Testosterone Therapy in Canada

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madman

Super Moderator
@Marcel



We have always been far worse off than the US when it comes to the treatment of men for testosterone deficiency.

Although there has been some improvement in certain areas we are still lacking in many others.

*In 2013, a comprehensive Canada-wide needs assessment revealed that over 25% of Canadian physicians were uncomfortable with the diagnosis and treatment of TD and identified significant knowledge gaps related to patient management.4 To address the knowledge gaps, the “Canadian clinical practice guideline on the diagnosis and management of testosterone deficiency syndrome in adult males” was published in the CMAJ.5 As part of its mandate, the guideline was offered as a “living document,” to be updated

Most doctors especially endos and GPs would not treat a man who is suffering from symptoms of low-T unless his numbers are flagged low (reference range).

Even then there are many men who can suffer from symptoms of low testosterone even with a TT hovering on the low end (low-normal) of the reference range yet your doctor keeps telling you that it must be something else because your T levels are still in range.

Clueless as to where the unbound active fraction responsible for the positive effects sits. Got FT, anyone!

Gets even nuttier as there are many men with what would be considered a robust TT 500-700 ng/dL but are still suffering from symptoms of low testosterone due to highish/high SHBG which would have their FT levels low/low-normal of the (reference range).

Most doctors are still caught up on TT and although it is important to know FT is what truly matters as it is the active unbound fraction of testosterone responsible for the positive effects.

Many still tend to only look at TT, LH/FSH.

Some may also test estradiol but it is far from common.

Yet they pay no attention to the most critical blood markers free testosterone and SHBG (sex hormone binding globulin).

Even if you do manage to get treatment finding a doctor well-versed in TRT is a feat in and of itself!

Options are slim compared to what is offered in the US, especially through pay-out-of-pocket clinics which are numerous there.

We only have a handful of these clinics and they are expensive.

Most men are being treated by a GP, endocrinologist, or urologist.

I would opt for the urologist if you are seeking treatment and even then finding someone well-versed in TRT would be difficult.

Most doctors are still caught up in the numbers game and seem to be dead set on keeping your levels within a set reference range without understanding that symptom relief is what truly matters

When it comes to formulations available in Canada you are basically stuck with a big pharma transdermal T patch (Androderm), transdermal T gels (Androgel, Testim), transdermal compounded T cream, oral TU (Andriol), nasal gel (Natesto), or injectable T enanthate (Delatestryl) or T cypionate (Depo-Testosterone/generic).

The majority of men opt for injectable TE or TC as they are the most effective when it comes to increasing your T levels, especially well beyond the physiological range let alone the cost is much cheaper as your private or provincial health plan covers the costs in most cases.

Pipe dreams if you think you are going to get your hands on T propionate or the so-called optimal HRT treats such as nandrolone decanoate, oxandrolone, or stanozolol which is easy to come by if you were being treated in the US.

These would all be considered illegal to prescribe in Canada for HRT.

Nandrolone, oxandrolone, and stanozolol may be prescribed for certain medical conditions although far from common.

When it comes to blood work and testing methods we are still way behind compared to the US.

Although TT used to be tested using the standard immunoassay most labs now use the most accurate assays (LC/MS-MS) and although estradiol is still tested using the standard immunoassay we now have the option for estradiol sensitive (LC/MS-MS) through labs such as Dynacare.

Unfortunately when it comes to one of the most important blood markers free testosterone the only option we have is the calculated method as the older outdated known to be inaccurate direct analog immunoassay was phased out in 2014.

Many fail to realize that we do have access to what would be considered the most accurate assays for free testosterone such as the gold standard Equilibrium Dialysis or Ultrafiltration but the cost is absurd and is not covered by your provincial health plan.

This is unfortunate and needs to be addressed as it is critical to know where your FT level truly sits.

Although most should be using/relying upon the most accurate assays when testing FT, especially in cases of altered SHBG the cost of such testing methods for Canadians is too absurd.

