Empirical estimation of free testosterone from testosterone and sex hormone-binding globulin immunoassays
Abstract
Background: The growing interest in measuring blood free testosterone (FT) is constrained by the unsuitability of the laborious reference methods for wider adoption in routine diagnostic laboratories. Various alternative derived testosterone measures have been proposed to estimate FT from either additional assay steps or calculations using total testosterone (TT) and sex hormone-binding globulin (SHBG) measured in the same sample. However, none have been critically validated in large numbers of blood samples. Methods: We analyzed a large dataset comprising over 4000 consecutive blood samples in which FT as well as TT and SHBG were measured. Dividing the dataset into samples with blood TT above and below 5 nM, using a bootstrap regression modeling approach guided by Akaike Information Criterion for model selection to balance parsimony against reduction of residual error, empirical equations were developed for FT in terms of TT and SHBG. Results: Comparison between the empirical FT equations with the laboratory FT measurements as well as three widely used calculated FT methods showed the empirical FT formulae had superior fidelity with laboratory measurements while previous FT formulae overestimated and deviated systematically from the laboratory FT values. Conclusion: We conclude that these simple, assumption-free empirical FT equations can estimate accurately blood FT from TT and SHBG measured in the same samples with the present assay methods and have suitable properties for wider application to evaluate the clinical utility of blood FT measurements.
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Free T algorithms can be divided into three categories: linear mass action, non-linear allosteric, and empirical bootstrap.
“A wide spectrum of algorithms for free T exists, which can broadly be divided into three categories (Table 6).”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [214]
The third category of free T models uses empirical bootstrap regression methods on cohort datasets.
“Empirical models exploiting bootstrap regression methods on cohort datasets comprise the third and last category [214, 215].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [214]
Additional factors that may account for variability include specimen handling and preparation, calibration methods, specimen commutability, and interference from matrix material used to store and transport testosterone preparations.
“Additional factors, which may account for variability of results include specimen handling and preparation, calibration methods utilized, specimen commutability, and interference from the matrix material used to store and transport sample T preparations.”
From Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials (2016) · cites this paper as [89]
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- Authors
- Ly, L. P., & Handelsman, D. J.
- Affiliations
- The University of Sydney (AU)
- Corresponding author
- Handelsman, David J
- ORCID
- Handelsman, David J
- Venue
- European Journal of Endocrinology
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-03
- Volume
- 152
- Issue
- 3
- Pages
- 471-478
- ISSN
- 0804-4643 (ISSN-L)
- 1479-683X
- OpenAlex
- W2125097866
- Cited by
- 180
- References
- 3
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 6 · 2023: 7 · 2022: 7 · 2021: 5 · 2020: 4 · 2019: 9 · 2018: 8 · 2017: 8 · 2016: 4 · 2015: 8 · 2014: 6 · 2013: 11 · 2012: 9
- FWCI
- 8.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Health Sciences › Medicine › Physiology › Clinical Laboratory Practices and Quality Control
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- free testosterone, total testosterone, sex hormone-binding globulin, bootstrap regression, model selection, Akaike information criterion
- MeSH terms
- Adult, Female, Humans, Immunoassay, Male, Models, Biological, Sex Hormone-Binding Globulin, Testosterone
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