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Reassessing Free-Testosterone Calculation by Liquid Chromatography-Tandem Mass Spectrometry Direct Equilibrium Dialysis

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Abstract
Context: Assessment of free testosterone (FT) might help evaluate androgen status in patients with borderline total testosterone (T) and/or altered sex hormone-binding globulin (SHBG) levels. However, the validity of different methods to measure FT is debatable. Methods: Serum from 183 women and 146 men was analyzed using equilibrium dialysis (ED), with FT directly measured by liquid chromatography-tandem mass spectrometry. FT calculation was reevaluated for the mass action law-based equation according to Vermeulen (cFT-V), empirical equations according to Ly (cFT-L), and a proposed calculation based on a multistep, dynamic, allosteric model according to Zakharov (cFT-Z). Results: FT level analyzed by ED [median, 13 pmol/L (1.2% of T) in women; 248 pmol/L (1.5% of T) in men] was strongly inversely correlated to SHBG level, significantly to albumin level in women, and only weakly to SHBG level in men. The median [percentile (p) range, 2.5 to 97.5] ratios of calculated FT (cFT) over ED-FT (from European Male Aging Study samples) were 1.19 (0.9 to 1.47), 1.00 (0.69 to 1.42), and 2.05 (1.26 to 3.26) for cFT-V, cFT-L, and cFT-Z, respectively. The ratio for cFT-V was not significantly affected by SHBG, T, or albumin levels (rho range, 0.17 to20.01); ratios for cFT-L and cFT-Z were affected (P < 0.05 and P < 0.001, respectively) and strongly correlated with SHBG levels (rho = 0.72 and 0.75, respectively). Rank correlations between cFT% and ED-FT% (for men) were 0.62, 0.74, and 0.89 for cFT-Z, cFT-L, and cFT-V, respectively. Conclusion: FT results by direct ED confirm prior FT data from indirect ED and ultrafiltration methodologies. Calculations have inherent limitations, with clinically important differences among evaluated equations: cFT-V, although overestimating FT level, appears the most robust approximation, largely independent of SHBG, albumin, and T levels.

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Chicago
Fiers, Tom, Frederick Wu, Paolo Moghetti, Dirk Vanderschueren, Bruno Lapauw, and Jean Kaufman. 2018. “Reassessing Free-Testosterone Calculation by Liquid Chromatography-Tandem Mass Spectrometry Direct Equilibrium Dialysis.” Journal of Clinical Endocrinology & Metabolism 103 (6): 2167–2174.
APA
Fiers, T., Wu, F., Moghetti, P., Vanderschueren, D., Lapauw, B., & Kaufman, J. (2018). Reassessing Free-Testosterone Calculation by Liquid Chromatography-Tandem Mass Spectrometry Direct Equilibrium Dialysis. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 103(6), 2167–2174.
Vancouver
1.
Fiers T, Wu F, Moghetti P, Vanderschueren D, Lapauw B, Kaufman J. Reassessing Free-Testosterone Calculation by Liquid Chromatography-Tandem Mass Spectrometry Direct Equilibrium Dialysis. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM. 2018;103(6):2167–74.
MLA
Fiers, Tom et al. “Reassessing Free-Testosterone Calculation by Liquid Chromatography-Tandem Mass Spectrometry Direct Equilibrium Dialysis.” JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 103.6 (2018): 2167–2174. Print.
@article{8607966,
  abstract     = {Context: Assessment of free testosterone (FT) might help evaluate androgen status in patients with borderline total testosterone (T) and/or altered sex hormone-binding globulin (SHBG) levels. However, the validity of different methods to measure FT is debatable. Methods: Serum from 183 women and 146 men was analyzed using equilibrium dialysis (ED), with FT directly measured by liquid chromatography-tandem mass spectrometry. FT calculation was reevaluated for the mass action law-based equation according to Vermeulen (cFT-V), empirical equations according to Ly (cFT-L), and a proposed calculation based on a multistep, dynamic, allosteric model according to Zakharov (cFT-Z). Results: FT level analyzed by ED [median, 13 pmol/L (1.2\% of T) in women; 248 pmol/L (1.5\% of T) in men] was strongly inversely correlated to SHBG level, significantly to albumin level in women, and only weakly to SHBG level in men. The median [percentile (p) range, 2.5 to 97.5] ratios of calculated FT (cFT) over ED-FT (from European Male Aging Study samples) were 1.19 (0.9 to 1.47), 1.00 (0.69 to 1.42), and 2.05 (1.26 to 3.26) for cFT-V, cFT-L, and cFT-Z, respectively. The ratio for cFT-V was not significantly affected by SHBG, T, or albumin levels (rho range, 0.17 to20.01); ratios for cFT-L and cFT-Z were affected (P {\textlangle} 0.05 and P {\textlangle} 0.001, respectively) and strongly correlated with SHBG levels (rho = 0.72 and 0.75, respectively). Rank correlations between cFT\% and ED-FT\% (for men) were 0.62, 0.74, and 0.89 for cFT-Z, cFT-L, and cFT-V, respectively. Conclusion: FT results by direct ED confirm prior FT data from indirect ED and ultrafiltration methodologies. Calculations have inherent limitations, with clinically important differences among evaluated equations: cFT-V, although overestimating FT level, appears the most robust approximation, largely independent of SHBG, albumin, and T levels.},
  author       = {Fiers, Tom and Wu, Frederick and Moghetti, Paolo and Vanderschueren, Dirk and Lapauw, Bruno and Kaufman, Jean},
  issn         = {0021-972X},
  journal      = {JOURNAL OF CLINICAL ENDOCRINOLOGY \& METABOLISM},
  number       = {6},
  pages        = {2167--2174},
  title        = {Reassessing Free-Testosterone Calculation by Liquid Chromatography-Tandem Mass Spectrometry Direct Equilibrium Dialysis},
  url          = {http://dx.doi.org/10.1210/jc.2017-02360},
  volume       = {103},
  year         = {2018},
}

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