As you know blood work is done through your treating physician and is usually done every 6 months on trt.

Your private or provincial health plan covers the costs.

*The federal government provides health care funding to the provinces and territories through the Canada Health Transfer

Unfortunately, we only have a few options when it comes to paying out of pocket for private testing which I have mentioned in previous threads.

This would be done through About Blue Horizon Medicals | Blood Testing Services in Ontario and is only available for Canadians living in the province of Ontario, Quebec, or Manitoba.

Blue Horizon medicals are based in the UK and have a partnership with Dynacare Labs which allows them to offer a private payout of pocket testing.

Unfortunately, BlueHorizon is overpriced and they do not even offer the most accurate assays for free testosterone (ED/UF) let alone estradiol sensitive (LC/MS-MS).

Only worthwhile if you wanted to pay out of pocket for private blood work to check your Total Testosterone, SHBG, Estradiol (standard), prolactin, and CBC.

The only place you can get the estradiol sensitive is through Dynacare which would need to be requested by your treating physician and you would be stuck with paying out of pocket as it is not covered by your provincial health plan.

Canadians also have the option of ordering blood tests through Nelsons discountedlabs.com which will be done at Quest Diagnostics but you would need to find a location close to the border as you will have to drive across the border to have blood work done.

The main benefit is you would have access to the most accurate assays for TT/estradiol/DHT (LC/MS-MS) and FT (Equilibrium Dialysis or Ultrafiltration) let alone the prices offered by Nelson are reasonable (USD currency).


$43.06 USD ($63.58 CAD)

$76.38 USD ($105.43)

$97.85 USD ($135.07)

$200.21 USD ($276.36)

$203.61 USD ($281.05)
 
Defy Medical TRT clinic doctor
*Anabolic steroids and their derivatives are classified as Schedule IV drugs under the Controlled Drugs and Substances Act of Canada, meaning that it is not illegal to possess them for personal use (Government of Canada, 2019). If an individual is performing in any athletic events, such as professional sporting events, and takes steroids, they will be disqualified and possibly banned from competing




Controlled Drugs and Substances Act

NOTE This consolidation is current to March 6, 2023. The last amendments came into force on January 14, 2023. Any amendments that were not in force as of March 6, 2023, are set out at the end of this document under the heading “Amendments Not in Force”.


S.C. 1996, c. 19

An Act respecting the control of certain drugs, their precursors and other substances and to amend certain other Acts and repeal the Narcotic Control Act in consequence thereof

[Assented to 20th June 1996]




PART I

Offenses and Punishment

Particular Offences

Possession of substance

4 (1) Except as authorized under the regulations, no person shall possess a substance included in Schedule I, II, or III.


Obtaining substance

(2) No person shall seek or obtain

(a) a substance included in Schedule I, II, III, or IV, or

(b) an authorization to obtain a substance included in Schedule I, II, III, or IV

from a practitioner, unless the person discloses to the practitioner particulars relating to the acquisition by the person of every substance in those Schedules, and of every authorization to obtain such substances, from any other practitioner within the preceding thirty days.


Trafficking in substance

5 (1) No person shall traffic in a substance included in Schedule I, II, III, IV, or V or in any substance represented or held out by that person to be such a substance.


Possession for purpose of trafficking

(2) No person shall, for the purpose of trafficking, possess a substance included in Schedule I, II, III, IV, or V.


Importing and exporting

6 (1) Except as authorized under the regulations, no person shall import into Canada or export from Canada a substance included in Schedule I, II, III, IV, V, or VI.


Possession for the purpose of exporting

(2) Except as authorized under the regulations, no person shall possess a substance included in Schedule I, II, III, IV, V, or VI for the purpose of exporting it from Canada.


Production of substance

7 (1) Except as authorized under the regulations, no person shall produce a substance included in Schedule I, II, III, IV, or V.


Possession, sale, etc., for use in production of or trafficking in substance

7.1 (1) No person shall possess, produce, sell, import, or transport anything intending that it will be used

(a) to produce a controlled substance, unless the production of the controlled substance is lawfully authorized; or

(b) to traffic in a controlled substance.
 

