, described herein is a method for determining a need for adjustment of a dose of testosterone administered to an individual comprising a) determining the concentration of free testosterone in an individual receiving testosterone therapy at a first dose, wherein the concentration of free testosterone is determined by b) measuring i) a total SHBG concentration, ii) a total testosterone concentration, and iii) a total albumin concentration in a biological sample obtained from an individual, to determine free testosterone concentration from the individual; c) attributing at least two distinct interconverting microstates of an unliganded SHBG dimer having a first monomer and a second monomer by applying the New Multi-Step Dynamic Binding Model with Complex Allostery to the data of steps a) and b); d) calculating the free testosterone concentration in the individual using the New Multi-step Dynamic Binding Model with Complex Allostery encompassing readjustment of a first equilibria between the microstates upon binding of a first testosterone molecule to the first monomer and an allosteric interaction between two binding sites of the SHBG dimer; e) providing a second dose of testosterone that is higher than the first dose when the free testosterone concentration is below the lower end of the target therapeutic range (e.g.164 pg/ml); and f) providing a second dose of testosterone that is lower than the first dose when the free testosterone concentration is above the upper end of the target therapeutic range (314 pg/ml).

[0019] In some embodiments of any of the foregoing aspects, the step of attributing can be performed according to Figures 2, 3, 5, and 7. In some embodiments, of any of the foregoing aspects, the step of calculating can be performed according to Figure 7 or Example 5. In some embodiments of any of the foregoing aspects, the individual is a male over the age of 35. In some embodiments of any of the foregoing aspects, the androgen disorder is selected from the group consisting of a testosterone deficiency, an androgen deficiency, a hyperandrogenic disorder, an androgen expressing tumor, and a hypogonadism disorder. In some embodiments of any of the foregoing aspects, the androgen disorder is a hyperandrogenic disorder selected from the group consisting of an acne disorder, a hirsutism disorder, and an androgenic alopecia disorder. In some embodiments of any of the foregoing aspects, the individual has been diagnosed with a disease selected from the group consisting of diabetes, human immunodeficiency virus (HIV), hepatitis B, hepatitis C, hypothyroidism or hyperthyroidism, androgen insensitivity, acromegaly, anorexia, muscular dystrophy, liver disease, cancer cachexia, malnutrition, nephrotic syndrome, and obesity, and other conditions in which SHBG or albumin concentrations are altered. In some embodiments of any of the foregoing aspects, the assay, method, system, or medium can further comprise the step of classifying the individual into categories based on additional clinical symptoms. In some embodiments of any of the foregoing aspects, the assay, method, system, or medium can further comprise the step of using the free testosterone concentration determined using the new Multistep Dynamic Binding Model with Complex Allostery to determine the dose or to individually adjust the dose of a formulation of testosterone for the treatment of a medical disease, taking into account patient's age, body weight and body mass index, medical conditions, including any co-morbid conditions, albumin and SHBG, and/or LH and FSH concentrations, and other patient-specific factors. In some embodiments of any of the foregoing aspects, instead of steps a-c, the data received is a previously calculated concentration of free testosterone.

[0029] Fig. 10 depicts a schematic of the control of testosterone levels.
View attachment 23677

[0030] Fig. 11 depicts a schematic of an exemplary system of determining free testosterone levels and/or dosages.
View attachment 23678

[0031] Fig. 12 depicts a device or a computer system 1000 comprising one or more processors 1300 and a memory 1500 storing one or more programs 1600 for execution by the one or more processors 1300.
View attachment 23679

EXAMPLE 5

[00217] Binding proteins (e.g. SHBG, albumin, orosomucoid, and transcortin) and testosterone (T) dynamically interact in multiple steps to regulate testosterone availability.

[00218] Circulating testosterone is bound mostly to plasma proteins, sex-hormone binding globulin (SHBG), and albumin. There are several states in which the testosterone and binding proteins are distributed. They continually re-partition into a series of states that are in conformational equilibria. The populations of the intermediate states redistribute as the concentrations of testosterone and binding proteins change. In one of its embodiments (as an example), SHBG exists in two distinct states in the solution governed by a unimolecular equilibrium constant. Both states are capable of binding T and upon binding T, they proceed to the corresponding states with one monomer bound to T and the other monomer is unoccupied within the dimer. The binding of first T induces allosteric changes in monomer that is still unoccupied and therefore results in a distinct change in affinity for the second molecule of T for the SHBG dimer. Consistent with the crystal structure of liganded SHBG, Binding of the second molecule to either of the intermediates results in the identical state of fully occupied SHBG dimer.

[00219] In one embodiment, free testosterone is calculated as described below.

[00220] The relative population of the intermediates is closely coupled through the multiple equilibria and dynamically readjust. Accordingly, testosterone's binding to SHBG cannot be described as a simple linear equation of ligand binding equilibrium. Described herein is a multi-species allostery model, e.g., in Lab VIEW framework, that fits the experimental data and permits the development of a set of parameters that accurately described the multiple interactions listed below:

[00221] Using a set of equilibrium constants derived from the fits to the biophysical data provided in Figs. 5A, 5B, and 5C, an exemplary solution of the series of equations is presented below to calculate free T. The solution below doesn't imply presence of a unique equation rather that distinct equations can be developed to achieve accurate calculation of free T with a model of interaction that involves (and is not limited to) inter-subunit allostery in SHBG, regulation of free T levels by albumin and conformational states of binding proteins (albumin and SHBG).

[00222] Tf*(4311602270490*T_0-792951348000*S_0+95385510*Alb0-5341588560000)+Tf^2*(916102610798*T_0-210702480309*S_0+153989202*Alb0- 8623204540980)+Tf^3*(18366076550*T_0-22591273900*S_0+32723450*Alb0-1832205221596)+Tf^4*(1539342900*T_0-3079192900*S_0+657100*Alb0-36732153100)+2670794280000 *T_0+Tf^5*( 55000*T_0+110000*S_0+55000*Alb0-3078685800)+110000*Tf^6=0

View attachment 23680