genetic impact on testosterone binding by SHBG

I am wondering what people make of this study. It appears to show there is a genetic trait that increases SHBG binding.

"Importantly, one of the identified genetic variations was associated with an alteration in SHBG's binding affinity for testosterone and the measured free testosterone fraction."

Genetic Determinants of Serum Testosterone Concentrations in Men




if there are significant differences in SHBG/Testosterone binding, doesn't this make the standard free testosterone calculators problematic?

As a guy with low SHBG that has been on TRT for five years, all I can say is that I would not wish low SHBG on anyone. In rough numbers maybe one low SHBG guy out of ten actually feels good, or feels much of anything from TRT, the other nine don't feel much of a difference between Low T and TRT even with excellent numbers. (High Total & Free T, E2 in the optimal range, no thyroid issues, etc...)

jabbahop said:

I am wondering what people make of this study. It appears to show there is a genetic trait that increases SHBG binding.

"Importantly, one of the identified genetic variations was associated with an alteration in SHBG's binding affinity for testosterone and the measured free testosterone fraction."

Genetic Determinants of Serum Testosterone Concentrations in Men


sorry - I am new so can't post with links but you can do a google search on this study

if there are significant differences in SHBG/Testosterone binding, doesn't this make the standard free testosterone calculators problematic?

Click to expand...

here's a good post on shbg, low SHBG good or bad https://www.excelmale.com/forum/showthread.php?3085-Low-SHBG-!-Good-or-bad

"By examining 14,429 men, we show that genetic variants in the sex hormone-binding globulin (SHBG) locus and on the X chromosome are associated with a substantial variation in serum testosterone concentrations and increased risk of low testosterone. The reported associations may now be used in order to better understand the functional background of recently identified disease associations related to low testosterone. Importantly, we identified the first known genetic variant, which affects SHBG's affinity for binding testosterone and the free testosterone fraction and could therefore influence the calculation of free testosterone. This finding suggests that individual-based SHBG-testosterone affinity constants are required depending on the genotype of this single-nucleotide polymorphism.'

The rs6258 polymorphism affects SHBG binding affinity for testosterone and the measured free testosterone fraction

As rs6258 is non-synonymous (P156L) and located in exon 4 of SHBG, we evaluated the serum SHBG steroid-binding capacity of the different rs6258 genotypes. As shown in Figure S5, serum SHBG from CT but not CC subjects had a lower steroid-binding capacity than expected from values obtained by an SHBG immunoassay (p = 0.003). Therefore, we analyzed the SHBG affinity for testosterone using Scatchard plots of SHBG in serum of men with the rs6258 genotype (Figure 3A), and revealed (Figure 3B) a higher mean dissociation constant (Kd) indicative of a lower affinity in CT (Kd = 4.5 nM) and TT (Kd = 4.9 nM) individuals than in CC individuals (Kd = 2.8 nM). Recombinant SHBG corresponding to the T genotype demonstrated a higher dissociation constant (lower affinity) compared with recombinant SHBG corresponding to the C genotype (T genotype Kd 2.5 nM; C genotype Kd 1.2 nM, Figure 3C). In addition, the free testosterone fraction measured by an equilibrium dialysis method was 22% higher (p = 1.4×10−5) in serum from CT subjects than in serum from CC subjects (Figure 3D)."


Jabbahop

I agree. In men with a certain mutation on the SHBG locus and on their X chromosome, calculating free T may not be accurate since they may show OK amounts of SHBG but poor binding of T to it. I guess the only way is to actually measure both free and total T.

Note:
DiscountedLabs.com TT and FT test actually measures both and it does not calculate free T by subtracting albumin and SHBG from total T.


Thanks for posting such an intriguing study!