Attachments

  • C-38.8.pdf
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I am at a loss for words of thanks! I can’t thank you enough, all of you who have responded to my original post. I had no idea of how much there is to learn about TRT in order to achieve an optimal response with an appropriate, effective treatment/dose. The challenge is scary, almost overwhelming! But again, words are not enough to express my gratitude for taking the time and making the effort to assist me. Richard
 
@Marcel



We have always been far worse off than the US when it comes to the treatment of men for testosterone deficiency.

Although there has been some improvement in certain areas we are still lacking in many others.

*In 2013, a comprehensive Canada-wide needs assessment revealed that over 25% of Canadian physicians were uncomfortable with the diagnosis and treatment of TD and identified significant knowledge gaps related to patient management.4 To address the knowledge gaps, the “Canadian clinical practice guideline on the diagnosis and management of testosterone deficiency syndrome in adult males” was published in the CMAJ.5 As part of its mandate, the guideline was offered as a “living document,” to be updated

Most doctors especially endos and GPs would not treat a man who is suffering from symptoms of low-T unless his numbers are flagged low (reference range).

Even then there are many men who can suffer from symptoms of low testosterone even with a TT hovering on the low end (low-normal) of the reference range yet your doctor keeps telling you that it must be something else because your T levels are still in range.

Clueless as to where the unbound active fraction responsible for the positive effects sits. Got FT, anyone!

Gets even nuttier as there are many men with what would be considered a robust TT 500-700 ng/dL but are still suffering from symptoms of low testosterone due to highish/high SHBG which would have their FT levels low/low-normal of the (reference range).

Most doctors are still caught up on TT and although it is important to know FT is what truly matters as it is the active unbound fraction of testosterone responsible for the positive effects.

Many still tend to only look at TT, LH/FSH.

Some may also test estradiol but it is far from common.

Yet they pay no attention to the most critical blood markers free testosterone and SHBG (sex hormone binding globulin).

Even if you do manage to get treatment finding a doctor well-versed in TRT is a feat in and of itself!

Options are slim compared to what is offered in the US, especially through pay-out-of-pocket clinics which are numerous there.

We only have a handful of these clinics and they are expensive.

Most men are being treated by a GP, endocrinologist, or urologist.

I would opt for the urologist if you are seeking treatment and even then finding someone well-versed in TRT would be difficult.

Most doctors are still caught up in the numbers game and seem to be dead set on keeping your levels within a set reference range without understanding that symptom relief is what truly matters

When it comes to formulations available in Canada you are basically stuck with a big pharma transdermal T patch (Androderm), transdermal T gels (Androgel, Testim), transdermal compounded T cream, oral TU (Andriol), nasal gel (Natesto), or injectable T enanthate (Delatestryl) or T cypionate (Depo-Testosterone/generic).

The majority of men opt for injectable TE or TC as they are the most effective when it comes to increasing your T levels, especially well beyond the physiological range let alone the cost is much cheaper as your private or provincial health plan covers the costs in most cases.

Pipe dreams if you think you are going to get your hands on T propionate or the so-called optimal HRT treats such as nandrolone decanoate, oxandrolone, or stanozolol which is easy to come by if you were being treated in the US.

These would all be considered illegal to prescribe in Canada for HRT.

Nandrolone, oxandrolone, and stanozolol may be prescribed for certain medical conditions although far from common.

When it comes to blood work and testing methods we are still way behind compared to the US.

Although TT used to be tested using the standard immunoassay most labs now use the most accurate assays (LC/MS-MS) and although estradiol is still tested using the standard immunoassay we now have the option for estradiol sensitive (LC/MS-MS) through labs such as Dynacare.

Unfortunately when it comes to one of the most important blood markers free testosterone the only option we have is the calculated method as the older outdated known to be inaccurate direct analog immunoassay was phased out in 2014.

