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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone and Men's Health Articles
Free Testosterone & cardiometabolic parameters in men - comparison of algorithms
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<blockquote data-quote="madman" data-source="post: 195392" data-attributes="member: 13851"><p><strong><em>*The algorithm by Vermeulen is constructed using a linear model of binding where monomers within the SHBG dimer were assumed to have an identical affinity </em></strong><em><strong>(11). This model predates the resolution of the crystal structure of dimeric SHBG (13). Subsequently, several detailed biophysical studies have found the SHBG binding with testosterone to be a non-linear, multiphasic process (14). More recently, Zakharov et al. demonstrated that SHBG monomers within the dimer are allosterically coupled. <u>Allostery in the multimeric, heteromeric, or multidomain proteins allows for fine-tuned binding and release dynamics of ligands in diverse systems spanning oxygen transport by hemoglobin to transcription factors signaling</u>.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Since testosterone concentrations change several orders of magnitude during development, puberty, pregnancy, and aging, <u>it is conceivable that the SHBG dimer was designed to act as a non-linear logarithmic sensor (15)</u>.<u> If the two monomers were identical in the dimer, as is assumed by the simplified linear model, there will be no evolutionary benefit for the dimeric structure of SHBG</u>. <u>Detailed biophysical characterization of SHBG/testosterone interaction led to the development of a multistep, non-linear binding model upon the ensemble allostery framework (16), which also has been validated against equilibrium dialysis (17)</u>.</strong></em></p><p></p><p><strong><em>*<u>In general, levels of free T determined using the linear model systematically underestimated those determined using the ensemble allostery model (mean (sd) cFTZ = 647.1 (253.8) pmol/L and cFTV = 434.5 (163.8) pmol/L)</u>. The mean level of FAI, which is not directly comparable to the two other algorithms, was 67.9 (28.3). The relative standard deviations of the three calculated variables were 39%, 37%, and 41% for cFTZ, cFTV, and FAI respectively, indicating relatively similar dispersion of the frequency distribution.</em></strong></p><p></p><p><em><strong>*<u>There was an apparent correlation between cFTV and cFTZ (r=0.9, p<0.01) although the agreement decreased with higher mean free testosterone level (Figure 1A and 1B) and the values from the two methods could not be interconverted by a simple scalar multiple</u>. Stratification according to quartiles of TT indicated that higher levels of TT contributed to the difference between the two free testosterone algorithms.</strong></em></p><p><em><strong></strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Despite the differences in absolute levels, the algorithms suggested by Vermeulen et al. and Zakharov et al. were in general in agreement in relation to the survival outcomes (Figure 2). However, the algorithm by Zakharov et al. tended to be in closer agreement with the associations seen for total testosterone indicating that the algorithm is more dependent on the levels of total testosterone compared to the algorithm by Vermeulen et al.<u> However, with findings from recent studies on crystal structure and multisite binding of testosterone with albumin (31, 32), it is conceivable that simplified assumptions in extant models should be examined in detail</u>. It is unclear why the algorithm by Vermeulen et al. was largely independent of both the levels of SHBG, albumin and total testosterone level in contrast to the algorithm by Zakharov.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*In the present study, free testosterone was calculated in men from the general population with only a minor proportion of the men being characterized by extreme hormone levels.<u> The agreement between the algorithms may differ in a clinical setting with patients exhibiting extreme values of binding proteins and/or total testosterone levels where a more comprehensive model incorporating dynamic repartitioning of testosterone between SHBG and albumin-bound fractions may be superior</u>.</strong></em></p></blockquote><p></p>
[QUOTE="madman, post: 195392, member: 13851"] [B][I]*The algorithm by Vermeulen is constructed using a linear model of binding where monomers within the SHBG dimer were assumed to have an identical affinity [/I][/B][I][B](11). This model predates the resolution of the crystal structure of dimeric SHBG (13). Subsequently, several detailed biophysical studies have found the SHBG binding with testosterone to be a non-linear, multiphasic process (14). More recently, Zakharov et al. demonstrated that SHBG monomers within the dimer are allosterically coupled. [U]Allostery in the multimeric, heteromeric, or multidomain proteins allows for fine-tuned binding and release dynamics of ligands in diverse systems spanning oxygen transport by hemoglobin to transcription factors signaling[/U]. *Since testosterone concentrations change several orders of magnitude during development, puberty, pregnancy, and aging, [U]it is conceivable that the SHBG dimer was designed to act as a non-linear logarithmic sensor (15)[/U].[U] If the two monomers were identical in the dimer, as is assumed by the simplified linear model, there will be no evolutionary benefit for the dimeric structure of SHBG[/U]. [U]Detailed biophysical characterization of SHBG/testosterone interaction led to the development of a multistep, non-linear binding model upon the ensemble allostery framework (16), which also has been validated against equilibrium dialysis (17)[/U].[/B][/I] [B][I]*[U]In general, levels of free T determined using the linear model systematically underestimated those determined using the ensemble allostery model (mean (sd) cFTZ = 647.1 (253.8) pmol/L and cFTV = 434.5 (163.8) pmol/L)[/U]. The mean level of FAI, which is not directly comparable to the two other algorithms, was 67.9 (28.3). The relative standard deviations of the three calculated variables were 39%, 37%, and 41% for cFTZ, cFTV, and FAI respectively, indicating relatively similar dispersion of the frequency distribution.[/I][/B] [I][B]*[U]There was an apparent correlation between cFTV and cFTZ (r=0.9, p<0.01) although the agreement decreased with higher mean free testosterone level (Figure 1A and 1B) and the values from the two methods could not be interconverted by a simple scalar multiple[/U]. Stratification according to quartiles of TT indicated that higher levels of TT contributed to the difference between the two free testosterone algorithms. *Despite the differences in absolute levels, the algorithms suggested by Vermeulen et al. and Zakharov et al. were in general in agreement in relation to the survival outcomes (Figure 2). However, the algorithm by Zakharov et al. tended to be in closer agreement with the associations seen for total testosterone indicating that the algorithm is more dependent on the levels of total testosterone compared to the algorithm by Vermeulen et al.[U] However, with findings from recent studies on crystal structure and multisite binding of testosterone with albumin (31, 32), it is conceivable that simplified assumptions in extant models should be examined in detail[/U]. It is unclear why the algorithm by Vermeulen et al. was largely independent of both the levels of SHBG, albumin and total testosterone level in contrast to the algorithm by Zakharov. *In the present study, free testosterone was calculated in men from the general population with only a minor proportion of the men being characterized by extreme hormone levels.[U] The agreement between the algorithms may differ in a clinical setting with patients exhibiting extreme values of binding proteins and/or total testosterone levels where a more comprehensive model incorporating dynamic repartitioning of testosterone between SHBG and albumin-bound fractions may be superior[/U].[/B][/I] [/QUOTE]
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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone and Men's Health Articles
Free Testosterone & cardiometabolic parameters in men - comparison of algorithms
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