Tread lightly when you speak on free testosterone, T:SHBG binding, stickiness, blah, blah!
Throw in those CAG repeat lengths (short/long)/sensitivity of the AR (androgen receptor) too!
Take home points here!
*our results show no substantial effects of most of these SNPs on free T concentrations. This indicates an only limited effect, if any, of the SHBG SNPs on free T concentrations and is compatible with the view that it is the free T concentration that is primarily determined through hypothalamic-pituitary feedback regulation, which annuls the effects of altered SHBG binding on free T concentrations in healthy men
*Further, no effects of SNPs were observed on the difference between calculated and measured free T, indicating a minimal effect of SNPs on calculator performance
*In this study, we have shown that SNPs that potentially affect SHBG concentration or binding affinity for sex steroids are common in a population of healthy men but that effects of these SNPs on SHBG and testosterone concentrations were mostly mild.
*In contrast, directly measured free T concentrations were unaffected as were also the differences between measured and calculated free T
*Secondly, our results are also largely in line with earlier literature showing, for example, lower (total) SHBG serum concentrations in individuals with rs6258 [18] and higher SHBG concentrations in rs6259 heterozygous individuals [26]. However, our results show no substantial effects of most of these SNPs on free T concentrations. This indicates an only limited effect, if any, of the SHBG SNPs on free T concentrations and is compatible with the view that it is the free T concentration that is primarily determined through hypothalamic-pituitary feedback regulation, which annuls the effects of altered SHBG binding on free T concentrations in healthy men. The higher total T concentrations without concomitant higher free T which we observed for several SNPs also suggest that clinical decisions based on total T concentrations alone may lead to a potentially incorrect diagnosis of hypogonadism in carriers of these SNPs
*There was a trend towards higher free T concentrations observed in rs6259 homozygous carriers, which was significant only in the larger dataset (n = 989) for calculated free T. However, this is unlikely to greatly affect the use of calculated free T in clinical practice as this genotype only occurs in 1.4% of the population (Table 1). Our results also confirm that the binding affinity is altered in heterozygous rs6258 carriers, manifesting in a higher percentage measured free T in these individuals, albeit maybe to a lesser extent that what would be expected from experimental studies [17,18]. Further, no effects of SNPs were observed on the difference between calculated and measured free T, indicating a minimal effect of SNPs on calculator performance. Rs5934505 served as a control for calculator performance, confirming the expected higher free T but non-affected percentage free T in carriers of this SNP which causes higher total T but non-affected SHBG concentrations
*In this study, we have shown that SNPs that potentially affect SHBG concentration or binding affinity for sex steroids are common in a population of healthy men but that effects of these SNPs on SHBG and testosterone concentrations were mostly mild. In contrast, directly measured free T concentrations were unaffected as were also the differences between measured and calculated free T. Further, we have also demonstrated the potential of LC-MS/MS to detect mutant P156L SHBG. We found that P156L SHBG is indeed present in the serum of mutation carriers, albeit in lower concentration than expected. In conclusion, free T measurements and calculations appear less affected by variations induced by SNPs compared to total T measurements. As such, clinical decision making based on total T may be more vulnerable to the effects of SNPs while no extra measures should be taken when using the calculations in SNP carriers