Many fail to realize that we do have access to what would be considered the most accurate assays for free testosterone such as the gold standard Equilibrium Dialysis or Ultrafiltration but the cost is absurd and is not covered by your provincial health plan.

This is unfortunate and needs to be addressed as it is critical to know where your FT level truly sits.

Although most should be using/relying upon the most accurate assays when testing FT, especially in cases of altered SHBG the cost of such testing methods for Canadians is too absurd.

As you know blood work is done through your treating physician and is usually done every 6 months on trt.

Your private or provincial health plan covers the costs.

*The federal government provides health care funding to the provinces and territories through the Canada Health Transfer

Unfortunately, we only have a few options when it comes to paying out of pocket for private testing which I have mentioned in previous threads.

This would be done through About Blue Horizon Medicals | Blood Testing Services in Ontario and is only available for Canadians living in the province of Ontario, Quebec, or Manitoba.

Blue Horizon medicals are based in the UK and have a partnership with Dynacare Labs which allows them to offer a private payout of pocket testing.

Unfortunately, BlueHorizon is overpriced and they do not even offer the most accurate assays for free testosterone (ED/UF) let alone estradiol sensitive (LC/MS-MS).

Only worthwhile if you wanted to pay out of pocket for private blood work to check your Total Testosterone, SHBG, Estradiol (standard), prolactin, and CBC.

The only place you can get the estradiol sensitive is through Dynacare which would need to be requested by your treating physician and you would be stuck with paying out of pocket as it is not covered by your provincial health plan.

Canadians also have the option of ordering blood tests through Nelsons discountedlabs.com which will be done at Quest Diagnostics but you would need to find a location close to the border as you will have to drive across the border to have blood work done.

The main benefit is you would have access to the most accurate assays for TT/estradiol/DHT (LC/MS-MS) and FT (Equilibrium Dialysis or Ultrafiltration) let alone the prices offered by Nelson are reasonable (USD currency).


$43.06 USD ($63.58 CAD)

$76.38 USD ($105.43)

$97.85 USD ($135.07)

$200.21 USD ($276.36)

$203.61 USD ($281.05)

Update

Private testing is no longer available for anyone living in the province of Quebec.

As I have state previously we only have a few options when it comes to paying out of pocket for private testing which I have mentioned in previous threads.

This would be done through About Blue Horizon Medicals | Blood Testing Services in Ontario and is only available for Canadians living in the province of Ontario, Quebec, or Manitoba.

Blue Horizon medicals are based in the UK and have a partnership with Dynacare Labs which allows them to offer a private payout of pocket testing.

Unfortunately, BlueHorizon is overpriced and they do not even offer the most accurate assays for free testosterone (ED/UF) let alone estradiol sensitive (LC/MS-MS).

As I have stated numerous times on the forum you always have the option of using/relying upon calculated FT which would be the linear law-of-mass action cFTV as it has already been validated twice (1st time was done using TT/SHBG assays no longer available) and was then eventually re-validated using current state-of-the-art ED method (higher order reference method) let alone more recently against CDCs standardized Equilibrium Dialysis assay.

Yes it tends to overestimate slightly but it is nothing to fret over!




* Calculated free T using high-quality T and SHBG assays has been considered the most useful for clinical purposes [99]. All algorithms suffer from some inaccuracies, including the variable quality of SHBG IAs [100], not replicating the non-linear nature of T-SHBG binding, different and inaccurate association constants for SHBG and albumin binding [101], and variable agreement with equilibrium dialysis results [99,100]. However, until further developments in the field materialize, the linear model algorithms [in particular, the most used Vermeulen equation [102]] appear to give, despite a small systematic positive bias, acceptable data for the clinical management and research[37,103].








Only worthwhile if you wanted to pay out of pocket for private blood work to check your Total Testosterone, SHBG, Estradiol (standard), prolactin, and CBC.

The only place you can get the estradiol sensitive is through Dynacare which would need to be requested by your treating physician and you would be stuck with paying out of pocket as it is not covered by your provincial health plan.

