Factors associated with variations in calculated free testosterone in men

[madman]

OBJECTIVE

Sociodemographic, lifestyle and medical variables influence total testosterone (T) and sex hormone-binding globulin (SHBG) concentrations. The relationship between these factors and “free” T remains unclear. We examined 21 sociodemographic, lifestyle and medical predictors influencing calculated free T (cFT) in community-dwelling men across ages.


METHODOLOGY

Individual participant data (IPD) were provided by nine population cohorts. Factors associated with cFT were analyzed using two-stage random effects IPD meta analyses. Covariates including age, body mass index (BMI), marital status, and education were incorporated across all models. Additionally, alcohol consumption,physical activity, and smoking were accounted for in models for lifestyle and medical variables.


STUDY DESIGN

Cross-sectional analysis: Androgens in Men study (AIMS) [1]- 20,631 participants- Total T by LC-MS/MS- SHBG by immunoassay- cFT using the Vermeulen formula [2]


RESULTS

CONCLUSION

Calculated free testosterone was most prominently associated with age and BMI. The linear, inverse association with age, non-linear association with BMI, and presence of diabetes, cancer and socio-demographic factors should be considered when using calculated free testosterone as a proxy for free testosterone.

 

[madman]

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

Use of calculated FT in men: advantages and limitations

https://journals.lww.com/co-endocrinology/abstract/2024/12000/use_of_calculated_free_testosterone_in_men_.7.aspx INTRODUCTION Clinical practice guidelines on the diagnosis of male hypogonadism focus on clinical signs and symptoms of androgen deficiency, as well as biochemical assessment of...

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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.