Again keep in mind they are overpriced!









1731081865640.png
 
Beyond Testosterone Book by Nelson Vergel
@Marcel



We have always been far worse off than the US when it comes to the treatment of men for testosterone deficiency.

Although there has been some improvement in certain areas we are still lacking in many others.

*In 2013, a comprehensive Canada-wide needs assessment revealed that over 25% of Canadian physicians were uncomfortable with the diagnosis and treatment of TD and identified significant knowledge gaps related to patient management.4 To address the knowledge gaps, the “Canadian clinical practice guideline on the diagnosis and management of testosterone deficiency syndrome in adult males” was published in the CMAJ.5 As part of its mandate, the guideline was offered as a “living document,” to be updated

Most doctors especially endos and GPs would not treat a man who is suffering from symptoms of low-T unless his numbers are flagged low (reference range).

Even then there are many men who can suffer from symptoms of low testosterone even with a TT hovering on the low end (low-normal) of the reference range yet your doctor keeps telling you that it must be something else because your T levels are still in range.

Clueless as to where the unbound active fraction responsible for the positive effects sits. Got FT, anyone!

Gets even nuttier as there are many men with what would be considered a robust TT 500-700 ng/dL but are still suffering from symptoms of low testosterone due to highish/high SHBG which would have their FT levels low/low-normal of the (reference range).

Most doctors are still caught up on TT and although it is important to know FT is what truly matters as it is the active unbound fraction of testosterone responsible for the positive effects.

Many still tend to only look at TT, LH/FSH.

Some may also test estradiol but it is far from common.

Yet they pay no attention to the most critical blood markers free testosterone and SHBG (sex hormone binding globulin).

Even if you do manage to get treatment finding a doctor well-versed in TRT is a feat in and of itself!

Options are slim compared to what is offered in the US, especially through pay-out-of-pocket clinics which are numerous there.

We only have a handful of these clinics and they are expensive.

Most men are being treated by a GP, endocrinologist, or urologist.

I would opt for the urologist if you are seeking treatment and even then finding someone well-versed in TRT would be difficult.

Most doctors are still caught up in the numbers game and seem to be dead set on keeping your levels within a set reference range without understanding that symptom relief is what truly matters

When it comes to formulations available in Canada you are basically stuck with a big pharma transdermal T patch (Androderm), transdermal T gels (Androgel, Testim), transdermal compounded T cream, oral TU (Andriol), nasal gel (Natesto), or injectable T enanthate (Delatestryl) or T cypionate (Depo-Testosterone/generic).

The majority of men opt for injectable TE or TC as they are the most effective when it comes to increasing your T levels, especially well beyond the physiological range let alone the cost is much cheaper as your private or provincial health plan covers the costs in most cases.

Pipe dreams if you think you are going to get your hands on T propionate or the so-called optimal HRT treats such as nandrolone decanoate, oxandrolone, or stanozolol which is easy to come by if you were being treated in the US.

These would all be considered illegal to prescribe in Canada for HRT.

Nandrolone, oxandrolone, and stanozolol may be prescribed for certain medical conditions although far from common.

When it comes to blood work and testing methods we are still way behind compared to the US.

Although TT used to be tested using the standard immunoassay most labs now use the most accurate assays (LC/MS-MS) and although estradiol is still tested using the standard immunoassay we now have the option for estradiol sensitive (LC/MS-MS) through labs such as Dynacare.

Unfortunately when it comes to one of the most important blood markers free testosterone the only option we have is the calculated method as the older outdated known to be inaccurate direct analog immunoassay was phased out in 2014.

Many fail to realize that we do have access to what would be considered the most accurate assays for free testosterone such as the gold standard Equilibrium Dialysis or Ultrafiltration but the cost is absurd and is not covered by your provincial health plan.

This is unfortunate and needs to be addressed as it is critical to know where your FT level truly sits.

Although most should be using/relying upon the most accurate assays when testing FT, especially in cases of altered SHBG the cost of such testing methods for Canadians is too absurd.

As you know blood work is done through your treating physician and is usually done every 6 months on trt.

Your private or provincial health plan covers the costs.

*The federal government provides health care funding to the provinces and territories through the Canada Health Transfer

Unfortunately, we only have a few options when it comes to paying out of pocket for private testing which I have mentioned in previous threads.

This would be done through About Blue Horizon Medicals | Blood Testing Services in Ontario and is only available for Canadians living in the province of Ontario, Quebec, or Manitoba.

Blue Horizon medicals are based in the UK and have a partnership with Dynacare Labs which allows them to offer a private payout of pocket testing.

Unfortunately, BlueHorizon is overpriced and they do not even offer the most accurate assays for free testosterone (ED/UF) let alone estradiol sensitive (LC/MS-MS).

Only worthwhile if you wanted to pay out of pocket for private blood work to check your Total Testosterone, SHBG, Estradiol (standard), prolactin, and CBC.

The only place you can get the estradiol sensitive is through Dynacare which would need to be requested by your treating physician and you would be stuck with paying out of pocket as it is not covered by your provincial health plan.

Canadians also have the option of ordering blood tests through Nelsons discountedlabs.com which will be done at Quest Diagnostics but you would need to find a location close to the border as you will have to drive across the border to have blood work done.

The main benefit is you would have access to the most accurate assays for TT/estradiol/DHT (LC/MS-MS) and FT (Equilibrium Dialysis or Ultrafiltration) let alone the prices offered by Nelson are reasonable (USD currency).


$43.06 USD ($63.58 CAD)

$76.38 USD ($105.43)

$97.85 USD ($135.07)

$200.21 USD ($276.36)

$203.61 USD ($281.05)

As I previously stated when it comes to blood work and testing methods we are still way behind compared to the US.

Although TT used to be tested using the standard immunoassay most labs now use the most accurate assays (LC/MS-MS) and although estradiol is still tested using the standard immunoassay we now have the option for estradiol sensitive (LC/MS-MS) through labs such as Dynacare.

Unfortunately when it comes to one of the most important blood markers free testosterone the only option we have is the calculated method as the older outdated known to be inaccurate direct analog immunoassay was phased out in 2014.

Many fail to realize that we do have access to what would be considered the most accurate assays for free testosterone such as the gold standard Equilibrium Dialysis or Ultrafiltration but the cost is absurd and is not covered by your provincial health plan.

This is unfortunate and needs to be addressed as it is critical to know where your FT level truly sits.

Although most should be using/relying upon the most accurate assays when testing FT, especially in cases of altered SHBG the cost of such testing methods for Canadians is too absurd.

Another critical point that needs to be mentioned here which I have stated numerous times on the forum you always have the option of using/relying upon calculated FT which would be the linear law-of-mass action cFTV as it has already been validated twice (1st time was done using TT/SHBG assays no longer available) and was then eventually re-validated using current state-of-the-art ED method (higher order reference method) let alone more recently against CDCs standardized Equilibrium Dialysis assay.

Keep in mind it tends to overestimate FT 20-30%!


* However, the Vermeulen formula exhibits suboptimal accuracy and tends to overestimate measured free T by 20–30%.

* Calculated free T using high-quality T and SHBG assays has been considered the most useful for clinical purposes [99]. All algorithms suffer from some inaccuracies, including the variable quality of SHBG IAs [100], not replicating the non-linear nature of T-SHBG binding, different and inaccurate association constants for SHBG and albumin binding [101], and variable agreement with equilibrium dialysis results [99,100]. However, until further developments in the field materialize, the linear model algorithms [in particular, the most used Vermeulen equation [102]] appear to give, despite a small systematic positive bias, acceptable data for the clinical management and research[37,103].




Some key points here!

* While the use of cFT may be of value in preventing misdiagnosis and overtreatment of hypogonadism, it has its limitations. Therefore, reassessing cFT calculators to enhance their accuracy and alignment with equilibrium dialysis measurement of free T is needed. Additionally, standardizing and validating cFT calculators, as well as optimizing available assays for total T and SHBG are crucial steps.




Again something to keep in mind when it comes to using/relying upon the calculated FT methods!

*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






1731257971021.png





WHAT ARE THE LIMITATIONS OF CALCULATED FREE TESTOSTERONE?

Although free T, if accurately measured, may be physiologically and clinically relevant, the complexity of directly measuring free T limits its introduction into routine clinical practice. Alternatively, clinicians rely on cFT as an acceptable estimate, and thus proxy,of free T concentrations. Existing calculators, including models by Vermeulen, Ly-Handelsman and Zakharov, use calculation methodologies based on total T and SHBG concentrations [3&&]. Free T calculator performance was investigated by comparing cFT values using these three different calculators against measured free T values obtained through the gold standard LC/MS-MS coupled with equilibrium dialysis. The Vermeulen formula appeared to perform best across a wide range of SHBG levels, whereas the Ly-Handelsman model showed significant divergence from measured free T at lower SHBG levels [9]. However, the Vermeulen formula exhibits suboptimal accuracy and tends to overestimate measured free T by 20–30%. Despite this, the current model remains a widely accepted tool for free T calculation due to its ability to integrate a broad range of SHBG, total T and albumin concentrations. This advantage is particularly important in conditions where SHBG concentrations are impacted and/or when total T concentrations are in the borderline range of the lower limit of normal [9].

The use of free T calculators in clinical routine is, however, hindered by a number of imperfections of which clinicians should be aware of when interpreting cFT values (Table 2). Firstly, quality of cFT results depends on the performance of assays used to measure total T, SHBG and albumin. For instance, automated SHBG immunoassays lack standardization[24]. Furthermore, these models are simplified representations of the true binding milieu and may not account for all variables influencing the equilibrium between total and free T, such as SHBG-binding affinity variability and stoichiometry [3&&].

This could particularly be important in men with SHBG polymorphisms. These genetic variations can potentially influence binding affinity between T and SHBG, which is not taken into account in calculators that use a constant binding affinity. In a recent study focusing on the impact of relatively common SHBG single nucleotide polymorphisms (allelic prevalence between 0.5 and 58.2%), healthy men who were heterozygotes for rs6258 had lower serum SHBG levels, while those who were heterozygotes for rs6259, homozygotes for rs727428 and carriers of rs1799941 had higher serum SHBG levels compared to healthy men with wild-type SHBG. These SHBG polymorphisms influenced both SHBG and total T levels, with total T being higher in rs727428 homozygotes and in carriers of rs5934505, rs1799941 and rs6259. Interestingly, these variants did not influence cFT or measured free T concentrations [25&&].

As cFT is a calculated variable, its validity is debated and limited by a lack of standardization and quality control resulting in variable reference ranges. The Vermeulen model, for instance, overestimates free T by 20–30%. Moreover, there is no consensus on a universal cut-off between low and normal cFT values. A thorough review detailing the pitfalls of various methodologies for total and free T assessment was recently published [3&&].

There is a need to enhance the measurement of free T, as cFT values are only approximations. There is also a pressing requirement to reassess current freeT calculators to improve their accuracy and alignment with direct measurement methods. Moreover, additional research is necessary to optimize existing commercially available assays for SHBG, as well as studying SHBG-binding affinity in specific patient groups (e.g. obesity and diabetic individuals) to accurately reflect the true binding environment. Standardizing and validating cFT calculators is also crucial to establish harmonized reference ranges and achieve consensus on cutoff values between low and normal cFT levels. Promising recent developments include the establishment of age-stratified reference ranges for free T in healthy nonobese adult men using the gold standard equilibrium dialysis coupled to LC-MS/MS, showing the expected age-related decline in serum-free T concentrations [26,27]. These efforts represent a significant step towards improving the accuracy of free T measurements and calculations in clinical practice.
 
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